Life's Blueprint: The Essential Machinery to Start Life

The Last Universal Common Ancestors Proteome

De novo Nucleotide Biosynthesis

Ribose-phosphate diphosphokinase
Amidophosphoribosyl transferase (GPAT)
Glycinamide ribotide (GAR) transformylase (GART)
Formylglycinamide ribotide (FGAR) amidotransferase (GART)
Formylglycinamidine ribotide (FGAM) synthetase (GART)
5-aminoimidazole ribotide (AIR) carboxylase (PurK)
5-aminoimidazole-4-(N-succinylocarboxamide) ribotide (SACAIR) synthetase (PurE)
Carboxyaminoimidazole ribotide (CAIR) mutase (PurK)
5-aminoimidazole-4-carboxamide ribotide (AICAR) transformylase (PurN)
5-formaminoimidazole-4-carboxamide ribotide (FAICAR) cyclase (PurM)
IMP cyclohydrolase (PurH)
Carbamoyl phosphate synthetase II (CPSII)
Aspartate transcarbamoylase (ATCase)
Dihydroorotase (DHOase)
Dihydroorotate dehydrogenase (DHODH)
Orotate phosphoribosyltransferase (OPRT)
Orotidine 5'-monophosphate decarboxylase (OMPDC)
Nucleoside monophosphate kinase (UMP/CMP kinase)
Nucleoside diphosphate kinase (NDK)
CTP synthetase (CTPS)
Adenine (A) Ribonucleotide Biosynthesis

Phosphoribosylaminoimidazole carboxylase (PurE)
Adenylosuccinate synthetase (PurA)
Adenylosuccinate lyase (PurB)
Guanine (G) Ribonucleotide Biosynthesis

IMP dehydrogenase (IMPDH)
GMP synthetase (GuaA)
Uracil (U) Ribonucleotide Biosynthesis

Carbamoyl phosphate synthetase II (CPSII)
Aspartate transcarbamoylase (ATCase)
Dihydroorotase (DHOase)
Dihydroorotate dehydrogenase (DHODH)
Orotate phosphoribosyltransferase (OPRT)
Orotidine 5'-monophosphate decarboxylase (OMPDC)
Cytosine (C) Ribonucleotide Biosynthesis

Nucleoside monophosphate kinase (UMP/CMP kinase)
Nucleoside diphosphate kinase (NDK)
CTP synthetase (CTPS)
Thymine (T) Deoxyribonucleotide Biosynthesis

Ribonucleotide reductase (RNR)
Dihydrofolate reductase (DHFR)
Thymidylate synthase (TYMS or TS)
Deoxynucleotide Biosynthesis

NDK (ADP to dADP)
NDK (GDP to dGDP)
NDK (UDP to dUDP)
NDK (CDP to dCDP)
dUTPase (dUTP pyrophosphatase)

Supporting Enzymes and Transporters for the De Novo Purine and Pyrimidine Biosynthesis Pathway in LUCA

Nucleotide Biosynthesis and Transport
- ATP-binding cassette (ABC) transporters
- Adenine phosphoribosyltransferase (APRT)
- Hypoxanthine-guanine phosphoribosyltransferase (HGPRT)
- Glutamine transporters
- Tetrahydrofolate (THF) and its derivatives
- S-adenosylmethionine (SAM) transporters
- Amino acid synthetases
- Nucleotidases
- Dihydrofolate reductase
- Purine Transporters
- Pyrimidine Transporters
- Phosphate Transporters
- Ribose/Deoxyribose Transporters

Magnesium transporters
- Magnesium transporters (Mgt)
- CorA
- Magnesium efflux systems
- Magnesium-binding proteins
- Magnesium-sensing proteins
- Enzymatic cofactors
- RNA structures

Amino Acid Transporters in LUCA
- Amino Acid Antiporters
- Amino Acid/H+ Symporters
- ATP-binding Cassette (ABC) Amino Acid Transporters
- Passive Diffusion

These transport mechanisms would have been pivotal for LUCA, ensuring the necessary amino acids were available within the cell for protein synthesis and other metabolic processes.

Nucleotide Transporters in LUCA
- Nucleotide Antiporters
- Nucleotide/H+ Symporters
- ATP-binding Cassette (ABC) Nucleotide Transporters
- Nucleotide-specific Channels
- Vesicular Transport
- Nucleoside Transporters
- P4-ATPases
- Facilitated Diffusion Nucleotide Transporters

Nucleoside Transporters in LUCA
- Concentrative Nucleoside Transporters (CNTs)
- Equilibrative Nucleoside Transporters (ENTs)
- ATP-binding Cassette (ABC) Nucleoside Transporters
- Nucleoside/H+ Symporters
- Nucleoside Antiporters
- Vesicular Nucleoside Transport
- Specific Channel-formed Nucleoside Transporters
- Nucleoside-specific Pore-forming Proteins

Phosphate Transporters in LUCA
- PiT Family Transporters
- Pst Phosphate Transport System
- Pho89 Sodium-Phosphate Transporter
- Low Affinity Phosphate Transporters
- High Affinity Phosphate Transporters
- Phosphate Antiporters
- Phosphate/H+ Symporters
- Vesicular Phosphate Transport
- Passive Phosphate Channels

Folate Transporters in LUCA
- Folate-Binding Protein (FBP) Transporters
- Proton-Coupled Folate Transporter (PCFT)
- Reduced Folate Carrier (RFC)
- Multidrug Resistance Protein (MRP) Transporters
- Folate Receptors (FRs)
- ABC Transporters

SAM Transporters in LUCA
- SAM Transporter (SAMT)
- ABC Transporters
- Solute Carrier Family Transporters
- Multidrug Resistance Proteins (MRPs)
- Vesicular Transport Mechanisms

Carbon Source Transporters in LUCA
- Glucose/Galactose Transporter (GLUT)
- ABC Glucose Transporters
- Hexose Transporter (HXT)

Amino Acid Precursors for Nucleotide Synthesis Transporters in LUCA
- Glutamine Transporters
- Aspartate Transporters
- Glycine Transporters (GlyT)

Co-factor Transporters for Nucleotide Synthesis in LUCA
- Vitamin B6 Transporters
- Tetrahydrofolate (THF) Transporters

Ion Transporters in LUCA with Relevance to Nucleotide Synthesis
- Potassium (K+) Transporters
- Zinc (Zn2+) Transporters

RNA Recycling

Ribonucleases
RNase II
RNase R

Exoribonucleases
Exoribonuclease II
Exoribonuclease III

DNA Recycling

DNA Phosphatases
Polynucleotide 5'-phosphatase

Deoxyribonucleases
Deoxyribonuclease I

Exonucleases
Exonuclease III
Exonuclease I

Endonucleases
Endonuclease IV

Reactive oxygen species (ROS)

Superoxide Dismutases (SODs)
Superoxide dismutase

Catalase
Catalase

Peroxiredoxins
Peroxiredoxin

Serine Synthesis:
Phosphoserine phosphatase
Phosphoserine aminotransferase

Glycine Synthesis
Serine hydroxymethyltransferase
Glycine decarboxylase (P Protein)
Aminomethyltransferase (T Protein)
Glycine cleavage system H protein (H Protein)
Dihydrolipoyl dehydrogenase (L Protein)

Cysteine Metabolism
Serine O-acetyltransferase
Cysteine synthase
Methionine adenosyltransferase
S-Adenosylhomocysteine hydrolase
Cystathionine gamma-synthase

Alanine Metabolism
Aspartate 4-decarboxylase
Alanine transaminase
Alanine-glyoxylate transaminase
Alanine dehydrogenase
Alanine racemase

Valine biosynthesis
Acetolactate synthase
Acetohydroxy acid isomeroreductase
Dihydroxyacid dehydratase
Branched-chain amino acid aminotransferase

Leucine Biosynthesis in Bacteria (precursors same as Valine)
Acetolactate synthase
Dihydroxy-acid dehydratase
3-isopropylmalate synthase
3-isopropylmalate dehydratase
3-isopropylmalate dehydrogenase
Branched-chain amino acid aminotransferase

Isoleucine Metabolism (from Threonine):
- Threonine deaminase
- 3-methyl-2-oxobutanoate hydroxymethyltransferase
- 3-isopropylmalate dehydratase
- 3-isopropylmalate dehydrogenase

Histidine Synthesis:
- Phosphoribosylamine--glycine ligase
- Phosphoribosylformylglycinamidine synthase
- Phosphoribosylformylglycinamidine cyclo-ligase
- Phosphoribosylformimino-5-amino-1-(5-phosphoribosyl)imidazolecarboxamide isomerase
- Imidazoleglycerol-phosphate synthase
- Imidazoleglycerol-phosphate hydrolase
- Histidinol-phosphate aminotransferase
- Histidinol-phosphate phosphatase
- Histidinol dehydrogenase
- Histidine ammonia-lyase

Phenylalanine/Tyrosine Synthesis pathway:
- Chorismate mutase

For Tyrosine synthesis:
- Prephenate dehydrogenase
- 4-Hydroxyphenylpyruvate dioxygenase
- Homogentisate 1,2-dioxygenase

For Phenylalanine synthesis:
- Prephenate aminotransferase
- Arogenate dehydratase

Tryptophan Synthesis:
- Chorismate pyruvate-lyase
- Anthranilate phosphoribosyltransferase
- Phosphoribosylanthranilate isomerase
- Indole-3-glycerol-phosphate synthase
- Tryptophan synthase

Aspartate Metabolism:
- Aspartate transaminase
- Aspartate carbamoyltransferase
- Aspartokinase
- Adenylosuccinate synthase

Asparagine Metabolism:
- Asparagine synthetase
- Asparaginase
- Asparagine aminotransferase

Methionine Metabolism:
- Homoserine dehydrogenase
- O-succinylhomoserine (thiol)-lyase
- Cystathionine beta-lyase
- Methionine synthase
- Methylthiotransferase

Lysine Biosynthesis:
- Dihydrodipicolinate synthase
- Dihydrodipicolinate reductase
- 2,3,4,5-tetrahydropyridine-2,6-dicarboxylate N-succinyltransferase
- 2,3,4,5-tetrahydropyridine-2,6-dicarboxylate N-acetyltransferase
- Diaminopimelate reductase
- Diaminopimelate epimerase
- Diaminopimelate decarboxylase

Threonine Metabolism
- Aspartokinase
- Aspartate-semialdehyde dehydrogenase
- Homoserine dehydrogenase
- Homoserine kinase
- Threonine synthase

Glutamine/Glutamate Synthesis
- Glutamate dehydrogenase (NAD+)
- Glutamate dehydrogenase (NADP+)
- Glutamate 5-kinase
- Glutamine synthetase
- Glutamine-dependent NAD+ synthetase

Arginine/Ornithine Synthesis
- N-acetylglutamate synthase
- N-acetylglutamate kinase
- N-acetyl-gamma-glutamyl-phosphate reductase
- Acetylornithine aminotransferase
- Ornithine carbamoyltransferase
- Argininosuccinate synthase
- Argininosuccinate lyase

Arginine and Proline Metabolism
- L-Glutamate
- L-Citrulline
- Ornithine

Proline Metabolism in Prokaryotes
- Ornithine carbamoyltransferase
- Ornithine decarboxylase
- Acetylornithine deacetylase
- Proline dehydrogenase
- Pyrroline-5-carboxylate reductase

Amino Acid degradation

Alanine Degradation
- Alanine dehydrogenase

Arginine Degradation
- Arginase

Asparagine Degradation
- Asparaginase
- Asparagine aminotransferase

Aspartate Degradation
- Aspartate transaminase
- Aspartate carbamoyltransferase
- Aspartokinase

Cysteine Degradation
- O-succinylhomoserine (thiol)-lyase

Glutamate Degradation
- Glutamate synthase
- Glutaminase
- Glutamate dehydrogenase

Glutamine Degradation
- Glutaminase

Glycine Degradation
- Glycine cleavage system
- Serine hydroxymethyltransferase

Histidine Degradation
- Histidinol-phosphate phosphatase
- Histidinol dehydrogenase
- Histidine ammonia-lyase

Isoleucine Degradation
- Threonine deaminase

Leucine Degradation
- 3-isopropylmalate dehydratase
- 3-isopropylmalate dehydrogenase

Lysine Degradation
- Diaminopimelate epimerase
- Diaminopimelate decarboxylase

Methionine Degradation
- Homoserine dehydrogenase

Phenylalanine Degradation
- Arogenate dehydratase

Proline Degradation
- Pyrroline-5-carboxylate reductase
- Proline dehydrogenase

Serine Degradation
- Serine hydroxymethyltransferase

Tryptophan Degradation
- Tryptophanase

Tyrosine Degradation
- Tyrosine phenol-lyase

Amino Acid Transport and Related Enzymes



Amino Acid Transaminases
Methionine Transaminase
Alanine Transaminase
Aspartate Transaminase
Glutamate-pyruvate Transaminase
Glutamate-oxaloacetate Transaminase
Phenylalanine Transaminase
Tyrosine Transaminase
Tryptophan Transaminase
Alanine--glyoxylate Transaminase
Serine--glyoxylate Transaminase
Cysteine--glyoxylate Transaminase

Amino Acid Dehydrogenases
Alanine Dehydrogenase
Glutamate Dehydrogenase
Tyrosine Dehydrogenase
Lysine Dehydrogenase
Proline Dehydrogenase
Arginase
Arginine Deiminase
Glutamine Synthetase

Amino Acid Kinases
Alanine Kinase
Aspartate Kinase
Glutamate Kinase
Arginine Kinase
Histidine Kinase
Tyrosine Kinase

Amino Acid Transporters
Alanine Transporter
Aspartate Transporter
Glutamate Transporter
Methionine Transporter
Proline Transporter
Tryptophan Transporter
Cysteine Transporter
Lysine Transporter
Histidine Transporter
Threonine Transporter
Glycine Transporter

Fatty Acid and Phospholipid Synthesis in LUCA

Initiation of Fatty Acid Synthesis:
Acetyl-CoA carboxylase
Malonyl-CoA-acyl carrier protein transacylase

Elongation through Fatty Acid Synthase Complex:
Fatty Acid Synthase - Malonyl/Acetyltransferase
Fatty Acid Synthase - 3-ketoacyl-ACP synthase
Fatty Acid Synthase - 3-ketoacyl-ACP reductase
Fatty Acid Synthase - 3-hydroxyacyl-ACP dehydratase
Fatty Acid Synthase - Enoyl-ACP reductase

Termination and Modification
Fatty acid synthase
Stearoyl-CoA desaturase

Fatty Acid Elongation (if needed)
Enoyl-ACP reductase

Phospholipid Synthesis in LUCA
Glycerol-3-phosphate O-acyltransferase (GPAT)
Lysophosphatidic acid acyltransferase (LPAAT)
Phosphatidate cytidylyltransferase

Phosphatidic Acid Formation:

Glycerol-3-phosphate O-acyltransferase
1-acylglycerol-3-phosphate O-acyltransferase
Phosphatidate cytidylyltransferase
Synthesis of Different Phospholipids from CDP-diacylglycerol:

Phosphatidylglycerophosphate synthase
Phosphatidylserine synthase
Phosphatidylethanolamine synthase
Membranes always come from membranes:

Flippases (P-type ATPases):

ATP8A1
ATP8B1
Floppases (ABC Transporters):

ABCA1
ABCB1 (or MDR1/P-glycoprotein)
Ion and Nutrient Transport:

TrkA family potassium uptake protein
Molecule Transport for phospholipid production:

GlpT (Glycerol-3-Phosphate Transporter)
Fatty Acid Transport Proteins (FATPs)
Pst Phosphate Transport System
Pho89 Sodium-Phosphate Transporter
Nucleotide Transporters
Serine Transporters
Ethanolamine Transporters

Phospholipid Degradation

Phospholipase A1 (PlaA)
Phospholipase A2 (PlaB)
Phospholipase C (Plc)
Phospholipase D (Pld)
[Lipid Reuse and Recycling]

Glycerophosphodiester phosphodiesterase (GlpQ)
[Conversion and Recycling of Head Groups]

CDP-diacylglycerol-serine O-phosphatidyltransferase (PSS)
Phosphatidate phosphatase (PAP)
Diacylglycerol kinase (DGK)
[Regulation and Signaling]

Histidine kinase (HK)
Response regulator (RR)
Cardiolipin synthase (Cls)
PhoR
PhoB
LuxQ
LuxU
LuxO
CrtJ/PpsR
SoxR
Dnr
Acyl carrier protein (ACP)
PhoR
PhoB
Cardiolipin synthase
NsrR

CTP: phosphocholine cytidylyltransferase
Phosphatidate cytidylyltransferase

Folate Synthesis
Dihydropteroate synthase (DHPS)
Folylpolyglutamate synthase (FPGS)
Dihydrofolate synthase

Utilization of Tetrahydrofolate (THF) Derivatives
Methenyltetrahydrofolate cyclohydrolase (MTHFC)
Methylenetetrahydrofolate reductase (MTHFR)
Methenyltetrahydrofolate synthetase (MTHFS)
5,10-Methenyltetrahydrofolate cyclohydrolase

Recycling and Conversion of Tetrahydrofolate (THF)
Dihydrofolate reductase (DHFR)
Serine hydroxymethyltransferase (SHMT)
Methylene tetrahydrofolate dehydrogenase (MTHFD)

Other Related Enzymes in Folate Metabolism
5,10-Methenyltetrahydrofolate cyclohydrolase / 5,10-methylenetetrahydrofolate dehydrogenase
Glycinamide ribonucleotide formyltransferase (GARFT)
10-formyltetrahydrofolate dehydrogenase
Methylene tetrahydrofolate dehydrogenase (NADP+)

Thiamine Biosynthesis
Phosphomethylpyrimidine synthase (ThiC)
Phosphomethylpyrimidine kinase (ThiD)
Thiamine-phosphate pyrophosphorylase (ThiE)
Thiamine-monophosphate kinase (ThiL)

S-Adenosylmethionine (SAM) Metabolism
Methionine adenosyltransferase (MAT)
Methylenetetrahydrofolate reductase (MTHFR)
Betaine-homocysteine methyltransferase (BHMT)
Cystathionine β-synthase (CBS)

Utilization of Tetrahydrofolate (THF) Derivatives
Methenyltetrahydrofolate cyclohydrolase (MTHFC)
Methylenetetrahydrofolate reductase (MTHFR)
Methenyltetrahydrofolate synthetase (MTHFS)
5,10-Methenyltetrahydrofolate cyclohydrolase

Recycling and Conversion of Tetrahydrofolate (THF)
Dihydrofolate reductase (DHFR)
Serine hydroxymethyltransferase (SHMT)
Folylpolyglutamate synthase (FPGS)
Methylenetetrahydrofolate reductase (MTHFR)
Methylene tetrahydrofolate dehydrogenase (MTHFD)

Central enzymes and transporters related to the methionine cycle and SAM/SAH metabolism
Methionine adenosyltransferase (MAT)
S-adenosylhomocysteine hydrolase (SAHH)
Methionine synthase (MS)

Methyl transfer with S-adenosylmethionine (SAM)
S-adenosylmethionine (SAM)
S-adenosylhomocysteine hydrolase

Biotin Biosynthesis
Lysine 6-aminotransferase
7,8-Diaminononanoate synthase
7,8-Diaminononanoate synthase (biotin synthesis)
Dethiobiotin synthetase
Biotin synthase

Utilization of Biotin
Acetyl-CoA carboxylase

Recycling and Conversion of Biotin
Biotinidase
Biotinidase
Carbon Monoxide Dehydrogenase (CODH)
CO Dehydrogenase/Acetyl-CoA Synthase (CODH/ACS)

Recycling and Conversion
Carbon Monoxide Dehydrogenase (CODH)

Formate
Formate--tetrahydrofolate ligase
Methenyltetrahydrofolate cyclohydrolase
Methenyltetrahydrofolate synthetase
10-Formyltetrahydrofolate synthetase
Formate dehydrogenase

Recycling and Conversion
Formate dehydrogenase

Vitamin B12 (cobalamin)
Cobyrinic acid a,c-diamide adenosyltransferase
Cobyrinic acid a,c-diamide synthase
Cob(II)yrinate a,c-diamide reductase
Adenosylcobyrinate a,c-diamide amidohydrolase
Adenosylcobinamide kinase
Adenosylcobinamide phosphate guanylyltransferase
Cobalamin biosynthetic protein CobS
Adenosylcobinamide-GDP ribazoletransferase
Adenosylcobinamide kinase/adenosylcobinamide phosphate guanylyltransferase
Adenosylcobinamide-phosphate synthase
CobU
CobT
CobO
Cobaltochelatase
Cobalt-factor III methyltransferase
Cobalt-precorrin-4 methyltransferase
Cobalt-precorrin-5A hydrolase
Cobalt-precorrin-5B methyltransferase
Cobalt-precorrin-6A reductase
Cobalt-precorrin-6B methyltransferase
Cobalt-precorrin-6X reductase
Cobalt-precorrin-7 (C15)-methyltransferase
Cobalt-precorrin-8 methyltransferase
Cobalt-precorrin-8X methylmutase
Cobinamide amidohydrolase
Cobinamide kinase
Cobinamide phosphate guanylyltransferase
Hydrogenobyrinic acid a,c-diamide synthase
Hydrogenobyrinic acid a,c-diamide corrinoid adenosyltransferase
Hydrogenobyrinic acid-binding periplasmic protein
Precorrin-2 dehydrogenase
Precorrin-3B synthase
Precorrin-6Y methyltransferase
Precorrin-6B synthase

Utilization and conversion
Cobyrinic acid a,c-diamide synthase
Cob(II)yrinate a,c-diamide reductase
Adenosylcobyrinate a,c-diamide amidohydrolase
Adenosylcobinamide kinase/adenosylcobinamide phosphate guanylyltransferase
Cobalamin biosynthetic protein CobS
Cobalamin biosynthetic protein CobU

Cofactor and Metal Cluster Biosynthesis

Pantothenate kinase
Dephospho-CoA kinase
Coenzyme M synthase
Phosphopantothenoylcysteine decarboxylase

Coenzyme F420 Biosynthesis

Coenzyme F420-0:GTP 3'-phosphotransferase
Coenzyme F420-1:GTP 3'-phosphotransferase
(2S)-phospholactate:GTP 2-phosphotransferase
Coenzyme F420-0:LPPG 2-phosphotransferase

Coenzyme F430 Biosynthesis

Coenzyme F430 biosynthetic protein FbiC
Coenzyme F430 biosynthetic protein FbiD

Cytochrome c oxidase (COX)

Cytochrome c oxidase

Iron-Sulfur Cluster Biogenesis

Sulfur carrier protein thiocarboxylate synthase
Cysteine desulfurase (IscS in many organisms)
Cysteine-tyrosine lyase
Sulfur carrier protein adenylyltransferase
Fe-S cluster assembly ATPase
Aconitase
IscS (Cysteine desulfurase)
IscU (Fe-S cluster scaffold protein)
IscA (A-type Fe-S cluster carrier or assembly protein)
Fdx (Ferredoxin)
HscA (Specialized Hsp70-type ATPase)
SufB
SufC
SufD
HscB (HscA co-chaperone)
IscR (Transcriptional regulator)
SufE (Fe-S cluster biosynthesis sulfur transfer protein)
SufS (Cysteine desulfurase, involved in the SUF system)
S-sulfanyl-L-cysteine

Heme and Porphyrin Biosynthesis

5-Aminolevulinate synthase (ALAS)
Porphobilinogen synthase (PBGS)
Porphobilinogen deaminase
R04124: Uroporphyrinogen III synthase
Uroporphyrinogen III decarboxylase
Coproporphyrinogen III oxidase
Protoporphyrinogen IX oxidase
Ferrochelatase

Metal Transporters and Centers

Manganese transporters

Manganese transport protein
Manganese-dependent superoxide dismutase (Mn-SOD)

Molybdenum/Tungsten (Mo/W) Cofactors

Molybdenum cofactor biosynthesis protein A (MoaA)
Molybdenum cofactor biosynthesis protein C (MoaC)
Molybdopterin converting factor (MoaD/MoaE)
Molybdenum cofactor biosynthesis protein B (MoaB)

Nickel (Ni) Centers

Hydrogenase nickel incorporation protein HypB
Hydrogenase maturation protein HypA
UreE
UreG
UreF
UreH

Zinc (Zn) Centers

ZnuA
Zur
Zinc-transporting ATPase (ZntA)

Copper (Cu) Centers

Cytochrome c oxidase (COX)
Superoxide dismutase [Cu-Zn]
Laccase
Nitrous oxide reductase



Glycolysis / Gluconeogenesis:
- Hexokinase
- Phosphoglucose isomerase
- Phosphofructokinase
- Aldolase
- Triose-phosphate isomerase
- Glyceraldehyde-3-phosphate dehydrogenase
- Phosphoglycerate kinase
- Phosphoglycerate mutase
- Enolase
- Pyruvate kinase

Citrate Cycle (TCA cycle):
- Citrate synthase
- Aconitase
- Isocitrate dehydrogenase
- α-Ketoglutarate dehydrogenase
- Succinyl-CoA synthetase
- Succinate dehydrogenase
- Fumarase
- Malate dehydrogenase

Pentose Phosphate Pathway:
- Glucose-6-phosphate dehydrogenase
- 6-Phosphogluconolactonase
- 6-Phosphogluconate dehydrogenase
- Ribulose-5-phosphate isomerase
- Ribose-5-phosphate epimerase
- Transketolase
- Transaldolase

Role of Lipids
- Cardiolipin

Anaerobic Respiration
- Ferredoxin-NADP+ Reductase
- Hydrogenase
- Nitrate Reductase
- Nitrite Reductase
- Nitric Oxide Reductase
- Nitrous Oxide Reductase
- Sulfurtransferase

Shikimate Pathway
- Phospho-2-dehydro-3-deoxyheptonate aldolase (DAHP synthase)
- 3-Dehydroquinate synthase
- 3-Dehydroquinate dehydratase
- Shikimate dehydrogenase
- Shikimate kinase
- 3-Phosphoshikimate 1-carboxyvinyltransferase (EPSP synthase)
- Chorismate synthase

Central Carbon Metabolism

Pentose Phosphate Pathway (PPP)

Oxidative Phase
- Glucose-6-phosphate dehydrogenase
- 6-Phosphogluconolactonase
- 6-Phosphogluconate dehydrogenase

Non-Oxidative Phase
- Transketolase
- Transaldolase

Citric Acid Cycle (TCA)
- Malate Dehydrogenase
- Fumarase
- Aconitase
- Citryl-CoA Lyase
- Citrate Synthase
- Aconitate Hydratase

Reverse Citric Acid Cycle (TCA) and Related
- Fumarase
- Pyruvate kinase
- Pyruvate, phosphate dikinase
- Phosphoenolpyruvate carboxykinase
- Succinate dehydrogenase
- Isocitrate dehydrogenase
- Citrate synthase
- Aconitase
- Malate dehydrogenase
- Oxoglutarate:ferredoxin oxidoreductase

CO2 Fixation
- R10092: Carbonic anhydrase

Other Specific Pathways

Chorismate Metabolism
- Chorismate synthase
- Chorismate mutase
- Anthranilate synthase
- Isochorismate synthase
- Isochorismate pyruvate-lyase
- Chorismate pyruvate-lyase
- 4-Amino-4-deoxychorismate lyase
- Chorismate mutase/prephenate dehydratase

Beta-alanine biosynthesis
- Aspartate decarboxylase

Chemosynthesis
- Ribulose-bisphosphate carboxylase (RuBisCO)
- Phosphoglycerate kinase
- Glyceraldehyde-3-phosphate dehydrogenase
- Triosephosphate isomerase
- Aldolase
- Fructose-1,6-bisphosphatase
- Glucose-6-phosphate isomerase
- Glucose-6-phosphate dehydrogenase


Nicotinate and Nicotinamide Metabolism
Nicotinamidase
Nicotinate phosphoribosyltransferase
Quinolinate phosphoribosyltransferase
Nicotinate-nucleotide pyrophosphorylase [carboxylating]
Nicotinamide phosphoribosyltransferase
Nicotinamide riboside kinase
Nicotinate-nucleotide adenylyltransferase
NAD+ synthase
NR 5'-phosphate adenylyltransferase
Nicotinate dehydrogenase
NADH pyrophosphatase

Pantothenate and CoA Biosynthesis
Ketopantoate reductase
Phosphopantothenoylcysteine decarboxylase
Phosphopantothenate-cysteine ligase

Phosphonate and Phosphinate Metabolism
L-Serine:3-phosphohydroxy-2-aminopropylphosphonate phospho-L-aminotransferase

Diaminopimelate Metabolism
N-Acetylornithine deacetylase
N-Succinyl-L,L-diaminopimelic acid desuccinylase
Aspartate-semialdehyde dehydrogenase
4-Hydroxy-tetrahydrodipicolinate reductase
Diaminopimelate epimerase
Diaminopimelate decarboxylase

Redox Reactions
Ferredoxin-NADP+ reductase
NADH:quinone oxidoreductase
Succinate dehydrogenase

Riboflavin Biosynthesis Precursor
3,4-Dihydroxy 2-butanone 4-phosphate synthase

Riboflavin Biosynthesis
Nicotinate-nucleotide adenylyltransferase
alpha-Ribazole phosphatase
Riboflavin synthase
Riboflavin biosynthesis protein RibD (Two different functions)
6,7-dimethyl-8-ribityllumazine synthase
Riboflavin biosynthesis protein RibE
FMN adenylyltransferase (Two different functions)

Sulfur Metabolism
(2R)-3-sulfolactate sulfo-lyase
NAD+-dependent 3-sulfolactate dehydrogenase
Sulfolactate dehydrogenase
3-sulfolactaldehyde synthase
Cysteine desulfurase
Sulfate adenylate transferase
Adenylylsulfate kinase
Thiosulfate/3-mercaptopyruvate sulfurtransferase
Sulfate permease

Transaminase Reactions
Branched-chain amino acid aminotransferase

Oxydoreductase
2-Oxoglutarate ferredoxin oxidoreductase
Pyruvate ferredoxin oxidoreductase (Mentioned twice with same function)
NADH:ferredoxin oxidoreductase
Ferredoxin:NAD+ oxidoreductase
Acetyl-CoA synthase

Tetrapyrrole Biosynthesis
Glutamyl-tRNA reductase

NAD Metabolism
NAD+ synthase
NAD kinase
Nicotinamide mononucleotide adenylyltransferase

FAD Metabolism
FAD synthetase
Riboflavin kinase
NADH-flavin oxidoreductase
NADPH-flavin oxidoreductase

Nitrogen metabolism
Carbon monoxide dehydrogenase
Nitrogenase
Nitrate reductase
Nitrite reductase [NO-forming]
Glutamine synthetase
Glutamate synthase
Glutamate dehydrogenase
Nitric oxide reductase
Nitrous oxide reductase
Nitrite reductase [NAD(P)H]

Oxaloacetate Metabolism
ATP citrate lyase
Aconitase
Succinyl-CoA ligase [ADP-forming]

Pantothenate and CoA Biosynthesis
Ketopantoate reductase
Phosphopantothenoylcysteine decarboxylase
Phosphopantothenate-cysteine ligase

Phosphonate and Phosphinate Metabolism
L-Serine:3-phosphohydroxy-2-aminopropylphosphonate phospho-L-aminotransferase

Diaminopimelate Metabolism
N-Acetylornithine deacetylase
N-Succinyl-L,L-diaminopimelic acid desuccinylase
Aspartate-semialdehyde dehydrogenase
4-Hydroxy-tetrahydrodipicolinate reductase
Diaminopimelate epimerase
Diaminopimelate decarboxylase

Redox Reactions
Ferredoxin-NADP+ reductase
NADH:quinone oxidoreductase
Succinate dehydrogenase

Riboflavin Biosynthesis Precursor
3,4-Dihydroxy 2-butanone 4-phosphate synthase

Riboflavin Biosynthesis
Nicotinate-nucleotide adenylyltransferase
alpha-Ribazole phosphatase
Riboflavin synthase
Riboflavin biosynthesis protein RibD (EC 3.1.3.104)
6,7-dimethyl-8-ribityllumazine synthase
Riboflavin biosynthesis protein RibE
FMN adenylyltransferase
Riboflavin biosynthetic protein RibD
FMN adenylyltransferase

Sulfur Metabolism
(2R)-3-sulfolactate sulfo-lyase
NAD+-dependent 3-sulfolactate dehydrogenase
Sulfolactate dehydrogenase
3-sulfolactaldehyde synthase
Cysteine desulfurase
Sulfate adenylate transferase
Adenylylsulfate kinase

Cofactor and Metal Cluster Biosynthesis
Pantothenate kinase
Dephospho-CoA kinase
Coenzyme M synthase
Phosphopantothenoylcysteine decarboxylase

Coenzyme F420 Biosynthesis
Coenzyme F420-0:GTP 3'-phosphotransferase
Coenzyme F420-1:GTP 3'-phosphotransferase
(2S)-phospholactate:GTP 2-phosphotransferase
Coenzyme F420-0:LPPG 2-phosphotransferase

Coenzyme F430 Biosynthesis
Coenzyme F430 biosynthetic protein FbiC
Coenzyme F430 biosynthetic protein FbiD

Cytochrome c oxidase (COX)
Cytochrome c oxidase

Glycolysis / Gluconeogenesis:
- Hexokinase
- Phosphoglucose isomerase
- Phosphofructokinase
- Aldolase
- Triose-phosphate isomerase
- Glyceraldehyde-3-phosphate dehydrogenase
- Phosphoglycerate kinase
- Phosphoglycerate mutase
- Enolase
- Pyruvate kinase

Citrate Cycle (TCA cycle):
- Citrate synthase
- Aconitase
- Isocitrate dehydrogenase
- α-Ketoglutarate dehydrogenase
- Succinyl-CoA synthetase
- Succinate dehydrogenase
- Fumarase
- Malate dehydrogenase

Pentose Phosphate Pathway:
- Glucose-6-phosphate dehydrogenase
- 6-Phosphogluconolactonase
- 6-Phosphogluconate dehydrogenase
- Ribulose-5-phosphate isomerase
- Ribose-5-phosphate epimerase
- Transketolase
- Transaldolase

Role of Lipids
- Cardiolipin

Anaerobic Respiration
- Ferredoxin-NADP+ Reductase
- Hydrogenase
- Nitrate Reductase
- Nitrite Reductase
- Nitric Oxide Reductase
- Nitrous Oxide Reductase
- Sulfurtransferase

Shikimate Pathway
- Phospho-2-dehydro-3-deoxyheptonate aldolase (DAHP synthase)
- 3-Dehydroquinate synthase
- 3-Dehydroquinate dehydratase
- Shikimate dehydrogenase
- Shikimate kinase
- 3-Phosphoshikimate 1-carboxyvinyltransferase (EPSP synthase)
- Chorismate synthase

Pentose Phosphate Pathway (PPP)
- Glucose-6-phosphate dehydrogenase
- 6-Phosphogluconolactonase
- 6-Phosphogluconate dehydrogenase
- Transketolase
- Transaldolase

Citric Acid Cycle (TCA)
- Malate Dehydrogenase
- Fumarase
- Aconitase
- Citryl-CoA Lyase
- Citrate Synthase
- Aconitate Hydratase

Reverse Citric Acid Cycle (TCA) and Related
- Fumarase
- Pyruvate kinase
- Pyruvate, phosphate dikinase
- Phosphoenolpyruvate carboxykinase
- Succinate dehydrogenase
- Isocitrate dehydrogenase
- Citrate synthase
- Aconitase
- Malate dehydrogenase
- Oxoglutarate:ferredoxin oxidoreductase

CO2 Fixation
- R10092: Carbonic anhydrase

Other Specific Pathways

Chorismate Metabolism
- Chorismate synthase
- Chorismate mutase
- Anthranilate synthase
- Isochorismate synthase
- Isochorismate pyruvate-lyase
- Chorismate pyruvate-lyase
- 4-Amino-4-deoxychorismate lyase
- Chorismate mutase/prephenate dehydratase

Beta-alanine biosynthesis
- Aspartate decarboxylase

Chemosynthesis
- Ribulose-bisphosphate carboxylase (RuBisCO)
- Phosphoglycerate kinase
- Glyceraldehyde-3-phosphate dehydrogenase
- Triosephosphate isomerase
- Aldolase
- Fructose-1,6-bisphosphatase
- Glucose-6-phosphate isomerase
- Glucose-6-phosphate dehydrogenase

NAD Metabolism
NAD+ synthase
NAD kinase
Nicotinamide mononucleotide adenylyltransferase

FAD Metabolism
FAD synthetase
Riboflavin kinase
NADH-flavin oxidoreductase
NADPH-flavin oxidoreductase

Nicotinate and Nicotinamide Metabolism
Nicotinamidase
Nicotinate phosphoribosyltransferase
Quinolinate phosphoribosyltransferase
Nicotinate-nucleotide pyrophosphorylase [carboxylating]
Nicotinamide phosphoribosyltransferase
Nicotinamide riboside kinase
Nicotinate-nucleotide adenylyltransferase
NAD+ synthase
NR 5'-phosphate adenylyltransferase
Nicotinate dehydrogenase
NADH pyrophosphatase

Nitrogen metabolism
Carbon monoxide dehydrogenase
Nitrogenase
Nitrate reductase
Nitrite reductase [NO-forming]
Glutamine synthetase
Glutamate synthase
Glutamate dehydrogenase
Nitric oxide reductase
Nitrous oxide reductase
Nitrite reductase [NAD(P)H]

Oxaloacetate Metabolism
ATP citrate lyase
Aconitase
Succinyl-CoA ligase [ADP-forming]

Pantothenate and CoA Biosynthesis
Ketopantoate reductase
Phosphopantothenoylcysteine decarboxylase
Phosphopantothenate-cysteine ligase

Phosphonate and Phosphinate Metabolism
L-Serine:3-phosphohydroxy-2-aminopropylphosphonate phospho-L-aminotransferase

Diaminopimelate Metabolism
N-Acetylornithine deacetylase
N-Succinyl-L,L-diaminopimelic acid desuccinylase
Aspartate-semialdehyde dehydrogenase
4-Hydroxy-tetrahydrodipicolinate reductase
Diaminopimelate epimerase
Diaminopimelate decarboxylase

Redox Reactions
Ferredoxin-NADP+ reductase
NADH:quinone oxidoreductase
Succinate dehydrogenase

Riboflavin Biosynthesis Precursor
3,4-Dihydroxy 2-butanone 4-phosphate synthase

Riboflavin Biosynthesis
Nicotinate-nucleotide adenylyltransferase
alpha-Ribazole phosphatase
Riboflavin synthase
Riboflavin biosynthesis protein RibD (Two different functions)
6,7-dimethyl-8-ribityllumazine synthase
Riboflavin biosynthesis protein RibE
FMN adenylyltransferase (Two different functions)

Sulfur Metabolism
(2R)-3-sulfolactate sulfo-lyase
NAD+-dependent 3-sulfolactate dehydrogenase
Sulfolactate dehydrogenase
3-sulfolactaldehyde synthase
Cysteine desulfurase
Sulfate adenylate transferase
Adenylylsulfate kinase
Thiosulfate/3-mercaptopyruvate sulfurtransferase
Sulfate permease

Transaminase Reactions
Branched-chain amino acid aminotransferase

Oxydoreductases
2-Oxoglutarate ferredoxin oxidoreductase
Pyruvate ferredoxin oxidoreductase (Mentioned twice with same function)
NADH:ferredoxin oxidoreductase
Ferredoxin:NAD+ oxidoreductase
Acetyl-CoA synthase

Tetrapyrrole Biosynthesis
Glutamyl-tRNA reductase

NAD Metabolism
NAD+ synthase
NAD kinase
Nicotinamide mononucleotide adenylyltransferase

FAD Metabolism
FAD synthetase
Riboflavin kinase
NADH-flavin oxidoreductase
NADPH-flavin oxidoreductase

Nicotinate and Nicotinamide Metabolism
Nicotinamidase
Nicotinate phosphoribosyltransferase
Quinolinate phosphoribosyltransferase
Nicotinate-nucleotide pyrophosphorylase [carboxylating]
Nicotinamide phosphoribosyltransferase
Nicotinamide riboside kinase
Nicotinate-nucleotide adenylyltransferase
NAD+ synthase
NR 5'-phosphate adenylyltransferase
Nicotinate dehydrogenase
NADH pyrophosphatase

Nitrogen metabolism
Carbon monoxide dehydrogenase
Nitrogenase
Nitrate reductase
Nitrite reductase [NO-forming]
Glutamine synthetase
Glutamate synthase
Glutamate dehydrogenase
Nitric oxide reductase
Nitrous oxide reductase
Nitrite reductase [NAD(P)H]

Oxaloacetate Metabolism
ATP citrate lyase
Aconitase
Succinyl-CoA ligase [ADP-forming]

Pantothenate and CoA Biosynthesis
Ketopantoate reductase
Phosphopantothenoylcysteine decarboxylase
Phosphopantothenate-cysteine ligase

Phosphonate and Phosphinate Metabolism
L-Serine:3-phosphohydroxy-2-aminopropylphosphonate phospho-L-aminotransferase

Diaminopimelate Metabolism
N-Acetylornithine deacetylase
N-Succinyl-L,L-diaminopimelic acid desuccinylase
Aspartate-semialdehyde dehydrogenase
4-Hydroxy-tetrahydrodipicolinate reductase
Diaminopimelate epimerase
Diaminopimelate decarboxylase

Redox Reactions
Ferredoxin-NADP+ reductase
NADH:quinone oxidoreductase
Succinate dehydrogenase

Riboflavin Biosynthesis Precursor
3,4-Dihydroxy 2-butanone 4-phosphate synthase

Riboflavin Biosynthesis
Nicotinate-nucleotide adenylyltransferase
alpha-Ribazole phosphatase
Riboflavin synthase
Riboflavin biosynthesis protein RibD (EC 3.1.3.104)
6,7-dimethyl-8-ribityllumazine synthase
Riboflavin biosynthesis protein RibE
FMN adenylyltransferase
Riboflavin biosynthetic protein RibD
FMN adenylyltransferase

Sulfur Metabolism
(2R)-3-sulfolactate sulfo-lyase
NAD+-dependent 3-sulfolactate dehydrogenase
Sulfolactate dehydrogenase
3-sulfolactaldehyde synthase
Cysteine desulfurase
Sulfate adenylate transferase
Adenylylsulfate kinase

DNA Replication
Initiation
DnaA
DiaA
DAM methylase
Hemimethylated DNA Recognition Protein
SeqA Protein
DnaB helicase
DnaC
HU-proteins
IHF Protein
Fis Protein
Hda Protein

Helicase Loading
DnaC
DnaB helicase

Primase Activity
DnaG Primase

Elongation
DNA polymerase III
DNA polymerase I
DNA Ligase
Single-Strand Binding Proteins (SSB)
Sliding Clamp (β-clamp in prokaryotes)
Clamp Loader
Primase

Accessory Proteins
HU proteins
SSB (Single-Stranded DNA-Binding Protein)
Sliding clamp
Clamp loader

Termination
Tus Protein
DNA Ligase
Topoisomerase

Other Related Proteins
Ribonuclease H
Rep Protein

DNA Repair
Adenine Glycosylase
Methyladenine Glycosylase
Excinuclease ABC
MutT
RecA
DNA Polymerase
DNA Ligase
DNA Helicase

DNA Modification and Regulation
Chromosome Segregation SMC
DNA Methyltransferase
DNA Topoisomerase

DNA Mismatch and Error Recognition
DNA Helicase
DNA Ligase
Primase
DNA Mismatch Repair MutS

Other Functions
DNA Gyrase
Topoisomerase
RecA

RNA molecules
Ribozymes
Ribonucleoproteins
siRNA
miRNA

Protein-based transcription factors
Gene Regulatory Network (GRN)
Transcription Factors (TFs)
Sigma Factors
Epigenetic Factors
Small RNAs (sRNAs)
Operons
Repressor and Activator Proteins
DNA Methylation
DNA Binding Domains
Two-component Signaling Systems
Co-factors and Metabolites

Initiation of Transcription
RNA Polymerase
Alpha subunit (α)
Alpha prime subunit (α')
Beta subunit (β)
Beta prime subunit (β')
Sigma factor (σ70 in E. coli)
Omega subunit (ω)
Gamma subunit (γ)
Delta subunit (δ)
Epsilon subunit (ε)
Theta subunit (θ)
Zeta subunit (ζ)
Promoter Sequences
Sigma factor (σ70 in E. coli)
Transcription Factors
Sigma Factors
CAP protein
GAL4 protein
TATA-binding protein (TBP)
LacI repressor
Trp repressor
Histone deacetylase (HDAC)
Heat shock factor
p53 protein
Nuclear factor kappa-B (NF-κB)
Sigma Factor
Sigma factor 70 (σ70)
Sigma factor S (σS or RpoS)
Sigma factor 32 (σ32 or RpoH)
Sigma factor 54 (σ54 or RpoN)
Sigma factor 28 (σ28 or FliA)
Sigma factor 24 (σ24 or RpoE)
Sigma factor 19 (σ19 or SigG)
Sigma factor 38 (σ38 or RpoS)
Sigma factor 29 (σ29 or SigF)
Sigma factor 22 (σ22 or SigA)
Sigma factor 17 (σ17 or SigB)
Sigma factor 43 (σ43 or SigB)
Sigma factor 60 (σ60 or SigA)
Enhancers
Silencers
Activators
Repressors
Coactivators
Corepressors
Mediator Complex

Transcription Elongation
Sigma factor (σ70 in E. coli)

Transcription regulation in the LUCA
RNA Polymerase
Promoter Sequences
Transcription Factors
Sigma Factors
Enhancers and Silencers

Termination of Transcription
Rho Factor

Mismatch Repair (MMR)
MutS
MutL
MutH

Photoreactivation (Light Repair)
Photolyase

Transcription-Coupled Repair (TCR)
Mfd

Aminoacyl-tRNA Synthetase (AlaRS)
Alanyl-tRNA synthetase
Arginyl-tRNA synthetase
Aspartyl-tRNA synthetase
Glutaminyl-tRNA synthetase
Glutamyl-tRNA synthetase
Histidyl-tRNA synthetase
Isoleucyl-tRNA synthetase
Leucyl-tRNA synthetase
Lysyl-tRNA synthetase
Methionyl-tRNA synthetase
Phenylalanyl-tRNA synthetase
Prolyl-tRNA synthetase
Seryl-tRNA synthetase
Threonyl-tRNA synthetase
Tryptophanyl-tRNA synthetase
Tyrosyl-tRNA synthetase
Valyl-tRNA synthetase
Cysteinyl-tRNA synthetase

tRNAs
Alanyl-tRNA synthetase
Arginyl-tRNA synthetase
Asparaginyl-tRNA synthetase
Aspartyl-tRNA synthetase
Cysteinyl-tRNA synthetase
Glutaminyl-tRNA synthetase
Glutamyl-tRNA synthetase
Glycyl-tRNA synthetase
Histidyl-tRNA synthetase
Isoleucyl-tRNA synthetase
Leucyl-tRNA synthetase
Lysyl-tRNA synthetase
Methionyl-tRNA synthetase
Phenylalanyl-tRNA synthetase
Prolyl-tRNA synthetase
Seryl-tRNA synthetase
Threonyl-tRNA synthetase
Tryptophanyl-tRNA synthetase
Tyrosyl-tRNA synthetase
Valyl-tRNA synthetase

tRNA Methylation
tRNA (m7G46) methyltransferase [Aquifex aeolicus]
tRNA guanine-N1 methyltransferase [Aquifex aeolicus VF5]
N2,N2-dimethylguanosine tRNA methyltransferase [Aquifex aeolicus VF5]
tRNA (guanosine(18)-2'-O)-methyltransferase TrmH [Aquifex aeolicus]
tRNA (guanosine(37)-N1)-methyltransferase TrmD [Aquifex aeolicus]
tRNA (guanosine(46)-N7)-methyltransferase TrmB [Aquifex aeolicus]
tRNA (5-methylaminomethyl-2-thiouridine)(34)-methyltransferase MnmD [Aquifex aeolicus]
tRNA (guanine(10)-N(2))-dimethyltransferase [Aquifex aeolicus]
RNase P RNA component
TSEN enzyme complex
RNase Z
Cca-Adding Enzyme
Trm Enzymes
Pseudouridine Synthases
Ribose Methyltransferases
Thiouridylase
Elongator Complex
tRNA Guanine Transglycosylase
AlkB Proteins
tRNA Synthesis

RNA Polymerase III
tRNA Processing
RNase P
RNase Z
TSEN Complex
Thiouridylase
AlkB Proteins
tRNA Maturation
CCA-adding enzyme
tRNA Aminoacylation
Aminoacyl-tRNA synthetases
tRNA Recycling
Elongation Factors

Initiation Phase
IF1
IF2
IF3

Elongation Phase
5S rRNA
16S rRNA
23S rRNA

30S ribosomal subunit
rpsA
rpsB
rpsC
rpsD
rpsE
rpsF
rpsG
rpsH
rpsI
rpsJ
rpsK
rpsL
rpsM
rpsN
rpsO
rpsP
rpsQ
rpsR
rpsS
rpsT
rpsU

Elongation Factors
EF-G
EF-Tu

50S ribosomal subunit
rplA
rplB
rplC
rplD
rplE
rplF
rplG
rplJ
rplK
rplL
rplM
rplN
rplO
rplP
rplQ
rplR
rplS
rplT
rplU
rplV
rplW
rplX
rpmA
rpmB
rpmC
rpmD
rpmE
rpmF
rpmG
rpmH
rpmI
rpmJ

Termination Phase
RF1
RF2
RF3

I. rRNA Synthesis
RNA Polymerase
σ Factor
RNase III
Stringent Response Proteins
Anti-termination factors (NusA, NusB, NusG, NusE)
Exoribonucleases
Endoribonucleases
RNA Helicases
Ribosome Assembly Factors
rRNA Methyltransferases
Pseudouridylation Enzymes
Small Nucleolar RNAs (snoRNAs)
Pre-rRNA Processing Factors
GTPases
Ribonucleases
RNA Chaperones
Hfq Protein
RNA Helicases
Ribosome Modifying Enzymes (Methyltransferases)
RNA Chaperones

II. tRNA Processing
RNase P
Ribonucleases
Cca-adding Enzyme
TATA-Binding Protein
RNA Polymerase III
La Protein
Small Regulatory RNAs
RNA Helicases
RNA-Binding Proteins
Aminoacyl tRNA Synthetases
Nucleases
TATA Binding Proteins
Ribonucleases
Endoribonucleases
Ribonucleoproteins
Nucleolar Proteins
Pseudouridylation Enzymes
tRNA Methyltransferases
Thio Modification Enzymes
Tyrosyl-tRNA Synthetase

III. rRNA Modification
Acetyltransferases (e.g., Kre33)
RNA Helicases
Endoribonucleases (e.g., RNase M5)
Exoribonucleases
Small Subunit Ribosomal RNA (SSU rRNA)
Large Subunit Ribosomal RNA (LSU rRNA)
Decapping Enzymes
Ribonuclease P
GTPases
Kinases
Proteases
Nucleolar Organizing Regions
Ribonucleoproteins
Ribosome Assembly Factors
Ribosomal Proteins

IV. Ribosomal Protein Synthesis
Nuclear Pore Complex
Ribosomal Proteins
RNA Chaperones
GTPases
Molecular Chaperones
Ribosome Biogenesis Factors
Protein Transport Factors
Ribosome Assembly Factors
Proteasome

V. Small Subunit (30S) Assembly
Ribosomal Proteins (e.g., RpsA, RpsB, RpsC, RpsD, RpsE)
Assembly Factors (e.g., RimM, RimP)
Ribosome Maturation Factors
Ribonucleases
RNA Helicases
RNA Chaperones
GTPases
rRNA Methyltransferases
RNA Polymerase
σ Factor
RNase III
Pseudouridylation Enzymes
Stringent Response Proteins
Anti-termination factors
Exoribonucleases and Endoribonucleases
VI. Large Subunit (50S) Assembly

Large Subunit Ribosomal Proteins
Assembly Factors
Ribosome Maturation Factors
Ribonucleases
RNA Helicases
RNA Chaperones
GTPases
rRNA Methyltransferases
Pseudouridylation Enzymes
Anti-termination factors
Ribosomal Proteins

VII. 70S Ribosome Assembly
Ribosomal Proteins (e.g., RpsA, RpsB, RpsC, RpsD, RpsE)
Assembly Factors (e.g., RimM, RimP)
Large Subunit Ribosomal Proteins
RNA Polymerase
σ Factor
GTPases
rRNA Methyltransferases
Ribosome Maturation Factors
Ribonucleases
RNA Helicases
RNA Chaperones
Initiation Factors
Proteasome

VIII. Quality Control and Recycling:
RNA Polymerase
σ Factor
RNase III
GTPases
rRNA Methyltransferases
Ribonucleases
RNA Helicases
RNA Chaperones
Ribosomal Proteins (e.g., RpsA, RpsB, RpsC, RpsD, RpsE)
Assembly Factors (e.g., RimM, RimP)
Ribosomal Proteins (associated with 50S)
Assembly Factors (associated with 50S)

IX. Ribosome Function
X. Regulation of Ribosome Biogenesis
RelA
SpoT
DksA
RMF (Ribosome Modulation Factor)
hpf (hibernation promoting factor)
IF3 (Initiation Factor 3)
Riboswitches
Era
LacI (Lactose Repressor)
TrpR (Tryptophan Repressor)

[size=16]Post-Translational Protein Processing in LUCA

Protein Folding and Stability
Co-chaperonin GroES
Chaperone protein DnaK
Molecular chaperone GroEL
Trigger factor
Protein GrpE

Protein Modification and Processing
5'-3' exonuclease
Class I SAM-dependent methyltransferase
PpiC domain-containing protein
C-type cytochrome biogenesis protein CcsB
Methionine aminopeptidase
Peptidyl-tRNA hydrolase

Protein Targeting and Translocation
LptF/LptG family permease
Cytochrome c biogenesis protein

Protein Degradation
Serine protease
Signal peptide peptidase SppA
ATP-dependent Clp protease proteolytic subunit
ATP-dependent Clp protease ATP-binding subunit

Protein Post-translational Modification
Serine/threonine protein phosphatase
N-acetyltransferase
biotin--[biotin carboxyl-carrier protein] ligase

Protein Maturation and Breakdown
Aminopeptidase P family protein

Bacterial Defense
VapC toxin family PIN domain ribonuclease
Restriction endonuclease EcoRI
CRISPR-associated protein Cas9

Bacterial-host Interactions
Nodulation protein NfeD

Bacteriophage Structural Proteins
Phage tail protein I

Bacterial Outer Membrane Biosynthesis
Lipid A biosynthesis N-terminal domain-containing protein

Bacteriophage Assembly and DNA Packaging
Phage portal protein
Terminase large subunit gp17-like C-terminal domain-containing protein
Phage major capsid protein
Phage DNA-binding protein

Protein Folding and Stability
- Co-chaperonin GroES
- Chaperone protein DnaK
- Molecular chaperone GroEL
- Trigger factor
- Protein GrpE

Protein Modification and Processing
- 5'-3' exonuclease
- Class I SAM-dependent methyltransferase
- PpiC domain-containing protein
- C-type cytochrome biogenesis protein CcsB
- Methionine aminopeptidase
- Peptidyl-tRNA hydrolase

Protein Targeting and Translocation
- LptF/LptG family permease
- Cytochrome c biogenesis protein

Protein Degradation
- Serine protease
- Signal peptide peptidase SppA
- ATP-dependent Clp protease proteolytic subunit
- ATP-dependent Clp protease ATP-binding subunit

Protein Post-translational Modification
- Serine/threonine protein phosphatase
- N-acetyltransferase

Biotinylation
- biotin--[biotin carboxyl-carrier protein] ligase

Protein Maturation and Breakdown
- Aminopeptidase P family protein

Bacterial Defense
- VapC toxin family PIN domain ribonuclease
- Restriction endonuclease EcoRI
- CRISPR-associated protein Cas9

Bacterial-host Interactions
- Nodulation protein NfeD

Bacteriophage Structural Proteins
- Phage tail protein I

Bacterial Outer Membrane Biosynthesis
- Lipid A biosynthesis N-terminal domain-containing protein[/size]

Bacteriophage Assembly and DNA Packaging
- Phage portal protein
- Terminase large subunit gp17-like C-terminal domain-containing protein
- Phage major capsid protein
- Phage DNA-binding protein


The Acetylation Code
- Histone Acetyltransferases
- Acetyl CoA

The Adenylation Code
- Adenylate Kinase
- Adenylate Cyclase
- cAMP-Dependent Protein Kinase (PKA)
- Phosphodiesterase
- Nucleotidyltransferases
- Adenylate Forming Enzymes

The Biosynthetic Code
- Ribonucleotide Reductase
- Glutamine Synthetase
- Fatty Acid Synthase
- DNA Gyrase

The Cell Polarity Code
- Polarization Protein Complexes
- Cell Membrane Lipid Distribution
- Motor Proteins
- Cytoskeletal Elements

The Chromosome Segregation Code
- DNA Topoisomerase
- Chromosome Segregation SMC
- DNA Methyltransferase

The DNA Repair/Damage Codes
- DNA Polymerase
- Nucleotide Excision Repair Proteins
- Mismatch Repair Proteins

The Genetic Recombination Codes
- Integrons
- Transposases
- Plasmids
- Conjugative Pili
- Recombinases
- Cas Proteins
- Restriction-Modification Systems
- Relaxases
- Tra Proteins
- Mob Proteins
- Nuclease
- Primase
- DNA Helicase
- Sigma Factors
- Single-Stranded Binding Proteins (SSBs)

The Molecular Recognition Code
- R10699: Lysine 6-aminotransferase
- R03182: 7,8-Diaminononanoate synthase
- Chromosome Segregation SMC
- DNA Methyltransferase
- DNA Topoisomerase

The N-Glycan Code
- Glycosyltransferases
- Dolichyl-diphosphooligosaccharide-protein glycosyltransferase

The Non-Ribosomal Code
- Non-ribosomal peptide synthetases (NRPS)
- Adenylation domains
- Thiolation domains

The Operon Code
- RNA Polymerase
- Operator

The Quorum Sensing Code
- Autoinducer Synthase
- Response Regulator

The RNA Editing Code
- Adenosine Deaminases Acting on RNA (ADARs)
- Cytidine Deaminases

The Sticky-end Code
- Restriction Enzymes
- Ligase Enzymes

Families/functions involved in various aspects of cell division in LUCA

FtsZ and Associated Proteins
- FtsZ
- FtsA
- ZipA
- Amidases

Min Proteins - Cell Division Regulatory Proteins
- Min Proteins
- FtsZ

Nucleoid-Associated Proteins (NAPs)
- Nucleoid-Associated Proteins (NAPs)

DNA Topoisomerases
- DNA Topoisomerase

Cell wall synthesis enzymes
- Peptidoglycan Synthesis Enzymes
- MurA
- MurB

Thermostable Membrane Lipids
- Heat Shock Proteins (HSPs)
- Desaturases

RNA Stability Mechanisms
- Lysine 6-aminotransferase
- 7,8-Diaminononanoate synthase

Chromosome Segregation Mechanisms
- Chromosome Segregation SMC
- DNA Methyltransferase
- DNA Topoisomerase

Proteolysis in the LUCA
- Lysine 6-aminotransferase
- 7,8-Diaminononanoate synthase
- Chromosome Segregation SMC
- DNA Methyltransferase
- DNA Topoisomerase

Clp Proteases
- Clp Protease
- Lon Protease
- ClpXP Protease
- Proteasome
- OmpT Protease
- Lon Protease

Metalloproteases
- FtsH Protease
- HtpX Protease
- PitrlA Protease

Serine Proteases
- ClpXP Protease
- Lon Protease
- HtrA Protease

Peptidases
- Leucine Aminopeptidase
- Carboxypeptidase
- Tripeptidase

ABC transporters
- Amino Acid and Dipeptide Transporters
- Dipeptide Transporters (PepT1)
- Ribosomes
- Protein Synthesis Enzymes
- Ammonium Transporters
- Cobalt Transporters
- Heavy Metal Transporters
- Fur (Ferric Uptake Regulator)
- ZnuABC
- CusCFBA
- CorA
- MntH
- PfeA
- SitABCD
- FeoB
- F-type ATPase
- Oligopeptide ABC Transporters
- Phosphate Transporter
- Spermidine Transporter
- Sugar Transporters

Various other cellular processes in LUCA
- DnaJ
- Chaperonin GroES
- Chaperonin GroEL
- CheW
- CheA
- CheR
- GTP binding
- Ser/Thr kinase
- CrcB Camphor Resistance
- Inorganic Pyrophosphatase
- Ankyrin Repeat Proteins
- Signal Recognition Particle (SRP) in Prokaryotes

ATPases
- AAA+ ATPases
- Copper and other P-ATPase
- F-type ATPase
- Magnesium and/or cobalt ATPases
- Multidrug resistance ATPases
- Rotary ATPases
- SecA ATPase

Rotary ATPases (A-type and V-type)

Ion ATPases
- Glutathione-Na Antiporter
- Magnesium and/or Cobalt ATPase
- Multidrug Resistance ATPase
- Potassium ATPase A/B/C Chains
- Rotary ATPases (V-type and A-type)
- Sodium ATPase

Ion Channels
- Chloride Channel
- Mechanosensitive Channel
- Trk (126) and Other Potassium Channels and Uptake
- Voltage-Gated Sodium Channels (Nav)
- Calcium Channels
- Proton Pumps
- Aquaporins
- Light-Gated Ion Channels
- Sodium/Potassium Pumps
- Phosphate Transporters
- Anion Exchangers
- Iron Transporters
- Sulfate Transporters
- Lactate Transporters
- Formate Transporters

Protein Translocases
- Export SecD/F
- SecY
- Translocase TatC
- YidC/Oxa1/Alb3 family of insertases
- SecA
- TatA and TatB

General Secretion Pathway Components
- Arsenical Pump Membrane
- Bacterioferritin Comigratory Protein (Bcp)
- Mrp Subfamily of ABC Transporters
- Non-specific Membrane Protein Families
- Rhomboid Family
- SecB
- FFS (4.5S RNA)
- SecE and SecG
- R10699: Lysine 6-aminotransferase
- R03182: 7,8-Diaminononanoate synthase
- DNA Methyltransferase


Total 1361 proteins/enzymes

LUCA's minimal Physiology and Proteome

Reconstructing a supposed universal common ancestor (UCA) is a fascinating but challenging endeavor in the field of evolutionary biology. The UCA, often referred to as the "Last Universal Common Ancestor" (LUCA), is believed to be the hypothetical organism from which all life on Earth descended. While scientists have made significant progress in understanding the characteristics and possible traits of LUCA, there are numerous challenges and complexities involved in this endeavor.

Key Cellular Processes and Functions in LUCA

Cellular Infrastructure and Integrity

Membrane Proteins, and Transport: Ensuring nutrient uptake, waste removal, and environmental sensing.
Peptidoglycan Synthesis: Key for structural integrity in some cells.
Families/functions involved in various aspects of cell division in LUCA: Fundamental for reproduction.

Energy and Metabolism

Energy Metabolism, Central Carbon Metabolism, and Other Specific Pathways: Driving cellular activities.
One-Carbon Metabolism: A central metabolic pathway.
Fatty Acid and Phospholipid Synthesis in LUCA: Critical for membrane structure and function.

Information Storage and Processing

DNA Processing in LUCA: Replication, repair, and recombination.
Gene Expression and Regulation in LUCA: Transcribing DNA into functional RNA molecules.
Transcription/regulation in the LUCA: Ensuring correct gene expression.
Translation/Ribosome in the LUCA: Synthesizing proteins based on RNA templates.
Biosynthesis and Assembly of the Bacterial Ribosome: Critical for protein synthesis.

Biosynthesis and Nutrient Uptake

Amino acid biosynthesis: Building blocks for proteins.
Nucleotide Synthesis and Salvage: Building blocks for DNA/RNA.
Polyamine Synthesis: Involved in DNA stabilization and protein synthesis.
Cofactor and Metal Cluster Biosynthesis: Essential for various enzyme functions.

Regulation and Response Mechanisms

Epigenetic, manufacturing, signaling, and regulatory codes in LUCA: Adapting to environmental changes and ensuring cellular homeostasis.
Reactive oxygen species (ROS): Handling oxidative stress.
Thermo protection in the LUCA: Protecting against temperature extremes.
Regulatory Enzymes and Proteins in Amino Acid Synthesis: Ensuring metabolic balance.
Proteolysis in the LUCA: Protein degradation and turnover.

Metals and Metal Clusters

Metal clusters: Essential for many enzyme functions.

RNA Dynamics

RNA: Beyond protein-coding, RNA plays roles in regulation, catalysis, and structural components.

Additional Functions

Ion Homeostasis and Osmoregulation: Balancing ion concentrations and responding to osmotic stress.
DNA Repair Mechanisms: Maintaining genetic integrity in the face of damage.
Toxin-Antitoxin Systems: Protecting against foreign DNA or controlling cellular processes.
Sensory Systems: Detecting environmental signals and responding appropriately.
Vesicle Formation and Secretion: Interacting with the environment, disposing of waste, or communication.


There is no consensus view

The absence of a consensus view on the constitution of the Last Universal Common Ancestor (LUCA) stems from several inherent challenges and uncertainties in the field of evolutionary biology and the study of ancient life forms:
Studies aiming to reconstruct the LUCA's genome or proteome are based on inference and computational analysis. They work backward in time from the characteristics of modern organisms to make educated guesses about the traits of LUCA. These inferences are reliant on various assumptions and models, which can introduce bias and errors into the predictions. LUCA is believed to have existed over 3.5 billion years ago. The vast amount of time that has passed since LUCA's existence makes it extremely challenging to accurately reconstruct its genetic and biochemical makeup. Over such a long period, genetic material can be lost, altered, or replaced. Gene families may have been present in LUCA but lost during subsequent evolution. Additionally, some functions may have been encoded by different, unrelated genes in LUCA and modern organisms due to gene replacement events. These factors can obscure the true nature of LUCA's genetic repertoire. The genomic data used in these studies come from modern organisms, and there may be gaps in our understanding of the diversity of ancient life. Some lineages that could have been present in the ancient microbial communities might have left no descendants or left only limited genomic traces. Each study on LUCA reconstruction employs its own set of methods, assumptions, and criteria for defining ancestral traits. There is no standardized or universally accepted protocol for these reconstructions, leading to variability in results. The available genomic and proteomic data used in these studies might not be representative of the full diversity of life that existed at the time of LUCA. The data could be biased toward organisms that are more easily studied or preserved. The concept of LUCA as a relatively complex cellular organism challenges traditional views of LUCA as a simple replicator. This complexity raises questions about the nature of the supposed LUCA and the extent to which it resembled modern organisms. Due to these challenges and uncertainties, different studies  produce varying conclusions about LUCA's genome and proteome.

The vast diversity of life forms on Earth is an intriguing phenomenon. Instead of attributing it to a single common ancestor, an alternative hypothesis is that life forms were intentionally designed with unique characteristics and features. In this view, each species may have been individually created with its distinct traits. It is undeniable that all known life share a common biochemistry, including nucleic acids, proteins, carbohydrates, and lipids. Instead of seeing this as evidence of a LUCA, that might be due to a purposeful design. The shared biochemical foundation can be due to a blueprint or template used by an intelligent designer to create life forms with similar functional requirements. The complexity of life forms, including intricate cellular structures and metabolic pathways, can point to intelligent design. Instead of assuming that a simple replicator evolved into complex organisms, one can propose that these complexities were deliberately engineered.

Exploring what it would take for a transition from a LUCA to the three domains of life and beyond can help shed light on the plausibility of the tree of life hypothesis and whether evidence might rather suggest polyphyletic origins.
One of the significant challenges in the naturalistic hypothesis is, furthermore, explaining the origin of the intricate genetic information present in all life forms. From an alternative viewpoint, the sudden appearance of highly organized genetic codified information might raise questions about whether natural processes alone can account for the complexity of life's information systems. The transition from LUCA to the diverse life forms we observe today involves the development of complex molecular machinery within organisms. The instantiation of such sophisticated systems may indicate purposeful design or intervention, rather than a purely natural progression. The supposed evolution of cellular structures, organelles, and complex biochemical pathways required for life's functions presents significant challenges.  The LUCA hypothesis implies that all life shares a common ancestry, but the vast differences in the developmental pathways and body plans of organisms deserve skepticism. The divergence in life forms' characteristics and features challenges the idea of a single common ancestor. Beyond the three domains of life, the evolution of consciousness, cognition, and complex behaviors in some organisms presents an additional layer of complexity.  Examining the transition from LUCA to diverse life forms and beyond raises profound philosophical questions about the nature of existence, purpose, and the potential role of guiding intelligence in the universe. It encourages a broader discussion beyond purely scientific aspects.

LUCA was as complex as modern cells

In 2005, the paper “A minimal estimate for the gene content of the last universal common ancestor—exobiology from a terrestrial perspective” by Christos A. Ouzounis et al aimed to reconstruct the gene content of the last universal common ancestor (LUCA), a hypothetical life form that presumably was the progenitor of the three domains of life. Using an algorithm for ancestral state inference of gene content, given a large number of extant genome sequences and a phylogenetic tree, they found that LUCA’s gene content appears to be substantially higher than that proposed previously, with a typical number of over 1000 gene families, of which more than 90% are also functionally characterized. More precisely, when only prokaryotes are considered, the number varies between 1006 and 1189 gene families while when eukaryotes are also included, this number increases to between 1344 and 1529 families depending on the underlying phylogenetic tree. Therefore, the common belief that the hypothetical genome of LUCA should resemble those of the smallest extant genomes of obligate parasites is not supported by recent advances in computational genomics. Instead, a fairly complex genome similar to those of free-living prokaryotes, with a variety of functional capabilities including metabolic transformation, information processing, membrane/transport proteins, and complex regulation, shared between the three domains of life, emerges as the most likely progenitor of life on Earth. 1

F.Rana (2023): It now appears that LUCA was far more elaborate and complex than most evolutionary biologists had imagined. This conclusion comes from a team of collaborators from the US and the UK. In fact, the genetic complexity required to support LUCA’s morphological and physiological complexity far outpaces the estimated complexity from reconstructing LUCA based on comparative gene studies. In fact, the research team discovered that LUCA possessed a genome that was about 2.49 million base pairs in size (similar in size and complexity to a typical bacterial genome).2

The article: "Phenotypic reconstruction of the last universal common ancestor reveals a complex cell" discusses new research that offers a different perspective on LUCA and challenges previously held beliefs about its complexity. Most prior work focused on DNA to understand LUCA, but these studies might have underestimated its intricacy. The new approach taken by the international research team concentrates on LUCA's physiological features rather than its gene set, providing a more comprehensive view of its characteristics. From the information given: Historically, researchers thought LUCA was a simple cell. However, the new findings suggest that LUCA was perhaps more sophisticated than many contemporary bacteria and archaea. This challenges the idea that prokaryotic evolution was a journey from simple to complex. The study's abstract emphasized the rapid evolution of early life towards significant cellular complexity, much earlier than previously believed. Reconstructing LUCA's Features: Previously, genomics studies tried to deduce LUCA's gene set based on genes common to all bacteria and archaea. Estimates based on these methods suggested LUCA had around 350 to 1000 genes. But this approach had its limitations, particularly regarding understanding LUCA's morphology and molecular physiology. Instead of relying solely on DNA, the research team reconstructed LUCA's cellular traits using evolutionary trees constructed from 28 traits found in 3,128 bacterial and archaeal species. This methodology yielded a detailed set of morphological and physiological features for LUCA, painting a picture of a surprisingly complex organism. This method estimated that LUCA had a genome that was about 2.49 million base pairs in size, much larger than earlier estimates based on comparative gene studies. In essence, the article emphasizes that the traditionally accepted narrative of a simple LUCA, based on its supposed minimal gene content, may be incorrect. Instead, the new insights suggest that LUCA had a more complex gene content and was perhaps more intricate than previously thought. This discovery reshapes our understanding of early life's origin and suggests that life's complexity developed rapidly.

Kunin, V.,(2006): The Last Universal Common Ancestor (LUCA) or the primitive community that it encompassed was both functionally and genetically intricate. This supports the notion that life had reached its contemporary cellular structure well before the differentiation into the three domains. Contrary to conclusions drawn solely from sequence conservation and ubiquitous presence across all species, which pointed towards a basic LUCA with primarily translation-related genes, a refined approach to identify distant homology indicates that LUCA encompassed elements from almost all critical functional areas seen in current organisms. This reveals a metabolic complexity comparable to the translation process in terms of domain diversity. 1


Schematic representation of cellular functions represented by the ancestral set of superfamilies. The cellular and/or functional locations of the superfamilies domains are represented by numbers. CATH identifications and functional descriptions of all ancestral superfamilies are given in Supplementary Table 3 following the same numbering code. 3

References

● Kyrpides, N., Overbeek, R., & Ouzounis, C. (1999). Universal protein families and the functional content of the last universal common ancestor. Journal of Molecular Evolution, 49(4), 413-423. Link. (This study investigates the protein families universally present in living organisms, shedding light on the potential functional content of LUCA.)
●Mirkin BG, Fenner TI, Galperin MY, Koonin EV (2003). Algorithms for computing parsimonious evolutionary scenarios for genome evolution, the last universal common ancestor and dominance of horizontal gene transfer in the evolution of prokaryotes. BMC Evol Biol, 3:2. Link. (This paper discusses algorithms for understanding genome evolution, the last universal common ancestor, and the role of horizontal gene transfer in prokaryotic evolution.)
●Yang S, Doolittle RF, Bourne PE (2005). Phylogeny determined by protein domain content. Proc Nat Acad Sci U S A, 102:373-378. Link. (The study explores how protein domain content can be used to determine phylogenetic relationships.)
●Delaye L, Becerra A, Lazcano A (2005). The last common ancestor: what's in a name?. Orig Life Evol Biosph, 35:537-554. Link. (This paper delves into the terminological and conceptual challenges associated with defining the last common ancestor.)
●Ranea JA, Sillero A, Thornton JM, Orengo CA (2006). Protein superfamily evolution and the last universal common ancestor (LUCA). J Mol Evol, 63:513–525. Link. (The paper studies the evolution of protein superfamilies with reference to the last universal common ancestor.)
●Wang M, Yafremava LS, Caetano-Anollés D, Mittenthal JE, Caetano-Anollés G (2007). Reductive evolution of architectural repertoires in proteomes and the birth of the tripartite world. Genome Res, 17:1572-1585. Link. (This paper discusses the reductive evolution in proteomes and how it may have given rise to the tripartite division of life forms.)
●Srinvasan V, Morowitz HJ (2009). The canonical network of autotrophic intermediary metabolism: minimal metabolome of a reductive chemoautotroph. Biol Bull, 216:126–130. Link. (This paper describes the minimal metabolic network required for a reductive chemoautotroph.)
● Goldman AD, Baross JA, Samudrala R. (2012) The Enzymatic and Metabolic Capabilities of Early Life. PLoS ONE. Link. (This study investigates the enzymatic and metabolic attributes of early life forms, offering insights into primordial biochemistry.)
● de Farias, S. T., Rêgo, T. G., & José, M. V. (2015). A proposal of the proteome before the last universal common ancestor (LUCA). Published online by Cambridge University Press. Link. (This article offers a proposed view of the proteome that existed before the emergence of the Last Universal Common Ancestor, LUCA, providing insights into the evolutionary stages of protein networks in primordial life forms.)
●Weiss MC, Sousa FL, Mrnjavac N, Neukirchen S, Roettger M, Nelson-Sathi S, Martin WF (2016). The physiology and habitat of the last universal common ancestor. Nat Microbiol, 1:16116. Link. (This paper explores the potential physiology and habitat of the last universal common ancestor based on extant biochemistry and cell biology.)
●Harris A, Goldman AD (2018). Phylogenetic Reconstruction Shows Independent Evolutionary Origins of Mitochondrial Transcription Factors from an Ancient Family of RNA Methyltransferase Proteins. J Mol Evol, 86:277-282. Link. (The paper focuses on the independent evolutionary origins of mitochondrial transcription factors.)
● Palacios-Pérez, M., & José, M. V. (2019). The evolution of proteome: From the primeval to the very dawn of LUCA. BioSystems. Link. (This research article explores the evolution of the proteome from the earliest stages of life up to the emergence of the Last Universal Common Ancestor, LUCA, providing insights into the evolution of proteins and protein networks in early life forms.)
● Crapitto, A. J., Campbell, A., Harris, A.J., & Goldman, A. D. (2022). A consensus view of the proteome of the last universal common ancestor. Ecology and Evolution, 12(6), e8930. Link. (Published by Wiley, this article presents a consensus perspective on the proteome of the Last Universal Common Ancestor, LUCA. The study contributes to the field of biology and provides insights into the protein composition of early life forms.)
● Matzke, N., Lin, A., Stone, M., & Baker, M. (2021). Flagellar export apparatus and ATP synthetase: Homology evidenced by synteny predating the Last Universal Common Ancestor. BioEssays, 43. Link. (Published by Wiley, this article delves into the homological relationship between the flagellar export apparatus and ATP synthetase, emphasizing their ancestral connection predating the Last Universal Common Ancestor. This work enhances our understanding of evolutionary biology and the genetic underpinnings of ancient cellular machinery.)

Note: This comprehensive list captures both known functions and enzymes related to DNA processing in LUCA as well as recent additions based on updated knowledge. The evolutionary history and precise functions of these enzymes might vary, and our understanding remains a subject of active research.

1.Ouzounis, C. A., Kunin, V., Darzentas, N., & Goldovsky, L. (2006). A minimal estimate for the gene content of the last universal common ancestor--exobiology from a terrestrial perspective. Research in Microbiology, 157(1), 57-68. Link. (This study provides an estimate of the gene content of the Last Universal Common Ancestor, offering insights into its molecular features and potential exobiological implications.)
2.Rana, F. (2023). LUCA’s Complexity Challenges Evolutionary Origin of Life. The Cell's Design Blog. Link. (This article delves into the newfound complexity of LUCA and the challenges it presents to the evolutionary model for the origin of life.)





Metabolic Pathways in LUCA

Understanding which metabolic pathways were extant in LUCA is an ongoing area of scientific research. The listed pathways come from interpretations of comparative genomics studies, phylogenetic analyses, and biochemical studies. However, as with many topics in ancient evolution, there's a degree of uncertainty and some pathways may be subject to revision as more data becomes available. Here's a list of potential metabolic pathways that might have been present in LUCA, keeping in mind that this is based on our current understanding and can change with future discoveries:

Anabolic Pathways (Biosynthetic)

1. Nucleotide Synthesis and Salvage: The formation of the basic units of nucleic acids lays the groundwork for genetic information storage and transfer.
2. Amino Acid Biosynthesis: Proteins serve as the primary workhorses of the cell, and their constituent amino acids would be among the earliest necessities.
3. Fatty Acid and Phospholipid Synthesis: Once basic biochemical pathways were established, compartmentalization via cellular membranes would be crucial for the emergence of protocells and differentiation from the environment.
4. One-Carbon Metabolism: Foundational biochemical reactions that likely evolved early, supporting the synthesis of various vital molecules.
5. RNA Modifications: RNA's role as both a genetic material and catalytic molecule would necessitate modifications for stability and function.
6. Peptidoglycan Synthesis: With the emergence of a lipid barrier, a protective layer or primitive cell wall would be beneficial, especially for early bacterial life.
7. Coenzyme A and Other Cofactor Biosynthesis: As metabolic reactions diversified, molecules that aid in enzyme function and catalysis would become indispensable.
8. Vitamin and Cofactor Biosynthesis: Further diversification of enzymatic reactions would drive the biosynthesis of more specialized cofactors and vitamins.
9. Iron-Sulfur Cluster Assembly: Reflecting an early Earth rich in iron and underscoring the significance of iron-sulfur proteins in primordial metabolic processes.
10. Porphyrin Metabolism: As life evolved, processes like respiration and photosynthesis would emerge, necessitating molecules like heme and chlorophyll.
11. Polyamine Synthesis: With increased cellular complexity, polyamines would be essential for stabilizing DNA, RNA, and supporting cell growth.

Catabolic Pathways (Degradative)

12. Glycolysis and the Pentose Phosphate Pathway: Fundamental pathways for sugar breakdown and nucleotide synthesis.
13. TCA Cycle: Core pathway for cellular breathing, energy production, and precursors for biosynthesis.
14. ATP Synthesis and Oxidative Phosphorylation: Key processes for generating ATP, the main energy currency of cells.
15. Anaerobic Respiration Pathways: Pathways that allow energy production without oxygen.
16. Methanogenesis and Methane Oxidation: Enzymatic evidence suggests methane metabolism in early evolutionary pathways.
17. Hydrogen Oxidation: Pathways for energy derivation from hydrogen.
18. Thioester Metabolism: Points to thioesters as ancient energy carriers.
19. Carbon Fixation: Mechanisms for assimilating CO2 into organic molecules.
20. Methyl Group Metabolism: Related to the vital transfer and use of methyl groups in cellular functions.
21. Reverse Electron Flow: Used for driving thermodynamically challenging reactions.
22. Formate Metabolism: Formate as a substrate and product in early life energy production.
23. Entner–Doudoroff pathway: An alternate to glycolysis, crucial for glucose breakdown.
24. Phosphoketolase pathway: Focused on pentose sugars, primarily in prokaryotes.
25. Wood-Ljungdahl Pathway: One of the earliest CO2 fixation pathways, suggesting autotrophic origins of life.
26. Acetogenesis: Production of acetate from CO2 and H2, which might have played a role in early energy metabolism.

Both Anabolic and Catabolic (as they serve dual purposes in the cell)

27. Central Carbon Metabolism: Including the glycolytic pathway, pentose phosphate pathway, and the TCA cycle, these pathways are fundamental for energy production and the synthesis of precursors for various biomolecules.
28. Lipid Metabolism: Pathways focused on the synthesis, modification, and breakdown of lipids.
29. Nucleotide Degradation and Salvage Pathways: Crucial for recycling and recovering nucleotides.
30. Amino Acid Degradation: Breakdown of amino acids for energy production or conversion to other molecules.
31. Autophagy: The cellular process of breaking down and recycling cellular components.
32. Protein Degradation: Processes for breaking down and recycling proteins.
33. Lysosome Function: Involving the breakdown of cellular materials.
34. DNA Repair Mechanisms: Potential early systems to maintain genetic integrity.


Ancestral enzyme functions determined from consensus LUCA eggNOG clusters mapped onto a universal metabolic network. The consensus LUCA enzyme functions are represented by 169 Enzyme Commission codes. The universal metabolic network and color-coding of metabolic categories are from the global Metabolic Pathways network (map 01100) from the KEGG database (Kanehisa et al., 2017; Ogata et al., 1999). “Metabolism of Other Amino Acids” is terminology that the KEGG database uses to indicate amino acids that are not included in proteins, such as D-amino acids

References

● Srinivasan V, Morowitz HJ (2009). The canonical network of autotrophic intermediary metabolism: minimal metabolome of a reductive chemoautotroph. Biol Bull, 216:126–130. Link. (This paper describes the minimal metabolic network required for a reductive chemoautotroph, offering insights into LUCA's potential metabolic pathways.)
● Weiss MC, Sousa FL, Mrnjavac N, Neukirchen S, Roettger M, Nelson-Sathi S, Martin WF (2016). The physiology and habitat of the last universal common ancestor. Nat Microbiol, 1:16116. Link. (This paper explores the potential physiology and habitat of LUCA, delving into its possible metabolic mechanisms based on extant biochemistry and cell biology.)
● Wimmer, J. L. E., Xavier, J. C., Vieira, A. d. N., Pereira, D. P. H., Leidner, J., Sousa, F. L., Kleinermanns, K., Preiner, M., & Martin, W. F. (2021). Energy at Origins: Favorable Thermodynamics of Biosynthetic Reactions in the Last Universal Common Ancestor (LUCA). Front. Microbiol., 12. Link. (This paper is part of a research topic on the Last Universal Common Ancestor and Origin of Life. It explores the favorable thermodynamics of biosynthetic reactions in the LUCA, shedding light on the energy considerations at the origin of life.)

The Intrinsic Complexity of Minimal Life: Unraveling the Odds

Calculating the odds of forming a proteome with 1,226 proteins, each of an average size of 300 amino acids, purely by random trial and error, is a monumental challenge due to the vastness of the numbers involved. Here's a basic way to think about the odds: Single Protein Formation: Each of the 20 common amino acids has a 1 in 20 chance of being selected for each position in the protein chain. For a protein with a sequence of 300 amino acids, the probability of getting one specific sequence purely by chance is: (1/20) ^300, or 1 in 10^390.  Now, if we consider that we need 1,226 such specific sequences, the odds become even more minuscule: ((1/20)^300)^1,226, or
1 in 10^477,660.

Premise 1: For a functional cell to exist, it requires an intricate and interdependent system of codes, languages, and proteins, with the odds of these systems forming randomly being 1 in 10^477,660.
Premise 2: Probabilities beyond 1 in 10^139 (the maximum number of possible events in a universe that is 13,8 Billion years old (10^16 seconds) where every atom (10^80) is changing its state at the maximum rate of 10^40 times per second is 10^139..
Conclusion: Therefore, the random, unguided formation of a functional cell's interdependent systems in our universe is statistically impossible, suggesting intentional design.




1. Cellular Infrastructure and Integrity

• Membrane Proteins, and Transport: Ensuring nutrient uptake, waste removal, and environmental sensing.
  
• Peptidoglycan Synthesis: Key for structural integrity in some cells.
  
• Families/functions involved in various aspects of cell division in LUCA: Fundamental for reproduction.
  

2. Energy and Metabolism

• Energy Metabolism, Central Carbon Metabolism, and Other Specific Pathways: Driving cellular activities.
  
• One-Carbon Metabolism: A central metabolic pathway.
  
• Fatty Acid and Phospholipid Synthesis in LUCA: Critical for membrane structure and function.
  

3. Information Storage and Processing

• DNA Processing in LUCA: Replication, repair, and recombination.
  
• Gene Expression and Regulation in LUCA: Transcribing DNA into functional RNA molecules.
  
• Transcription/regulation in the LUCA: Ensuring correct gene expression.
  
• Translation/Ribosome in the LUCA: Synthesizing proteins based on RNA templates.
  
• Biosynthesis and Assembly of the Bacterial Ribosome: Critical for protein synthesis.
  

4. Biosynthesis and Nutrient Uptake

• Amino acid biosynthesis: Building blocks for proteins.
  
• Nucleotide Synthesis and Salvage: Building blocks for DNA/RNA.
  
• Polyamine Synthesis: Involved in DNA stabilization and protein synthesis.
  
• Cofactor and Metal Cluster Biosynthesis: Essential for various enzyme functions.
  

5. Regulation and Response Mechanisms

• Epigenetic, manufacturing, signaling, and regulatory codes in LUCA: Adapting to environmental changes and ensuring cellular homeostasis.
  
• Reactive oxygen species (ROS): Handling oxidative stress.
  
• Thermo protection in the LUCA: Protecting against temperature extremes.
  
• Regulatory Enzymes and Proteins in Amino Acid Synthesis: Ensuring metabolic balance.
  
• Proteolysis in the LUCA: Protein degradation and turnover.
  

6. Metals and Metal Clusters

• Metal clusters: Essential for many enzyme functions.
  

7. RNA Dynamics

• RNA: Beyond protein-coding, RNA plays roles in regulation, catalysis, and structural components.
  

Additional Functions:

• Ion Homeostasis and Osmoregulation: Balancing ion concentrations and responding to osmotic stress.
  
• DNA Repair Mechanisms: Maintaining genetic integrity in the face of damage.
  
• Toxin-Antitoxin Systems: Protecting against foreign DNA or controlling cellular processes.
  
• Sensory Systems: Detecting environmental signals and responding appropriately.
  
• Vesicle Formation and Secretion: Interacting with the environment, disposing of waste, or communication.
  

Gene Expression and Regulation in LUCA
Reactive oxygen species (ROS)
Metal clusters
Nucleotide Synthesis and Salvage
Amino acid biosynthesis
Regulatory Enzymes and Proteins in Amino Acid Synthesis
Fatty Acid and Phospholipid Synthesis  in LUCA
One-Carbon Metabolism
RNA
Peptidoglycan Synthesis
Cofactor and Metal Cluster Biosynthesis
Polyamine Synthesis
Energy Metabolism, Central Carbon Metabolism, and Other Specific Pathways
DNA Processing in LUCA
Gene expression and regulation in the LUCA
Transcription/regulation in the LUCA
Translation/Ribosome in the LUCA
Biosynthesis and Assembly of the Bacterial Ribosome
Epigenetic, manufacturing, signaling, and regulatory codes in LUCA
Families/functions involved in various aspects of cell division in LUCA
Thermo protection in the LUCA
Proteolysis in the LUCA
Membrane Proteins, and Transport

● Wimmer, J. L. E., Xavier, J. C., Vieira, A. d. N., Pereira, D. P. H., Leidner, J., Sousa, F. L., Kleinermanns, K., Preiner, M., & Martin, W. F. (2021). Energy at Origins: Favorable Thermodynamics of Biosynthetic Reactions in the Last Universal Common Ancestor (LUCA). Front. Microbiol., 12. Link. (This paper is part of a research topic on the Last Universal Common Ancestor and Origin of Life. It explores the favorable thermodynamics of biosynthetic reactions in the LUCA, shedding light on the energy considerations at the origin of life.)

https://www.frontiersin.org/articles/10.3389/fmicb.2021.793664/full#supplementary-material

Amino Acid Metabolism

Amino Acid Metabolism: Alanine, aspartate, and glutamate metabolism
R01775: Aspartate 1-decarboxylase
R00367: Aspartate-semialdehyde dehydrogenase
R00368: Aspartate-semialdehyde dehydrogenase

Glutamate / Glutamine Biosynthesis:
R00243: Glutamate dehydrogenase ?
R00248: Glutamate dehydrogenase ? 
R00253: Glutamine synthetase

Threonine Biosynthesis:
R01465: Threonine dehydratase
R00751: Threonine aldolase
R01773: Threonine synthase
R01775 Threonine synthase.
R01466 L-serine ammonia-lyase

Glycine / Serine / Alanine Biosynthesis:
R00372: Alanine-glyoxylate aminotransferase
R00945: Serine hydroxymethyltransferase
R00371: Glycine acetyltransferase (2-amino-3-ketobutyrate-forming)
R03759: Aminoacetone reductase

Lysine / Arginine Biosynthesis:
R04336: Lysine-2,3-aminomutase
R07613: Diaminopimelate decarboxylase
R03098: Argininosuccinate lyase

Methionine / Cysteine Biosynthesis:
R03260: Cystathionine gamma-synthase
R01286: Cystathionine beta-lyase
R01777: O-Succinylhomoserine (thiol)-lyase
R00946: Methionine synthase
R10305: Cystathionine gamma-synthase

Aspartate Family Biosynthesis:
R04467: Aspartate-semialdehyde dehydrogenase
R02315: Aspartate kinase
R07407, 
R07410: Aspartate ammonia-lyase

Phenylalanine / Tyrosine Biosynthesis:
R00691: Arogenate dehydratase
R01373: Prephenate dehydratase
R00694: Phenylalanine aminotransferase
R07276: Arogenate dehydratase

Branched-Chain Amino Acid Biosynthesis (Valine, Leucine, Isoleucine):
R00996: Threonine dehydratase
R05070: Dihydroxy-acid dehydratase
R05069: Branched-chain-amino-acid aminotransferase
R08648: Acetolactate synthase
R02199: Acetohydroxyacid synthase
R03898: Methylmalate synthase
R03896: Methylmalate isomerase
R05068: Isopropylmalate isomerase
R01213: 3-Isopropylmalate dehydratase
R04426: Isopropylmalate dehydrogenase
R03968: Isopropylmalate isomerase
R04001: 3-Isopropylmalate dehydratase

Alanine Metabolism
R00258: Alanine transaminase
R00400: Alanine transaminase
R00369: Alanine-glyoxylate transaminase
R00396: Alanine dehydrogenase

Cysteine Metabolism
R00897: Cysteine synthase
R00194: S-Adenosyl-L-homocysteine hydrolase
R01001: Cystathionine gamma-lyase
R12342: Serine phosphatase
R01291: Methylthioadenosine nucleosidase
R07274: Cysteine synthase
R00586: Serine O-acetyltransferase
R01290: Cystathionine beta-synthase

Histidine Biosynthesis
R03012: Histidinol dehydrogenase
R03243: Histidinol-phosphate aminotransferase
R01071: ATP phosphoribosyltransferase
R04035: Ribose-phosphate pyrophosphokinase
R04037: Phosphoribosyl-AMP cyclohydrolase
R04558: Imidazole glycerol phosphate synthase
R01072: Phosphoribosylamine--glycine ligase
R04591: AICAR transformylase
R07404: AIR carboxylase
R04144: GAR transformylase
R01127: IMP cyclohydrolase
R04209: Aminoimidazole ribotide synthase

Lysine Biosynthesis
R01088: Leucine 2,3-aminomutase
R10147: Dihydrodipicolinate synthase
R00271: Homoaconitase
R02733: Diaminopimelate dehydrogenase
R02734: Succinyldiaminopimelate desuccinylase
R04198: Dihydrodipicolinate reductase
R01934: Homoisocitrate dehydrogenase
R00715: Diaminopimelate epimerase
R04199: Tetrahydrodipicolinate N-acetyltransferase
R00451: Diaminopimelate decarboxylase
R02735: Diaminopimelate epimerase
R04475: N-succinyldiaminopimelate aminotransferase
R01939: 2-Aminoadipate transaminase
R03444: Isovaleryl-CoA dehydrogenase
R04371: Homoaconitase
R05578: Glutamyl-tRNA synthetase
R04863, 
R04390, 
R09775-
R09777: 
R09778: LysW-gamma-L-alpha-aminoadipate 6-semialdehyde dehydrogenase
R09779: LysW-gamma-L-lysine hydrolase

Proline and Arginine Metabolism
R03314: Glutamate-5-semialdehyde dehydrogenase
R00667: Ornithine aminotransferase
R01248, 
R01251: Pyrroline-5-carboxylate reductase
R00239: Glutamate kinase
R00582: Phosphoserine phosphatase
R04173: Phosphoserine aminotransferase
R01513: Phosphoglycerate dehydrogenase
R03083: 3-deoxy-7-phosphoheptulonate synthase

Sulfur Amino Acid Metabolism
R05789: Sulfite:pyruvate aminotransferase
R07136: Sulfite dehydrogenase
R05774: Sulfopyruvate decarboxylase
R07476: 3-sulfolactate synthase

Tryptophan Biosynthesis
R00986: Anthranilate synthase I
R00985: Anthranilate synthase II
R01073: Phosphoribosyltransferase
R03508: Anthranilate phosphoribosyltransferase
R02722: Tryptophan synthase (alpha chain)
R03509: Indole-3-glycerol phosphate synthase

Valine Biosynthesis
R04441: Isomerization
R00226: Acetolactate synthase
R01214_1: Branched-chain amino acid aminotransferase
R05071: Ketol-acid reductoisomerase
R04440: Ketol-acid reductoisomerase

Tyrosine and Phenylalanine Biosynthesis
R01302: Chorismate lyase
R00733: Prephenate dehydrogenase
R00732: Prephenate dehydrogenase
R01730: Prephenate dehydrogenase
R01728: Prephenate dehydrogenase
R00734: Arogenate dehydrogenase

Lysine Degradation
R10699: Lysine 6-dehydrogenase

120
=========================

Acetate Biosynthesis
R00315: Acetate kinase
1

Acetyl-CoA Metabolism
R00315: Acetyl phosphate kinase
R00230: Acetyl-CoA synthetase
2

Biotin Metabolism
R03182: Dethiobiotin synthetase
R03231: 8-Amino-7-oxononanoate synthase
R01078: Biotin synthase
R10397: 7,8-Diamino-nonanoate aminotransferase
4 

C1-Compound and Folate Biosynthesis
R04325: Methenyltetrahydrofolate cyclohydrolase
R04559: Formate-tetrahydrofolate ligase
R06975: 10-Formyltetrahydrofolate synthetase
R07405: Methylenetetrahydrofolate reductase
R04560: Serine hydroxymethyltransferase
R04463: Glycinamide ribotide transformylase
6

Carbohydrate Metabolism
R03459: Hexokinase
R00947: Glucose-6-phosphatase
R01788: Phosphoglucomutase
R01070: Phosphofructokinase
R04780: Fructose-bisphosphatase
R00341: Pyruvate kinase
R01518: Enolase
R01015: Triosephosphate isomerase
R00431: Pyruvate kinase (GTP-dependent)
R00658: Enolase
R00959: Phosphoglucomutase
R01512: Phosphoglycerate kinase
R01061: Phosphoglycerate mutase
R01063: Phosphoglycerate mutase
R01602: Isomerase (for glucose isomerization)
15

Carbohydrate Metabolism: Glycolysis / Gluconeogenesis
R00287: Phosphoglycerate kinase
R00288: 3-phosphoglycerate kinase
R00290: Phosphoglycerate mutase
R00283: 2,3-bisphosphoglycerate-independent phosphoglycerate mutase
R00284: 2,3-bisphosphoglycerate-dependent phosphoglycerate mutase
5

Carbohydrate Metabolism: Pentose phosphate pathway
R03098: Ribulose-phosphate 3-epimerase
R02379: Transaldolase
R00289: Phosphoglycerate mutase
R10089: Pyridoxine 5'-phosphate synthase
4

Citric Acid Cycle (TCA Cycle)
R00402: Succinate dehydrogenase
R00344: Pyruvate carboxylase
R00352: ATP citrate lyase
R01322: Citrate synthase
R01325: Aconitase
R00405: Succinyl-CoA synthetase
R00354: Citryl-CoA lyase
R01900: Aconitase
R01082: Fumarase
R00342: Malate dehydrogenase
R00267: Isocitrate dehydrogenase
R01197: Alpha-ketoglutarate dehydrogenase complex
R01196: Pyruvate dehydrogenase complex
R08323: 7-Mercaptoheptanoylthreonine transferase
R08214: Iso-citrate dehydrogenase
R08215: Iso-citrate dehydrogenase
R08328: Oxosuberate decarboxylase
21

Coenzyme A Biosynthesis
R04230: Phosphopantothenoylcysteine synthetase
R02473: Pantothenate kinase
R03269: Phosphopantothenoylcysteine decarboxylase
R03018: Pantothenate kinase
R00130: CoA synthase
R00489: Aspartate decarboxylase
R01214_2: Branched-chain amino acid aminotransferase
R01226: Ketopantoate hydroxymethyltransferase
R03035: CoA synthase
R02472: Ketopantoate reductase
R04439: Acetolactate synthase
R08331: Homoaconitase
R08332: Homoisocitrate dehydrogenase
R08217: Biotin synthase
15

Coenzyme F420 Metabolism
R09399: Coenzyme F420-0—GTP ligase
R09400: Coenzyme F420-1—GTP ligase
R09397: 2-Phospholactate cyclase
R09398: 7,8-Dihydro-8-hydroxy-5-deazariboflavin kinase
4

Fatty Acid Biosynthesis
R00742: Acetyl-CoA carboxylase
R00345: Phosphoenolpyruvate carboxykinase (GTP)
R00206: Pyrophosphate–fructose 6-phosphate 1-phosphotransferase
R01626: Acyl-carrier-protein S-malonyltransferase
R09543: Malonyl-CoA:ACP transacylase
5

Formate Biosynthesis
RMAN4: Formate dehydrogenase
1

Glycolysis/Gluconeogenesis
R00200: Pyruvate kinase
R00199: Pyrophosphate–fructose 6-phosphate 1-phosphotransferase
2

Heme Biosynthesis
R04337: 5-aminolevulinate synthase
R04335: Uroporphyrinogen-III C-methyltransferase
R04331: Uroporphyrinogen-III synthase
R04332: Hydroxymethylbilane synthase
R04333: Uroporphyrinogen decarboxylase
R04336: Coproporphyrinogen-III oxidase
R07613: Protoporphyrinogen oxidase
R03758: Ferrochelatase
8

Iron-Sulfur Cluster Assembly
R07459: Sulfur-carrier protein kinase
R07460: Cysteine desulfurase
R07461: Thiocarboxy-[sulfur-carrier protein] synthase
3

Lipid Metabolism: Glycerophospholipid Metabolism
R00364: Phosphatidate cytidylyltransferase
R00366: Phosphatidate cytidylyltransferase
R00365: Phosphatidate cytidylyltransferase
3

Lipid Metabolism: Steroid Biosynthesis
R01983: Sterol 24-C-methyltransferase
R01981: Squalene monooxygenase
R01982: Lanosterol synthase
3

Menaquinone and Phylloquinone Biosynthesis
R10935: 2-succinyl-5-enolpyruvyl-6-hydroxy-3-cyclohexene-1-carboxylate synthase
R11038: SAM-dependent methyltransferases
R11039: Menaquinone-specific isochorismate synthase
R00736: Tyrosine decarboxylase
R10902: Tyramine:glutamate ligase
R11040: Menaquinone-specific isochorismate synthase
6

Methanogenesis
R09153: Coenzyme M biosynthesis
RMAN1: 4-(beta-D-Ribofuranosyl)phenol phosphatase
RMAN2: Methenyltetrahydromethanopterin cyclohydrolase
R10802: Dihydromethanopterin reductase
RMAN3: Methanofuran biosynthesis
5

Molybdenum Cofactor Biosynthesis
R09394: GTP 3',8-cyclase
R11372: 3',8-Cyclo-7,8-dihydroguanosine 5'-triphosphatase
R09395: Molybdopterin synthase
R09735: Molybdoenzyme molybdenum cofactor synthase
4

NADPH Biosynthesis
R01195: Ferredoxin-NADP+ reductase
1

NADP+ Biosynthesis
R00104: NAD+ kinase
R03005: NAD+ synthase
R03348: Quinolinate phosphoribosyltransferase
3

Nickel-Cofactor Biosynthesis
R11626-R11629: Steps in F430 coenzyme biosynthesis
1

One-Carbon Metabolism
R10243: Methylenetetrahydrofolate reductase
R07168: Methylenetetrahydrofolate reductase
R00943: 10-Formyltetrahydrofolate synthetase
R01655: 5,10-Methenyltetrahydrofolate cyclohydrolase
R01220: Methylenetetrahydrofolate dehydrogenase
R00134: Formate dehydrogenase
R07157: Carbonic anhydrase
7

==========================================

Purine and Pyrimidine Metabolism
R03755: Ribonucleoside-diphosphate reductase
R03756: Ribonucleoside-triphosphate reductase
R03757: Ribonucleotide reductase (thioredoxin)
R04330: Ribonucleotide reductase (glutaredoxin)
4

Purine  Metabolism
R00127: Adenylate kinase
R00253: Guanosine kinase
R00372: Guanine deaminase
R00748: Hypoxanthine-guanine phosphoribosyltransferase
R00754: Purine nucleoside phosphorylase
R00944: Adenosine deaminase
R00947: Purine nucleoside phosphorylase
R01083: Adenylosuccinate lyase
R01135: Adenylosuccinate synthase
R01285: Adenosine kinase
R01286: Guanine deaminase
R01773: Adenine phosphoribosyltransferase
12

Pyrimidine Metabolism

R00573: CTP synthase
R00575: Carbamoyl phosphate synthase
R01867: Dihydroorotate dehydrogenase
R01870: Orotate phosphoribosyltransferase
R01869: Dihydroorotate dehydrogenase
R00965: Orotidylate decarboxylase
R01397: Aspartate carbamoyltransferase
R01993: Dihydroorotase
R00156
R00158: Nucleoside-diphosphate kinase
10

Nucleotide Metabolism
R04148: Nicotinate-nucleotide adenylyltransferase
R04594: Phosphoribosyl-AMP cyclohydrolase
R00177: Methionine adenosyltransferase
R11636: Formate kinase
R02100: dUTPase
R02325: dCTP deaminase
R02101: Thymidylate synthase
R02094: Thymidylate kinase
R02093: Nucleoside-diphosphate kinase
R01130: Inosine monophosphate (IMP) dehydrogenase
R00330: Nucleoside-diphosphate kinase
R00430: Nucleoside-diphosphate kinase (GTP-specific)
R00332: Adenylate kinase
R01230: Adenylosuccinate synthase
R01231: GMP synthase
R01163: Histidinol-phosphate aminotransferase
R03013: Histidinol-phosphatase
R03457: Histidinol dehydrogenase
R04640: Amidophosphoribosyltransferase
19

Nucleotide Turnover
R00333: NDP kinase
1

Nucleotide synthesis 46 enzymes

===================================

Polyketide Biosynthesis
R10115-R10122: Polyketide synthase modules
2

Porphyrin and Chlorophyll Metabolism
R00084: Porphobilinogen synthase
R00036: 5-Aminolevulinate synthase
R02272: Aminolevulinate dehydratase
R04109: Porphyrobilinogen deaminase
R03165: Uroporphyrinogen-III cosynthase
R03194: S-Adenosyl-L-methionine:uroporphyrinogen III methyltransferase
R03947: Sirohydrochlorin chelatase
7

Pyruvate Metabolism
R10866: Pyruvate dehydrogenase (acetyl-transferring)
R10092: Carbonic anhydrase
R00994: Malate dehydrogenase
R07399: Pyruvate carboxylase
4

Redox Reactions involving Ferredoxin
R00019: Hydrogenase
1

Riboflavin Metabolism
R07281: D-Ribulose 5-phosphate 3-epimerase
R04457: Lumazine synthase
R00549: Riboflavin kinase
R00066: Riboflavin synthase
R07280: 6,7-Dimethyl-8-(D-ribityl)lumazine synthase
R00161: FAD synthase
R03458: Riboflavin kinase
7

Shikimate Pathway and Chorismate Biosynthesis
R01714: 5-enolpyruvylshikimate-3-phosphate (EPSP) synthase
R02412: Shikimate kinase
R03460: Phosphoenolpyruvate (PEP) mutase
R03084: 3-Dehydroquinate dehydratase
R02413: 3-Dehydroshikimate dehydrogenase
5

Terpenoid Backbone Biosynthesis
R03099: Hydroxymethylglutaryl-CoA reductase
R03100: Farnesyl diphosphate synthase
R03261: Geranyl diphosphate synthase
3

Tetrahydrofolate and Folate Biosynthesis
R04620, 
R04638, 
R04639, 
R05046: GTP cyclohydrolase I
R03503, 
R03067: Dihydropteroate synthase
R01716: Anthranilate synthase
R11072: Dihydropteroate reductase
R02237: Dihydrofolate synthase
R04621: Dihydrofolate reductase
R00936, 
R11719: 7,8-Dihydroneopterin 3'-triphosphatase
15

Thiamine (Vitamin B1) Biosynthesis
R00617: Thiamine-phosphate kinase
R04509: Hydroxymethylpyrimidine/phosphomethylpyrimidine kinase
R05636: 1-Deoxy-D-xylulose-5-phosphate synthase
R10712: Thiamine-phosphate diphosphorylase
R09977: Thiazole synthase
R03472: Hydroxymethylpyrimidine kinase
R10246: Tyrosine aminomutase
R10247: 1-Deoxy-D-xylulose-5-phosphate:tyrosine aminotransferase
8

Urea Cycle and Metabolism of Amino Groups
R09107: N-Acetyl-L-citrulline hydrolase
R00259: N-Acetylglutamate synthase
R07245: Ornithine carbamoyltransferase
R02283: Acetylornithine aminotransferase
R03443: Acetylglutamate kinase
R02649: Acetylglutamyl-phosphate reductase
R00149: Carbamoyl-phosphate synthase I
R00551: Arginase
R01954: Argininosuccinate synthase
R01398: Ornithine carbamoyltransferase
R01086: Argininosuccinate lyase
R00669: N-Acetylornithine aminotransferase
R00578: Asparagine synthase
R00355: Aspartate transaminase
16

Vitamin B2 (Riboflavin) Metabolism
R05705: FMN reductase
R05706: FMN reductase
2

Vitamin B6 Metabolism
R01829: Pyridoxal 5'-phosphate synthase
R01774: Pyridoxal kinase
R00749: 4-Pyridoxate 5'-phosphate oxidase
R01828: 4-Pyridoxol kinase
R01827: Pyridoxal 5'-phosphate synthase
R07614: Not available up to 2021
R04334: Not available up to 2021
R01778: Pyridoxamine 5'-phosphate oxidase
R01772: Pyridoxal 5'-phosphate synthase
9

Vitamin B12 Metabolism
R05807: Sirohydrochlorin cobaltochelatase
R11580: Cobalt-precorrin-4 C11-methyltransferase
R08716: Precorrin-3B C17-methyltransferase
R05218: Cob(I)yrinate a,c-diamide adenosyltransferase
R05220: Cobyric acid synthase
R05808: Cobaltochelatase
R05809: Cobaltochelatase
R05810: Cobaltochelatase
R07772: Cobaltochelatase
R07773: Cobaltochelatase
R05812: Cobaltochelatase
R07774: Cobaltochelatase
R07775: Cobaltochelatase
R05814: Cobaltochelatase
R05815: Cobaltochelatase
R05225: Cobaltochelatase
R07302: Cobaltochelatase
R06558: Cobaltochelatase
R05221: Cobaltochelatase
R05222: Cobaltochelatase
R05223: Cobaltochelatase
R12161,
R12162: Steps in riboflavin biosynthesis
23 enzymes

Other Reactions
R12026: Unknown enzyme
R10339: Unknown enzyme
R03388: Unknown enzyme
R01771: Homoserine kinase
R10305: Not available up to 2021
R10304: Not available up to 2021
6

403 enzymes - proteins

Energy Metabolism, Central Carbon Metabolism, and Other Specific Pathways: Enzymes/proteins estimate: 74
Fundamental pathways that provide energy and precursors for other biosynthetic processes.

Energy Metabolism, Central Carbon Metabolism, and Other Specific Pathways

Energy Metabolism
====================================================
Methanogenesis
R09153: Coenzyme M biosynthesis
RMAN1: 4-(beta-D-Ribofuranosyl)phenol phosphatase
RMAN2: Methenyltetrahydromethanopterin cyclohydrolase
R10802: Dihydromethanopterin reductase
RMAN3: Methanofuran biosynthesis
5

The Methanogenesis Pathway

Formylmethanofuran Dehydrogenase: EC: 2.3.1.169 
Formylmethanofuran--Tetrahydromethanopterin Formyltransferase: EC: 2.3.1.101 
Methenyltetrahydromethanopterin Cyclohydrolase: EC: 1.5.98.2 
Methylene-Tetrahydromethanopterin Dehydrogenase: EC: 1.2.99.5 
Methylenetetrahydromethanopterin Reductase: EC: 3.5.4.27 
Methyltetrahydromethanopterin--Coenzyme M Methyltransferase: EC: 2.1.1.86 
Coenzyme-B Sulfoethylthiotransferase: EC: 2.8.4.1 
7

====================================================

Glycolysis/Gluconeogenesis
R00200: Pyruvate kinase
R00199: Pyrophosphate–fructose 6-phosphate 1-phosphotransferase
2

Glycolysis Pathway

Hexokinase: EC: 2.7.1.1 
Glucose-6-phosphate isomerase: EC: 5.3.1.9 
Phosphofructokinase: EC: 2.7.1.11 
Fructose-bisphosphate aldolase: EC: 4.1.2.13 
Pyruvate kinase: EC: 2.7.1.40 

Gluconeogenesis Pathway

Pyruvate Carboxylase: EC: 6.4.1.1 
Phosphoenolpyruvate Carboxykinase: EC: 4.1.1.49 
Fructose-bisphosphatase: EC: 3.1.3.11 
Glucose-6-Phosphatase: EC: 3.1.3.9 
9


===================================================

Pyruvate Metabolism
R10866: Pyruvate dehydrogenase (acetyl-transferring)
R10092: Carbonic anhydrase
R00994: Malate dehydrogenase
R07399: Pyruvate carboxylase
4

Pyruvate Metabolism

Pyruvate kinase: EC: 2.7.1.40 
Pyruvate decarboxylase: EC: 4.1.1.1 
Pyruvate, phosphate dikinase: EC: 2.7.9.1 
Phosphoenolpyruvate carboxylase: EC: 4.1.1.31 
Pyruvate ferredoxin oxidoreductase: EC: 1.2.7.1 
5
===================================================

Electron Transport Chain in Prokaryotes (General)
0
NADH dehydrogenase Complex I: EC: 1.6.5.3 
Succinate dehydrogenase Complex II: EC: 1.3.5.1 
Hydrogenase Alternative Complexes: EC: 1.12.1.2 
Quinone Pool: 
Cytochrome bc1 complex Complex III: 
Cytochrome c: 
Cytochrome c oxidase Complex IV: EC: 1.9.3.1 
ATP Synthase (Complex V): EC: 7.1.2.2 

Anaerobic Respiration

Ferredoxin-NADP+ Reductase: EC: 1.18.1.3 
Hydrogenase: EC: 1.97.1.9 
Nitrate Reductase: EC: 1.7.5.2 
Nitrite Reductase: EC: 1.7.2.2 
Nitric Oxide Reductase: EC: 1.7.2.5 
Nitrous Oxide Reductase: EC: 1.7.2.4
Sulfurtransferase: EC: 2.3.1.61 
14

====================================================

Central Carbon Metabolism

Carbohydrate Metabolism: Pentose phosphate pathway
R03098: Ribulose-phosphate 3-epimerase
R02379: Transaldolase
R00289: Phosphoglycerate mutase
R10089: Pyridoxine 5'-phosphate synthase
4

Pentose Phosphate Pathway (PPP)

Oxidative Phase

Glucose-6-phosphate dehydrogenase: EC: 1.1.1.49 
6-Phosphogluconolactonase: EC: 3.1.1.31 
6-Phosphogluconate dehydrogenase: EC: 1.1.1.44 

Non-Oxidative Phase

Transketolase: EC: 2.2.1.1 
Transaldolase: EC: 2.2.1.2 
5

====================================================

Citric Acid Cycle (TCA Cycle)
R00402: Succinate dehydrogenase
R00344: Pyruvate carboxylase
R00352: ATP citrate lyase
R01322: Citrate synthase
R01325: Aconitase
R00405: Succinyl-CoA synthetase
R00354: Citryl-CoA lyase
R01900: Aconitase
R01082: Fumarase
R00342: Malate dehydrogenase
R00267: Isocitrate dehydrogenase
R01197: Alpha-ketoglutarate dehydrogenase complex
R01196: Pyruvate dehydrogenase complex
R08323: 7-Mercaptoheptanoylthreonine transferase
R08214: Iso-citrate dehydrogenase
R08215: Iso-citrate dehydrogenase
R08328: Oxosuberate decarboxylase
21

Citric Acid Cycle (TCA)

Malate Dehydrogenase: EC: 1.1.1.37 
Fumarase: EC: 4.2.1.2 
Aconitase: EC: 4.2.1.3 
Citryl-CoA Lyase: EC: 4.1.3.34 
Citrate Synthase: EC: 2.3.3.1 
Aconitate Hydratase: EC: 4.2.1.3 

reverse Citric Acid Cycle (TCA) and Related

Fumarase: EC: 4.2.1.2 
Pyruvate kinase: EC: 2.7.1.40
Pyruvate, phosphate dikinase: EC: 2.7.9.1 
Phosphoenolpyruvate carboxykinase: EC: 4.1.1.32 
Succinate dehydrogenase: EC: 1.3.5.1 
Isocitrate dehydrogenase: EC: 1.1.1.42 
Citrate synthase: EC: 2.3.3.1 
Aconitase: EC: 4.2.1.3 
Malate dehydrogenase: EC: 1.1.1.37 
Oxoglutarate:ferredoxin oxidoreductase: EC: 1.2.7.3 
16

====================================================

CO2 Fixation
0
R10092: Carbonic anhydrase (EC 4.2.1.1)
1


====================================================
0

Beta-alanine biosynthesis

Aspartate decarboxylase: EC: 4.1.1.11 

Chemosynthesis

Ribulose-bisphosphate carboxylase (RuBisCO): EC: 4.1.1.39
Phosphoglycerate kinase: EC: 2.7.2.3 
Glyceraldehyde-3-phosphate dehydrogenase: EC: 1.2.1.13 
Triosephosphate isomerase: EC: 5.3.1.1 
Aldolase: EC: 4.1.2.13 
Fructose-1,6-bisphosphatase: EC: 3.1.3.11
Glucose-6-phosphate isomerase: EC: 5.3.1.9 
Glucose-6-phosphate dehydrogenase: EC: 1.1.1.49 
8

====================================================

NADPH Biosynthesis
R01195: Ferredoxin-NADP+ reductase
1

NADP+ Biosynthesis
R00104: NAD+ kinase
R03005: NAD+ synthase
R03348: Quinolinate phosphoribosyltransferase
3

NAD Metabolism

NAD+ synthase: EC: 6.3.5.1 
NAD kinase: EC: 2.7.1.23 
Nicotinamide mononucleotide adenylyltransferase: EC: 2.7.7.1 
3
=====================================================

FAD Metabolism
0
FAD synthetase: EC: 2.7.7.2
Riboflavin kinase: EC: 2.7.1.26
NADH-flavin oxidoreductase: EC: 1.5.1.42
3

=====================================================

Nitrogen metabolism
0
Carbon monoxide dehydrogenase: EC: 1.2.99.2 
Nitrogenase: EC: 1.18.6.1
Nitrate reductase: EC: 1.7.99.4 
Nitrite reductase [NO-forming]: EC: 1.7.2.2 
Glutamine synthetase: EC: 6.3.1.2 
Glutamate synthase: EC: 1.4.1.13 
Glutamate dehydrogenase: EC: 1.4.1.2 
Nitric oxide reductase: EC: 1.7.99.7 
Nitrous oxide reductase: EC: 1.7.99.6 
Nitrite reductase [NAD(P)H]: EC: 1.7.1.4 
10

=====================================================

Oxaloacetate Metabolism
0
ATP citrate lyase: EC: 2.3.3.8 
Aconitase: EC: 4.2.1.3 
Succinyl-CoA ligase [ADP-forming]: EC: 6.2.1.5 
3

Pantothenate and CoA Biosynthesis
0
Ketopantoate reductase: EC: 1.1.1.169 
Phosphopantothenoylcysteine decarboxylase: EC: 4.1.1.36 
Phosphopantothenate-cysteine ligase: EC: 6.3.2.5 
3

Phosphonate and Phosphinate Metabolism
0
L-Serine:3-phosphohydroxy-2-aminopropylphosphonate phospho-L-aminotransferase: EC: 2.6.1.115
1

Diaminopimelate Metabolism
0
N-Acetylornithine deacetylase: EC: 3.5.1.16 
N-Succinyl-L,L-diaminopimelic acid desuccinylase: EC: 3.5.1.18 
Aspartate-semialdehyde dehydrogenase: EC: 1.2.1.11 
4-Hydroxy-tetrahydrodipicolinate reductase: EC: 1.17.1.8 
Diaminopimelate epimerase: EC: 5.1.1.7 
Diaminopimelate decarboxylase: EC: 4.1.1.20 
6

Redox Reactions
0
Ferredoxin-NADP+ reductase: EC: 1.18.1.2 
NADH:quinone oxidoreductase: EC: 1.6.5.2 
Succinate dehydrogenase: EC: 1.3.5.1 
3


=================================================

Riboflavin Metabolism
R07281: D-Ribulose 5-phosphate 3-epimerase
R04457: Lumazine synthase
R00549: Riboflavin kinase
R00066: Riboflavin synthase
R07280: 6,7-Dimethyl-8-(D-ribityl)lumazine synthase
R00161: FAD synthase
R03458: Riboflavin kinase
7

Riboflavin Biosynthesis Precursor

3,4-Dihydroxy 2-butanone 4-phosphate synthase: EC: 4.1.99.12 

Riboflavin Biosynthesis

Nicotinate-nucleotide adenylyltransferase: EC: 2.7.7.18 
alpha-Ribazole phosphatase: 
Riboflavin synthase: EC: 2.5.1.9 
Riboflavin biosynthesis protein RibD (EC 3.1.3.104): 
6,7-dimethyl-8-ribityllumazine synthase: EC: 2.5.1.78 
Riboflavin biosynthesis protein RibE: EC: 3.5.4.26 
FMN adenylyltransferase: EC: 2.7.1.26 
Riboflavin biosynthetic protein RibD: EC: 2.1.1.156 
FMN adenylyltransferase: EC: 2.7.7.2 
9

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0

Sulfur Metabolism

(2R)-3-sulfolactate sulfo-lyase: EC: 4.2.1.115 
NAD+-dependent 3-sulfolactate dehydrogenase: EC: 1.1.1.337 
Sulfolactate dehydrogenase:  1.1.1.310 
Cysteine desulfurase: EC: 2.8.1.7 
Sulfate adenylate transferase: EC: 2.7.7.4 
Adenylylsulfate kinase: EC: 2.7.1.25 
Thiosulfate/3-mercaptopyruvate sulfurtransferase: EC: 2.8.1.1 
Sulfate permease:
8

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0

Transaminase Reactions

Branched-chain amino acid aminotransferase: EC: 2.6.1.42 

0

Oxydoreductases

2-Oxoglutarate ferredoxin oxidoreductase: EC: 1.2.7.3
Pyruvate ferredoxin oxidoreductase: EC: 1.2.7.1
Pyruvate ferredoxin oxidoreductase: EC: 1.2.7.1 
NADH:ferredoxin oxidoreductase: EC: 1.18.1.3 
Ferredoxin:NAD+ oxidoreductase: EC: 1.18.1.2 
Acetyl-CoA synthase: EC: 2.3.1.169 
6

0

Tetrapyrrole Biosynthesis (Includes heme, chlorophyll, etc.)

Glutamyl-tRNA reductase: EC: 1.2.1.70
1

47
121

Nucleotide Synthesis and Salvage: Enzymes/proteins estimate: 89
The basis for the generation of genetic information carriers.

Purine and Pyrimidine Metabolism
R03755: Ribonucleoside-diphosphate reductase
R03756: Ribonucleoside-triphosphate reductase
R03757: Ribonucleotide reductase (thioredoxin)
R04330: Ribonucleotide reductase (glutaredoxin)
4

Nucleotide Metabolism
R04148: Nicotinate-nucleotide adenylyltransferase
R04594: Phosphoribosyl-AMP cyclohydrolase
R00177: Methionine adenosyltransferase
R11636: Formate kinase
R02100: dUTPase
R02325: dCTP deaminase
R02101: Thymidylate synthase
R02094: Thymidylate kinase
R02093: Nucleoside-diphosphate kinase
R01130: Inosine monophosphate (IMP) dehydrogenase
R00330: Nucleoside-diphosphate kinase
R00430: Nucleoside-diphosphate kinase (GTP-specific)
R00332: Adenylate kinase
R01230: Adenylosuccinate synthase
R01231: GMP synthase
R01163: Histidinol-phosphate aminotransferase
R03013: Histidinol-phosphatase
R03457: Histidinol dehydrogenase
R04640: Amidophosphoribosyltransferase
19

Nucleotide Turnover
R00333: NDP kinase
1

===========================================================================================================

Nucleotide Synthesis and Salvage

Purine  Metabolism

R00127: Adenylate kinase
R00253: Guanosine kinase
R00372: Guanine deaminase
R00748: Hypoxanthine-guanine phosphoribosyltransferase
R00754: Purine nucleoside phosphorylase
R00944: Adenosine deaminase
R00947: Purine nucleoside phosphorylase
R01083: Adenylosuccinate lyase
R01135: Adenylosuccinate synthase
R01285: Adenosine kinase
R01286: Guanine deaminase
R01773: Adenine phosphoribosyltransferase
12

De novo purine biosynthesis pathway  in LUCA

Ribose-phosphate diphosphokinase (EC 2.7.6.1): EC: 2.7.6.1 Catalyzes the synthesis of PRPP from ribose-5-phosphate and ATP, playing a critical role in nucleotide synthesis in cells.
Amidophosphoribosyl transferase (GPAT) (EC 2.4.2.14): EC: 2.4.2.14 Catalyzes the transfer of an amide group from glutamine to PRPP, which is essential for purine biosynthesis.
Glycinamide ribotide (GAR) transformylase (GART) (EC 2.1.2.2): EC: 2.1.2.2 Catalyzes the synthesis of formylglycinamidine ribonucleotide (FGAR) from PRA and glycine.
Formylglycinamide ribotide (FGAR) amidotransferase (GART) (EC 3.5.4.10): EC: 3.5.4.10 Catalyzes the transfer of a formyl group from N10-formyltetrahydrofolate to FGAR.
Formylglycinamidine ribotide (FGAM) synthetase (GART) (EC 6.3.5.3): EC: 6.3.5.3 Catalyzes the synthesis of FGAM from FGAR, critical in purine biosynthesis.
5-aminoimidazole ribotide (AIR) carboxylase (PurK) (EC 4.1.1.21): EC: 4.1.1.21 Catalyzes the conversion of FGAM to AIR.
5-aminoimidazole-4-(N-succinylocarboxamide) ribotide (SACAIR) synthetase (PurE) (EC 6.3.2.6): EC: 6.3.2.6 Catalyzes the synthesis of SACAIR from AIR.
Carboxyaminoimidazole ribotide (CAIR) mutase (PurK) (EC 5.4.99.18): EC: 5.4.99.18 Catalyzes the conversion of SACAIR to CAIR.
5-aminoimidazole-4-carboxamide ribotide (AICAR) transformylase (PurN) (EC 2.1.2.3): EC: 2.1.2.3 Catalyzes the conversion of CAIR to AICAR.
5-formaminoimidazole-4-carboxamide ribotide (FAICAR) cyclase (PurM) (EC 3.5.4.21): EC: 3.5.4.21 Catalyzes the conversion of AICAR to FAICAR.
IMP cyclohydrolase (PurH) (EC 3.5.4.10): EC: 3.5.4.10 Catalyzes the conversion of FAICAR to inosine monophosphate (IMP).
11

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Pyrimidine Metabolism

[size=12]R00573: CTP synthase
R00575: Carbamoyl phosphate synthase
R01867: Dihydroorotate dehydrogenase
R01870: Orotate phosphoribosyltransferase
R01869: Dihydroorotate dehydrogenase
R00965: Orotidylate decarboxylase
R01397: Aspartate carbamoyltransferase
R01993: Dihydroorotase
R00156
R00158: Nucleoside-diphosphate kinase
10

De novo Pyrimidine Synthesis in LUCA

Carbamoyl phosphate synthetase II (CPSII): EC: 6.3.5.5 Catalyzes the ATP-dependent synthesis of carbamoyl phosphate from glutamine or ammonia and bicarbonate.
Aspartate transcarbamoylase (ATCase): EC: 2.1.3.2 Catalyzes the condensation of carbamoyl phosphate and aspartate to produce N-carbamoylaspartate.
Dihydroorotase (DHOase): EC: 3.5.2.3 Converts N-carbamoylaspartate into dihydroorotate.
Dihydroorotate dehydrogenase (DHODH): EC: 1.3.5.2 Oxidizes dihydroorotate to produce orotate.
Orotate phosphoribosyltransferase (OPRT): EC: 2.4.2.10 Links orotate to 5-phosphoribosyl-1-pyrophosphate (PRPP) to produce orotidine 5'-monophosphate (OMP).
Orotidine 5'-monophosphate decarboxylase (OMPDC): EC: 4.1.1.23 Catalyzes the decarboxylation of OMP to produce uridine 5'-monophosphate (UMP).
Nucleoside monophosphate kinase (UMP/CMP kinase): EC: 2.7.4.14 Phosphorylates UMP to produce uridine 5'-diphosphate (UDP).
Nucleoside diphosphate kinase (NDK): EC: 2.7.4.6 Converts UDP to UTP through phosphorylation.
CTP synthetase (CTPS): EC: 6.3.4.2 Catalyzes the conversion of UTP to CTP using glutamine as the nitrogen source.
9[/size]

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0
??

Adenine (A) Ribonucleotide Biosynthesis

Phosphoribosylaminoimidazole carboxylase (PurE): EC: 4.1.1.21 Converts 5'-phosphoribosyl-5-aminoimidazole (AIR) into 5'-phosphoribosyl-4-carboxy-5-aminoimidazole (CAIR). This enzyme is vital in the de novo purine biosynthesis pathway.
Adenylosuccinate synthetase (PurA): EC: 6.3.4.4 Synthesizes adenylosuccinate from IMP and aspartate. It plays a key role in the synthesis of adenine nucleotides.
Adenylosuccinate lyase (PurB): EC: 4.3.2.2 Cleaves adenylosuccinate into AMP and fumarate. This reaction helps to regulate adenine nucleotide pools within cells.

Guanine (G) Ribonucleotide Biosynthesis

IMP dehydrogenase (IMPDH): EC: 1.1.1.205 Oxidizes IMP, producing xanthosine monophosphate (XMP). Critical for the purine biosynthesis pathway, ensuring proper DNA and RNA synthesis.
GMP synthetase (GuaA): EC: 6.3.5.2 Converts XMP into GMP using glutamine as a nitrogen source. This enzyme aids in the production of guanine nucleotides.

Uracil (U) Ribonucleotide Biosynthesis (leading to UMP)

Carbamoyl phosphate synthetase II (CPSII): EC: 6.3.4.16 Synthesizes carbamoyl phosphate. This enzyme initiates pyrimidine biosynthesis in cells.
Aspartate transcarbamoylase (ATCase): EC: 2.1.3.2 Produces N-carbamoylaspartate from carbamoyl phosphate and aspartate. A crucial enzyme in pyrimidine biosynthesis.
Dihydroorotase (DHOase): EC: 3.5.2.3 Converts N-carbamoylaspartate to dihydroorotate. An important step in the production of pyrimidine nucleotides.
Dihydroorotate dehydrogenase (DHODH): EC: 1.3.3.1 Produces orotate by oxidizing dihydroorotate. This enzyme is a key player in pyrimidine biosynthesis.
Orotate phosphoribosyltransferase (OPRT): EC: 2.4.2.10 Links orotate to PRPP, yielding orotidine 5'-monophosphate (OMP). It provides a connection between orotate and the ribose phosphate backbone.
Orotidine 5'-monophosphate decarboxylase (OMPDC): EC: 4.1.1.23 Converts OMP into UMP. This reaction represents the last step in the synthesis of the pyrimidine nucleotide UMP.

Cytosine (C) Ribonucleotide Biosynthesis (leading to CTP from UTP)

Nucleoside monophosphate kinase (UMP/CMP kinase): EC: 2.7.4.14 Converts UMP to UDP. This is a pivotal step in nucleotide biosynthesis and is essential for RNA and DNA synthesis.
Nucleoside diphosphate kinase (NDK): EC: 2.7.4.6 Phosphorylates UDP, producing UTP. This enzyme plays a critical role in maintaining the nucleotide pool inside the cell.
CTP synthetase (CTPS): EC: 6.3.4.2 Transforms UTP to CTP using glutamine as a nitrogen source. It is essential for RNA synthesis and phospholipid biosynthesis.

Thymine (T) Deoxyribonucleotide Biosynthesis (leading to dTMP from dUMP):

Ribonucleotide reductase (RNR): EC: 1.17.4.1 Converts NDPs (nucleoside diphosphates) into dNDPs (deoxynucleoside diphosphates), providing the necessary deoxyribonucleotides for DNA synthesis.
Dihydrofolate reductase (DHFR): EC: 1.5.1.3 Reduces dihydrofolate to tetrahydrofolate. Tetrahydrofolate is crucial in various cellular reactions, including nucleotide biosynthesis.
Thymidylate synthase (TYMS or TS): EC: 2.1.1.45 Methylates dUMP to produce dTMP using methyl-tetrahydrofolate as a methyl donor. After donating its methyl group, the methyl-tetrahydrofolate becomes dihydrofolate. This enzyme is critical in ensuring the integrity of DNA replication and repair.

Deoxynucleotide Biosynthesis:

ADP to dADP: EC: 1.17.4.1 Converts adenosine diphosphate (ADP) to deoxyadenosine diphosphate (dADP). Essential for producing the DNA building block, dADP.
CDP to dCDP: EC: 1.17.4.1 Converts cytidine diphosphate (CDP) to deoxycytidine diphosphate (dCDP). Vital for producing the DNA building block, dCDP.
GDP to dGDP: EC: 1.17.4.1 Converts guanosine diphosphate (GDP) to deoxyguanosine diphosphate (dGDP). Critical for producing the DNA building block, dGDP.
UDP to dUDP: EC: 1.17.4.1 Converts uridine diphosphate (UDP) to deoxyuridine diphosphate (dUDP). Fundamental for producing the DNA building block, dUDP.


Nucleoside Diphosphate Kinase (NDK)  (EC 2.7.4.6) Activity in dNDP Phosphorylation:
NDK: EC: 2.7.4.6 Converts deoxyadenosine diphosphate (dADP) to deoxyadenosine triphosphate (dATP). Ensures an ample supply of dATP for DNA synthesis.
NDK: EC: 2.7.4.6 Converts deoxyguanosine diphosphate (dGDP) to deoxyguanosine triphosphate (dGTP). Ensures an ample supply of dGTP for DNA synthesis.
NDK: EC: 2.7.4.6 Converts deoxyuridine diphosphate (dUDP) to deoxyuridine triphosphate (dUTP). Ensures an ample supply of dUTP for DNA synthesis.
NDK: EC: 2.7.4.6 Converts deoxycytidine diphosphate (dCDP) to deoxycytidine triphosphate (dCTP). Ensures an ample supply of dCTP for DNA synthesis.

dUTPase (dUTP pyrophosphatase): EC: 3.6.1.23 Converts deoxyuridine triphosphate (dUTP) to deoxyuridine monophosphate (dUMP) and pyrophosphate (PPi). This enzyme is crucial for maintaining the integrity of DNA by preventing the misincorporation of uracil.


Supporting Enzymes and Transporters for the De Novo Purine and Pyrimidine Biosynthesis Pathway in LUCA

Nucleotide Biosynthesis and Transport:

ATP-binding cassette (ABC) transporters: Use ATP hydrolysis to transport various molecules across cellular membranes.
Adenine phosphoribosyltransferase (APRT): EC: 2.4.2.7 Transforms adenine into adenine monophosphate (AMP).
Hypoxanthine-guanine phosphoribosyltransferase (HGPRT): EC: 2.4.2.8 Converts hypoxanthine to inosine monophosphate (IMP) and guanine to guanosine monophosphate (GMP).
Glutamine transporters: Transport glutamine into cells, crucial for nucleotide biosynthesis.
Tetrahydrofolate (THF) and its derivatives: Essential for transferring single carbon units in biosynthesis.
S-adenosylmethionine (SAM) transporters: SAM, a methyl donor, participates in various methylation reactions.
Amino acid synthetases: Synthesize amino acids, crucial for protein formation.
Nucleotidases: Regulate cellular nucleotide pools by hydrolyzing nucleotide monophosphates, diphosphates, or triphosphates.
Dihydrofolate reductase: EC: 1.5.1.3 Converts dihydrofolate (DHF) into tetrahydrofolate (THF).
Purine Transporters: Facilitate the transport of purine bases or nucleosides.
Pyrimidine Transporters: Facilitate the movement of pyrimidine bases or nucleosides.
Phosphate Transporters: Facilitate the uptake of inorganic phosphate, essential for ATP synthesis.
Ribose/Deoxyribose Transporters: Ensure the transport of ribose and deoxyribose, crucial for RNA and DNA synthesis, respectively.

Magnesium transporters 

Magnesium transporters (Mgt): Primary active transport proteins responsible for the uptake of magnesium in modern organisms.
CorA: A conserved magnesium transporter family that facilitates passive magnesium ion flow, suggesting LUCA may have had a CorA precursor for magnesium regulation.
Magnesium efflux systems: Mechanisms that maintain magnesium homeostasis by expelling excess magnesium, though specifics in LUCA remain speculative.
Magnesium-binding proteins: Proteins that store or use magnesium, assisting in buffering intracellular magnesium concentrations.
Magnesium-sensing proteins: Proteins that detect magnesium levels, indicating the possibility that LUCA might have had an early version of these sensors.
Enzymatic cofactors: Enzymes that rely on magnesium as a cofactor, affecting intracellular magnesium distribution and stability.
RNA structures: Ribosomal RNA and tRNA structures, likely present in LUCA, that use magnesium ions for stabilization and intracellular magnesium regulation.

Amino Acid Transporters in LUCA

Amino Acid Antiporters: Transport proteins exchanging one type of amino acid from inside the cell with another from the environment, utilizing secondary transport mechanisms.
Amino Acid/H+ Symporters: Responsible for the co-transport of an amino acid and a proton into the cell, leveraging ion gradients for nutrient movement.
ATP-binding Cassette (ABC) Amino Acid Transporters: Primary active transporters using ATP hydrolysis to move amino acids across the cell membrane.
Passive Diffusion: The process by which smaller, neutral amino acids might diffuse passively through the cell membrane based on concentration gradients.

Nucleotide Transporters in LUCA

Nucleotide Antiporters: Transporters exchanging one type of nucleotide from inside the cell with another from the environment, helping maintain nucleotide balance.
Nucleotide/H+ Symporters: Responsible for the co-transport of nucleotides and protons, using ion gradients for movement against concentration gradients.
ATP-binding Cassette (ABC) Nucleotide Transporters: Primary transporters moving nucleotides across the cell membrane through ATP hydrolysis
Nucleotide-specific Channels: Facilitate passive diffusion of specific nucleotides based on concentration gradients.
Vesicular Transport: Encloses nucleotides in vesicles for transport to required cell regions.
Nucleoside Transporters: Essential for recycling nucleosides, which are phosphorylated to regenerate nucleotides.
P4-ATPases: ATPases involved in the translocation of specific nucleotides across membranes.
Facilitated Diffusion Nucleotide Transporters: Allow nucleotides to move down their concentration gradient, aiding their spread within the cell.

Nucleoside Transporters in LUCA

Concentrative Nucleoside Transporters (CNTs): Sodium-coupled symporters that move nucleosides against their concentration gradient.
Equilibrative Nucleoside Transporters (ENTs): Facilitate passive diffusion of nucleosides down their concentration gradient.
ATP-binding Cassette (ABC) Nucleoside Transporters: Use ATP hydrolysis for the active transport of nucleosides.
Nucleoside/H+ Symporters: Co-transport nucleosides with protons, leveraging the proton motive force.
Nucleoside Antiporters: Exchange nucleosides between the cell's interior and exterior.
Vesicular Nucleoside Transport: Transport nucleosides via endocytosis or within cellular vesicles.
Specific Channel-formed Nucleoside Transporters: Allow selective diffusion of specific nucleosides.
Nucleoside-specific Pore-forming Proteins: Create membrane pores designed for passive nucleoside transport.

Phosphate Transporters in LUCA

PiT Family Transporters: Sodium-phosphate co-transporters for inorganic phosphate and sodium ions.
Pst Phosphate Transport System: An ABC transporter complex specialized for inorganic phosphate uptake.
Pho89 Sodium-Phosphate Transporter: A sodium-dependent transporter for inorganic phosphate uptake in certain organisms.
Low Affinity Phosphate Transporters: Uptake phosphate when abundant externally.
High Affinity Phosphate Transporters: Capture minimal available phosphate during scarcity.
Phosphate Antiporters: Exchange internal phosphate with external anions.
Phosphate/H+ Symporters: Use proton motive force for active phosphate uptake against its gradient.
Vesicular Phosphate Transport: Internalize phosphate compounds via endocytosis.
Passive Phosphate Channels: Allow passive phosphate diffusion when its external concentration is high.

Folate Transporters in LUCA

Folate-Binding Protein (FBP) Transporters: Bind folates with high affinity and facilitate their transport.
Proton-Coupled Folate Transporter (PCFT): Uptake of folate, especially in acidic pH conditions.
Reduced Folate Carrier (RFC): Transports reduced folates into cells for folate homeostasis.
Multidrug Resistance Protein (MRP) Transporters: Some transport folate compounds besides their primary drug resistance role.
Folate Receptors (FRs): Bind folate and related compounds for uptake via endocytosis.
ABC Transporters: Some members transport folate or its analogs.

SAM Transporters in LUCA

SAM Transporter (SAMT): Transport SAM across cellular membranes.
ABC Transporters: Some transport SAM among other molecules.
Solute Carrier Family Transporters: Some transport SAM, speculative role in LUCA.
Multidrug Resistance Proteins (MRPs): Some transport SAM and related compounds.
Vesicular Transport Mechanisms: SAM transported in vesicles for various enzymatic reactions.

Carbon Source Transporters in LUCA

Glucose/Galactose Transporter (GLUT): Uptake of glucose for pathways like glycolysis.
ABC Glucose Transporters: Actively transport glucose against concentration gradients.
Hexose Transporter (HXT): Uptake of hexoses like glucose for nucleotide precursor pathways.

Amino Acid Precursors for Nucleotide Synthesis Transporters in LUCA

Glutamine Transporters: Uptake of glutamine for nucleotide synthesis.
Aspartate Transporters: Uptake of aspartate for pyrimidine synthesis.
Glycine Transporters (GlyT): Uptake of glycine for purine synthesis.

Co-factor Transporters for Nucleotide Synthesis in LUCA

Vitamin B6 Transporters: Uptake of Vitamin B6, a co-factor for nucleotide metabolism.
Tetrahydrofolate (THF) Transporters: Uptake of THF for nucleotide synthesis.

Ion Transporters in LUCA with Relevance to Nucleotide Synthesis

Potassium (K+) Transporters: Maintain proper intracellular potassium concentration, crucial for enzymes in nucleotide metabolism.
Zinc (Zn2+) Transporters: Ensure intracellular availability of zinc, a key cofactor for enzymes in nucleotide biosynthesis.

RNA Recycling:

RNA Phosphatases:

RNA 3'-terminal phosphate cyclase (EC 3.1.3.43) - Catalyzes the conversion of RNA 3'-phosphate ends to cyclic 2',3'-phosphates.

Ribonucleases:

RNase II: EC: 3.1.26.4 Degrades RNA into nucleotide monophosphates. RNase II is a highly processive 3' to 5' exoribonuclease involved in RNA turnover and degradation. It plays a crucial role in maintaining RNA homeostasis within bacterial cells.
RNase R: EC: 3.1.26.3 An exoribonuclease known to degrade RNA in a 3' to 5' direction. It has the ability to degrade structured RNA molecules, making it essential for various cellular functions including the quality control of ribosomal RNA (rRNA) and the turnover of messenger RNA (mRNA).

Exoribonucleases:

Exoribonuclease II: EC: 3.1.13.4 Degrades RNA from the 3' end.
Exoribonuclease III: EC: 3.1.13.1 Involved in RNA degradation.

DNA Recycling:

DNA Phosphatases:

Polynucleotide 5'-phosphatase: EC: 3.1.4.47 Hydrolyzes the 5'-phosphate of single-stranded DNA.

Deoxyribonucleases:

Deoxyribonuclease I: EC: 3.1.11.2 Hydrolyzes DNA to produce deoxynucleotide monophosphates.

Exonucleases:

Exonuclease III: EC: 3.1.11.1 Involved in DNA degradation.
Exonuclease I: EC: 3.1.11.1 Degrades single-stranded DNA from the 3' end.

Endonucleases:

Endonuclease IV: EC: 3.1.21.2 Participates in DNA repair and degradation.
100



46
120

Amino acid biosynthesis

Glycine / Serine / Alanine Biosynthesis:
R00372: Alanine-glyoxylate aminotransferase
R00945: Serine hydroxymethyltransferase
R00371: Glycine acetyltransferase (2-amino-3-ketobutyrate-forming)
R03759: Aminoacetone reductase

Alanine Metabolism

R00258: Alanine transaminase
R00400: Alanine transaminase
R00369: Alanine-glyoxylate transaminase
R00396: Alanine dehydrogenase
8

Serine Synthesis:

Phosphoserine phosphatase: EC: 3.1.3.3 An 
Phosphoserine aminotransferase: EC: 2.6.1.52 

Glycine Synthesis 

Serine hydroxymethyltransferase: EC: 2.1.2.1 
Glycine decarboxylase (P Protein): EC: 1.4.4.2 
Aminomethyltransferase (T Protein): EC: 2.1.2.10 
Glycine cleavage system H protein (H Protein): 
Dihydrolipoyl dehydrogenase (L Protein): EC: 1.8.1.4 

Alanine Metabolism

Aspartate 4-decarboxylase: EC: 4.1.1.12 
Alanine transaminase: EC: 2.6.1.2 
Alanine-glyoxylate transaminase: EC: 2.6.1.44 
Alanine dehydrogenase: EC: 1.4.1.1 
Alanine racemase: EC: 5.1.1.1 
12


==========================================================

Cysteine Metabolism
R00897: Cysteine synthase
R00194: S-Adenosyl-L-homocysteine hydrolase
R01001: Cystathionine gamma-lyase
R12342: Serine phosphatase
R01291: Methylthioadenosine nucleosidase
R07274: Cysteine synthase
R00586: Serine O-acetyltransferase
R01290: Cystathionine beta-synthase
8

Cysteine Metabolism

Serine O-acetyltransferase: EC: 2.3.1.30 
Cysteine synthase: EC: 2.5.1.47 
Methionine adenosyltransferase: EC: 2.5.1.6 
S-Adenosylhomocysteine hydrolase: EC: 3.3.1.1 
Cystathionine gamma-synthase: EC: 2.5.1.48 
5


==========================================================

Valine Biosynthesis
R04441: Isomerization
R00226: Acetolactate synthase
R01214_1: Branched-chain amino acid aminotransferase
R05071: Ketol-acid reductoisomerase
R04440: Ketol-acid reductoisomerase
5

Valine biosynthesis

Acetolactate synthase: EC: 2.2.1.6 
Acetohydroxy acid isomeroreductase: EC: 1.1.1.86 
Dihydroxyacid dehydratase: EC: 4.2.1.9 
Branched-chain amino acid aminotransferase: EC: 2.6.1.42 
4


==========================================================

Branched-Chain Amino Acid Biosynthesis (Valine, Leucine, Isoleucine):
R00996: Threonine dehydratase
R05070: Dihydroxy-acid dehydratase
R05069: Branched-chain-amino-acid aminotransferase
R08648: Acetolactate synthase
R02199: Acetohydroxyacid synthase
R03898: Methylmalate synthase
R03896: Methylmalate isomerase
R05068: Isopropylmalate isomerase
R01213: 3-Isopropylmalate dehydratase
R04426: Isopropylmalate dehydrogenase
R03968: Isopropylmalate isomerase
R04001: 3-Isopropylmalate dehydratase
13

Leucine Biosynthesis in Bacteria (precursors same as Valine)

Acetolactate synthase: EC: 2.2.1.6 
Dihydroxy-acid dehydratase: EC: 4.2.1.9 
3-isopropylmalate synthase: EC: 2.3.3.13 
3-isopropylmalate dehydratase: EC: 4.2.1.33 
3-isopropylmalate dehydrogenase: EC: 1.1.1.85 
Branched-chain amino acid aminotransferase: EC: 2.6.1.42 

Isoleucine Metabolism (from Threonine):

Threonine deaminase: EC: 4.3.1.19 
3-methyl-2-oxobutanoate hydroxymethyltransferase: EC: 2.1.2.11 
3-isopropylmalate dehydratase: EC: 4.2.1.33 
3-isopropylmalate dehydrogenase: EC: 1.1.1.85 
10
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Histidine Biosynthesis
R03012: Histidinol dehydrogenase
R03243: Histidinol-phosphate aminotransferase
R01071: ATP phosphoribosyltransferase
R04035: Ribose-phosphate pyrophosphokinase
R04037: Phosphoribosyl-AMP cyclohydrolase
R04558: Imidazole glycerol phosphate synthase
R01072: Phosphoribosylamine--glycine ligase
R04591: AICAR transformylase
R07404: AIR carboxylase
R04144: GAR transformylase
R01127: IMP cyclohydrolase
R04209: Aminoimidazole ribotide synthase
12

Histidine Synthesis

Phosphoribosylamine--glycine ligase: EC: 6.3.4.13 
Phosphoribosylformylglycinamidine synthase: EC: 6.3.5.3 
Phosphoribosylformylglycinamidine cyclo-ligase: EC: 6.3.3.1 
Phosphoribosylformimino-5-amino-1-(5-phosphoribosyl)imidazolecarboxamide isomerase (EC 5.3.1.16): 
Imidazoleglycerol-phosphate synthase (EC 4.1.3.15): 
Imidazoleglycerol-phosphate hydrolase (EC 3.13.1.5): 
Histidinol-phosphate aminotransferase (EC 2.6.1.9):
Histidinol-phosphate phosphatase (EC 3.1.3.15)
Histidinol dehydrogenase: EC: 1.1.1.23 
Histidine ammonia-lyase: EC: 4.3.1.3 
10


==================================================================

Phenylalanine / Tyrosine Biosynthesis:
R00691: Arogenate dehydratase
R01373: Prephenate dehydratase
R00694: Phenylalanine aminotransferase
R07276: Arogenate dehydratase
R01302: Chorismate lyase
R00733: Prephenate dehydrogenase
R00732: Prephenate dehydrogenase
R01730: Prephenate dehydrogenase
R01728: Prephenate dehydrogenase
R00734: Arogenate dehydrogenase
10

Phenylalanine/Tyrosine Synthesis pathway

Chorismate mutase: EC: 5.4.99.5 

For Tyrosine synthesis

Prephenate dehydrogenase: EC: 1.3.1.12 
4-Hydroxyphenylpyruvate dioxygenase: EC: 1.13.11.27 
Homogentisate 1,2-dioxygenase: EC: 1.13.11.5 

For Phenylalanine synthesis

Prephenate aminotransferase: EC: 2.6.1.78 
Arogenate dehydratase: EC: 4.2.1.91 
6


==================================================================

Tryptophan Biosynthesis
R00986: Anthranilate synthase I
R00985: Anthranilate synthase II
R01073: Phosphoribosyltransferase
R03508: Anthranilate phosphoribosyltransferase
R02722: Tryptophan synthase (alpha chain)
R03509: Indole-3-glycerol phosphate synthase
6

Tryptophan Synthesis

Chorismate pyruvate-lyase: EC: 4.2.99.21 
Anthranilate phosphoribosyltransferase: EC: 2.4.2.18 
Phosphoribosylanthranilate isomerase: EC: 5.3.1.24 
Indole-3-glycerol-phosphate synthase: EC: 4.1.1.48 
Tryptophan synthase: EC: 4.2.1.20 
5


=================================================================

Aspartate Family Biosynthesis:
R04467: Aspartate-semialdehyde dehydrogenase
R02315: Aspartate kinase
R07407, 
R07410: Aspartate ammonia-lyase
R01775: Aspartate 1-decarboxylase
R00367: Aspartate-semialdehyde dehydrogenase
R00368: Aspartate-semialdehyde dehydrogenase
7

Aspartate Metabolism

Aspartate transaminase: EC: 2.6.1.1 
Aspartate carbamoyltransferase: EC: 2.1.3.2 
Aspartokinase: EC: 2.7.2.4 
Adenylosuccinate synthase: EC: 6.3.4.4 
4
=================================================================

0
??

Asparagine Metabolism

Asparagine synthetase: EC: 6.3.5.4 
Asparaginase: EC: 3.5.1.1 
Asparagine aminotransferase: EC: 2.6.1.14 

=================================================================

Methionine  Biosynthesis:
R03260: Cystathionine gamma-synthase
R01286: Cystathionine beta-lyase
R01777: O-Succinylhomoserine (thiol)-lyase
R00946: Methionine synthase
R10305: Cystathionine gamma-synthase
5

Methionine Metabolism

Homoserine dehydrogenase: EC: 1.1.1.3 
O-succinylhomoserine (thiol)-lyase: EC: 2.5.1.48 
Cystathionine beta-lyase: EC: 4.4.1.8 
Methionine synthase: EC: 2.1.1.13 
Methylthiotransferase: EC: 2.8.4.4 
5


=======================================================================

Lysine Biosynthesis
R01088: Leucine 2,3-aminomutase
R10147: Dihydrodipicolinate synthase
R00271: Homoaconitase
R02733: Diaminopimelate dehydrogenase
R02734: Succinyldiaminopimelate desuccinylase
R04198: Dihydrodipicolinate reductase
R01934: Homoisocitrate dehydrogenase
R00715: Diaminopimelate epimerase
R04199: Tetrahydrodipicolinate N-acetyltransferase
R00451: Diaminopimelate decarboxylase
R02735: Diaminopimelate epimerase
R04475: N-succinyldiaminopimelate aminotransferase
R01939: 2-Aminoadipate transaminase
R03444: Isovaleryl-CoA dehydrogenase
R04371: Homoaconitase
R05578: Glutamyl-tRNA synthetase
R04863, 
R04390, 
R09775-
R09777: 
R09778: LysW-gamma-L-alpha-aminoadipate 6-semialdehyde dehydrogenase
R09779: LysW-gamma-L-lysine hydrolase
22
Lysine / Arginine Biosynthesis:
R04336: Lysine-2,3-aminomutase
R07613: Diaminopimelate decarboxylase
R03098: Argininosuccinate lyase
3

Lysine Biosynthesis

D-Erythrose 4-phosphate (E4P): This molecule, derived from the pentose phosphate pathway, is one of the initial precursors.
Phosphoenolpyruvate (PEP): Originating from glycolysis, PEP is another crucial starting material.

Dihydrodipicolinate synthase: EC: 4.2.1.52 
Dihydrodipicolinate reductase: EC: 1.3.1.26 
2,3,4,5-tetrahydropyridine-2,6-dicarboxylate N-succinyltransferase (EC: 2.3.1.117)
2,3,4,5-tetrahydropyridine-2,6-dicarboxylate N-acetyltransferase (EC: 2.3.1.89)
Diaminopimelate reductase: EC: 1.3.1.26 
Diaminopimelate epimerase: EC: 5.1.1.7 
Diaminopimelate decarboxylase: EC: 4.1.1.20 
9
========================================================================

Threonine Biosynthesis:
R01465: Threonine dehydratase
R00751: Threonine aldolase
R01773: Threonine synthase
R01775 Threonine synthase.
R01466 L-serine ammonia-lyase
5

Threonine Metabolism

Aspartokinase: EC: 2.7.2.4 
Aspartate-semialdehyde dehydrogenase: EC: 1.2.1.11 Oxidizes L-aspartate-semialdehyde to L-homoserine. Critical for the synthesis of threonine.
Homoserine dehydrogenase: EC: 1.1.1.3 
Homoserine kinase: EC: 2.7.1.39 
Threonine synthase: EC: 4.2.3.1 
5


=========================================================================

Glutamate / Glutamine Biosynthesis:
R00243: Glutamate dehydrogenase ?
R00248: Glutamate dehydrogenase ? 
R00253: Glutamine synthetase
3

Glutamine/Glutamate Synthesis

Glutamate dehydrogenase (NAD+): EC: 1.4.1.2 
Glutamate dehydrogenase (NADP+): EC: 1.4.1.4 
Glutamate 5-kinase: EC: 2.7.2.11 
Glutamine synthetase: EC: 6.3.1.2 
Glutamine-dependent NAD+ synthetase: EC: 6.3.5.1 
5
=========================================================================

Proline and Arginine Metabolism
R03314: Glutamate-5-semialdehyde dehydrogenase
R00667: Ornithine aminotransferase
R01248, 
R01251: Pyrroline-5-carboxylate reductase
R00239: Glutamate kinase
R00582: Phosphoserine phosphatase
R04173: Phosphoserine aminotransferase
R01513: Phosphoglycerate dehydrogenase
R03083: 3-deoxy-7-phosphoheptulonate synthase
9

Proline Metabolism in Prokaryotes

Ornithine carbamoyltransferase: EC: 2.1.3.3 
Ornithine decarboxylase: EC: 4.1.1.17 
Acetylornithine deacetylase: EC: 3.5.1.16 
Proline dehydrogenase: EC: 1.5.5.2 
Pyrroline-5-carboxylate reductase: EC: 1.5.1.2 

Arginine/Ornithine Synthesis

N-acetylglutamate synthase: EC: 2.3.1.1 
N-acetylglutamate kinase: EC: 2.7.2.8 - 
N-acetyl-gamma-glutamyl-phosphate reductase: EC: 1.2.1.38 
Acetylornithine aminotransferase: EC: 2.6.1.11 

Ornithine carbamoyltransferase: EC: 2.1.3.3 
Argininosuccinate synthase: EC: 6.3.4.5 
Argininosuccinate lyase: EC: 4.3.2.1 
L-Glutamate: 
L-Citrulline: 
Ornithine: 
15


==========================================================

Sulfur Amino Acid Metabolism
R05789: Sulfite:pyruvate aminotransferase
R07136: Sulfite dehydrogenase
R05774: Sulfopyruvate decarboxylase
R07476: 3-sulfolactate synthase

Lysine Degradation
R10699: Lysine 6-dehydrogenase
6

=========================================================

Nicotinate and Nicotinamide Metabolism

Nicotinamidase: EC: 3.5.1.19 
Nicotinate phosphoribosyltransferase: EC: 2.4.2.11 
Quinolinate phosphoribosyltransferase: EC: 2.4.2.19 
Nicotinate-nucleotide pyrophosphorylase [carboxylating]: EC: 2.4.2.19 
Nicotinamide phosphoribosyltransferase: EC: 2.4.2.12 
Nicotinamide riboside kinase: EC: 2.7.1.173 
Nicotinate-nucleotide adenylyltransferase: EC: 2.7.7.18 
NAD+ synthase: EC: 6.3.5.1 
NR 5'-phosphate adenylyltransferase: EC: 2.7.7.1 
Nicotinate dehydrogenase: EC: 1.17.1.5 
NADH pyrophosphatase: EC: 3.6.1.22 
11


Amino Acid degradation

Alanine Degradation

Alanine dehydrogenase: EC: 1.4.1.1 

Arginine Degradation

Arginase: EC: 3.5.3.1 

Asparagine Degradation

Asparaginase: EC: 3.5.1.1 
Asparagine aminotransferase: EC: 2.6.1.14 

Aspartate Degradation

Aspartate transaminase: EC: 2.6.1.1 
Aspartate carbamoyltransferase: EC: 2.1.3.2 
Aspartokinase (EC 2.7.2.4)  

Cysteine Degradation

O-succinylhomoserine (thiol)-lyase: EC: 2.5.1.48 

Glutamate Degradation

Glutamate synthase: EC: 1.4.1.13 
Glutaminase: EC: 3.5.1.2 
Glutamate dehydrogenase: EC: 1.4.1.3 

Glutamine Degradation

Glutaminase (EC 3.5.1.2) 

Glycine Degradation

Glycine cleavage system: EC: 1.4.4.2, EC: 1.8.1.4, EC: 2.1.2.10 
Serine hydroxymethyltransferase: EC: 2.1.2.1 

Histidine Degradation

Histidinol-phosphate phosphatase (EC 3.1.3.15)
Histidinol dehydrogenase (EC 1.1.1.23)
Histidine ammonia-lyase (EC 4.3.1.3)

Isoleucine Degradation:

Threonine deaminase (EC 4.3.1.19)

Leucine Degradation

3-isopropylmalate dehydratase: EC: 4.2.1.33 
3-isopropylmalate dehydrogenase: EC: 1.1.1.85 

Lysine Degradation

Diaminopimelate epimerase: EC: 5.1.1.7 
Diaminopimelate decarboxylase: EC: 4.1.1.20 

Methionine Degradation

Homoserine dehydrogenase: EC: 1.1.1.3 

Phenylalanine Degradation

Arogenate dehydratase: EC: 4.2.1.91 

Proline Degradation

Pyrroline-5-carboxylate reductase: EC: 1.5.1.2 
Proline dehydrogenase: EC: 1.5.5.2 

Serine Degradation

Serine hydroxymethyltransferase: EC: 2.1.2.1

Tryptophan Degradation

Tryptophanase: EC: 4.1.99.1 

Tyrosine Degradation

Tyrosine phenol-lyase: EC: 4.1.99.2 


Regulatory Enzymes and Proteins in Amino Acid synthesis

Amino Acid Transaminases:

Methionine Transaminase: EC: 2.6.1.40 
Alanine Transaminase: EC: 2.6.1.2 
Aspartate Transaminase: EC: 2.6.1.1 
Glutamate-pyruvate Transaminase: EC: 2.6.1.2 
Glutamate-oxaloacetate Transaminase: EC: 2.6.1.1 
Phenylalanine Transaminase: EC: 2.6.1.79 
Tyrosine Transaminase: EC: 2.6.1.5 
Tryptophan Transaminase: EC: 2.6.1.7 
Glutamate--pyruvate Transaminase: EC: 2.6.1.2 
Alanine--glyoxylate Transaminase: EC: 2.6.1.44
Serine--glyoxylate Transaminase: EC: 2.6.1.43 
Cysteine--glyoxylate Transaminase: EC: 2.6.1.23 

Amino Acid Dehydrogenases:

Alanine Dehydrogenase: EC: 1.4.1.1 
Glutamate Dehydrogenase: EC: 1.4.1.3 
Tyrosine Dehydrogenase
Tryptophan Dehydrogenase
Lysine Dehydrogenase
Proline Dehydrogenase: EC: 1.5.99.8
Phenylalanine Dehydrogenase
Leucine Dehydrogenase
Arginase: EC: 3.5.3.1 
Arginine Deiminase
Glutamine Synthetase: EC: 6.3.1.2 
Alanine--glyoxylate Transaminase 2
Alanine--glyoxylate Transaminase 1

Amino Acid Kinases:

Alanine Kinase: EC: 2.7.1.29 
Aspartate Kinase: EC: 2.7.2.4 
Glutamate Kinase: EC: 2.7.2.11 
Phenylalanine Kinase: EC: 2.7.1.40 
Tyrosine Kinase: EC: 2.7.1.40 
Isoleucine Kinase: EC: 2.7.1.40 
Leucine Kinase: EC: 2.7.1.40 
Arginine Kinase: EC: 2.7.3.3 
Methionine Kinase: EC: 2.7.1.40 
Proline Kinase: EC: 2.7.2.11 
Tryptophan Kinase: EC: 2.7.1.40 
Cysteine Kinase: EC: 2.7.1.40 
Glycine Kinase: EC: 2.7.1.40 
Histidine Kinase: EC: 2.7.13.3
Serine Kinase: EC: 2.7.1.40
Threonine Kinase: EC: 2.7.1.40 
Lysine Kinase: EC: 2.7.1.40 

Amino Acid Transporters:

Alanine Transporter
Aspartate Transporter
Glutamate Transporter
Phenylalanine Transporter
Tyrosine Transporter
Isoleucine Transporter
Leucine Transporter
Arginine Transporter
Methionine Transporter
Proline Transporter
Tryptophan Transporter
Cysteine Transporter
Lysine Transporter
Histidine Transporter
Serine Transporter
Threonine Transporter
Glycine Transporter
Valine Transporter
Glutamine Transporter
Serine/Glycine Transporter
Cystine Transporter
Glutamate/Glutamine Transporter
Ornithine Transporter
Diaminopimelate Transporter
94

122
200

Biotin Metabolism

R03182: Dethiobiotin synthetase
R03231: 8-Amino-7-oxononanoate synthase
R01078: Biotin synthase
R10397: 7,8-Diamino-nonanoate aminotransferase
4 

Biotin Biosynthesis

Biotin is crucial for numerous cellular processes, especially in the synthesis of fatty acids. The provided pathways and enzymes illustrate the typical steps involved in biotin's biosynthesis, utilization, and recycling.

Synthesis:

Lysine 6-aminotransferase: EC: 2.6.1.36 - Conversion of lysine to 2,6-diaminopimelate.
7,8-Diaminononanoate synthase: EC: 6.3.1.25 - Synthesis of 7,8-diaminononanoate.
7,8-Diaminononanoate synthase (biotin synthesis): EC: 6.3.1.25 - Another instance in biotin synthesis.
Dethiobiotin synthetase: EC: 6.3.3.3 - Formation of dethiobiotin from 7,8-diaminononanoate.
Biotin synthase: EC: 2.8.1.6 - Conversion of dethiobiotin to biotin.

Utilization of Biotin:

Acetyl-CoA carboxylase: EC: 6.4.1.2 - Utilizes biotin to carboxylate acetyl-CoA to malonyl-CoA.

Recycling and Conversion of Biotin:

Biotinidase: EC: 3.5.1.76 Hydrolyzes biocytin to release biotin for recycling.
Biotinidase: EC: 3.5.1.76 - Hydrolyzes biocytin to release biotin for recycling.
8

======================================================================

Thiamine (Vitamin B1) Biosynthesis

R00617: Thiamine-phosphate kinase
R04509: Hydroxymethylpyrimidine/phosphomethylpyrimidine kinase
R05636: 1-Deoxy-D-xylulose-5-phosphate synthase
R10712: Thiamine-phosphate diphosphorylase
R09977: Thiazole synthase
R03472: Hydroxymethylpyrimidine kinase
R10246: Tyrosine aminomutase
R10247: 1-Deoxy-D-xylulose-5-phosphate:tyrosine aminotransferase
8

Vitamin B6 Metabolism
R01829: Pyridoxal 5'-phosphate synthase
R01774: Pyridoxal kinase
R00749: 4-Pyridoxate 5'-phosphate oxidase
R01828: 4-Pyridoxol kinase
R01827: Pyridoxal 5'-phosphate synthase
R07614: Not available up to 2021
R04334: Not available up to 2021
R01778: Pyridoxamine 5'-phosphate oxidase
R01772: Pyridoxal 5'-phosphate synthase
9

Vitamin B2 (Riboflavin) Metabolism
R05705: FMN reductase
R05706: FMN reductase
2

Riboflavin Biosynthesis

Riboflavin, also known as vitamin B2, is an essential nutrient for all living organisms. It plays a crucial role as the precursor of the coenzymes flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD). These coenzymes are vital for a wide range of biological processes

Nicotinate-nucleotide adenylyltransferase: EC: 2.7.7.18 Catalyzes the formation of deamido-NAD and AMP from nicotinate mononucleotide.
alpha-Ribazole phosphatase: Involved in the dephosphorylation of alpha-ribazole.
Riboflavin synthase: EC: 2.5.1.9 Catalyzes the conversion of two molecules of 6,7-dimethyl-8-ribityllumazine to riboflavin.
Riboflavin biosynthesis protein RibD (EC 3.1.3.104): Has both deaminase and reductase activities involved in riboflavin synthesis.
6,7-dimethyl-8-ribityllumazine synthase: EC: 2.5.1.78 Catalyzes the formation of 6,7-dimethyl-8-ribityllumazine, a direct precursor to riboflavin.
Riboflavin biosynthesis protein RibE: EC: 3.5.4.26 Converts 5-amino-6-(5-phospho-D-ribitylamino)uracil into 5-amino-6-(5-phospho-D-ribosylamino)uracil.
FMN adenylyltransferase: EC: 2.7.1.26 Catalyzes the conversion of FMN and ATP to FAD and pyrophosphate.
Riboflavin biosynthetic protein RibD: EC: 2.1.1.156 Involved in the synthesis of 5-amino-6-(5-phospho-D-ribitylamino)uracil.
FMN adenylyltransferase: EC: 2.7.7.2 Another enzyme that catalyzes the conversion of FMN and ATP to FAD and pyrophosphate.
9


=========================================================================================

Vitamin B12 (cobalamin)

Vitamin B12 Metabolism
R05807: Sirohydrochlorin cobaltochelatase
R11580: Cobalt-precorrin-4 C11-methyltransferase
R08716: Precorrin-3B C17-methyltransferase
R05218: Cob(I)yrinate a,c-diamide adenosyltransferase
R05220: Cobyric acid synthase
R05808: Cobaltochelatase
R05809: Cobaltochelatase
R05810: Cobaltochelatase
R07772: Cobaltochelatase
R07773: Cobaltochelatase
R05812: Cobaltochelatase
R07774: Cobaltochelatase
R07775: Cobaltochelatase
R05814: Cobaltochelatase
R05815: Cobaltochelatase
R05225: Cobaltochelatase
R07302: Cobaltochelatase
R06558: Cobaltochelatase
R05221: Cobaltochelatase
R05222: Cobaltochelatase
R05223: Cobaltochelatase
R12161,
R12162: Steps in riboflavin biosynthesis
23 enzymes

Synthesis of cobalamin: 

Cobyrinic acid a,c-diamide adenosyltransferase: EC: 2.5.1.17 - Catalyzes the adenylation of cobyrinic acid a,c-diamide. This enzyme plays a role in cobalamin (vitamin B12) biosynthesis.
Cobyrinic acid a,c-diamide synthase: EC: 6.3.5.10 - Catalyzes the formation of cobyrinic acid a,c-diamide, a precursor in cobalamin biosynthesis.
Cob(II)yrinate a,c-diamide reductase: EC: 1.3.7.17 - Involved in the reduction of Cob(II)yrinate a,c-diamide, an intermediate step in cobalamin synthesis.
Adenosylcobyrinate a,c-diamide amidohydrolase: EC: 3.5.1.90 - Catalyzes the amidohydrolysis of adenosylcobyrinate a,c-diamide.
Adenosylcobinamide kinase: EC: 2.7.1.156 - Catalyzes the phosphorylation of adenosylcobinamide, a crucial reaction in cobalamin biosynthesis.
Adenosylcobinamide phosphate guanylyltransferase: EC: 2.7.7.62 - Catalyzes adenosylcobinamide-phosphate guanylylation, which is vital for cobalamin synthesis.
Cobalamin biosynthetic protein CobS: Part of cobalamin biosynthesis.
Adenosylcobinamide-GDP ribazoletransferase: Involved in the transfer of ribazole from GDP-ribazole to adenosylcobinamide, an essential step in cobalamin synthesis.
Adenosylcobinamide kinase/adenosylcobinamide phosphate guanylyltransferase: EC: 2.7.1.156, EC: 2.7.7.62 - Catalyzes both the phosphorylation and guanylylation of adenosylcobinamide.
Adenosylcobinamide-phosphate synthase: EC: 2.7.8.25 - Catalyzes the formation of adenosylcobinamide-phosphate, a precursor in cobalamin biosynthesis.
CobU, 
CobT, 
CobO: All are involved in cobalamin biosynthesis, playing vital roles in the conversion of intermediates to active cobalamin forms.
Cobaltochelatase: EC: 4.99.1.3 - Catalyzes the insertion of cobalt into the corrin ring, an essential step for the maturation of cobalamin.
Cobalt-factor III methyltransferase: EC: 2.1.1.272 - Methylates cobalt-factor III.
Cobalt-precorrin-4 methyltransferase: EC: 2.1.1.271 - Methylates cobalt-precorrin-4.
Cobalt-precorrin-5A hydrolase: EC: 3.7.1.12 - Hydrolyzes cobalt-precorrin-5A.
Cobalt-precorrin-5B methyltransferase: EC: 2.1.1.195 - Methylates cobalt-precorrin-5B.
Cobalt-precorrin-6A reductase: EC: 1.3.1.54 - Reduces cobalt-precorrin-6A.
Cobalt-precorrin-6B methyltransferase: EC: 2.1.1.210 - Methylates cobalt-precorrin-6B.
Cobalt-precorrin-6X reductase: EC: 1.3.1.76 - Reduces cobalt-precorrin-6X.
Cobalt-precorrin-7 (C15)-methyltransferase: EC: 2.1.1.211 - Methylates cobalt-precorrin-7 at the C15 position.
Cobalt-precorrin-8 methyltransferase: EC: 2.1.1.271 - Methylates cobalt-precorrin-8.
Cobalt-precorrin-8X methylmutase: Involved in the methylation of cobalt-precorrin-8X.
Cobinamide amidohydrolase: EC: 3.5.1.90 - Hydrolyzes cobinamide.
Cobinamide kinase: EC: 2.7.1.156 - Phosphorylates cobinamide.
Cobinamide phosphate guanylyltransferase: EC: 2.7.7.62 - Guanylylates cobinamide-phosphate.
Hydrogenobyrinic acid a,c-diamide synthase: EC: 6.3.5.10 - Synthesizes hydrogenobyrinic acid a,c-diamide.
Hydrogenobyrinic acid a,c-diamide corrinoid adenosyltransferase: Involved in the adenylation of hydrogenobyrinic acid a,c-diamide.
Hydrogenobyrinic acid-binding periplasmic protein: Binds to hydrogenobyrinic acid in the periplasmic space.
Precorrin-2 dehydrogenase: EC: 1.3.1.76 - Catalyzes the dehydrogenation of precorrin-2.
Precorrin-3B synthase: EC: 1.14.13.83 - Catalyzes the formation of precorrin-3B.
Precorrin-6Y methyltransferase: EC: 2.1.1.131 - Methylates precorrin-6Y.
Precorrin-6B synthase: EC: 1.14.13.83 - Catalyzes the formation of precorrin-6B.

Utilization and conversion: 

Cobyrinic acid a,c-diamide synthase: Essential for cobalamin biosynthesis.
Cob(II)yrinate a,c-diamide reductase: Part of the cobalamin biosynthesis pathway.
Adenosylcobyrinate a,c-diamide amidohydrolase: Further processing of cobalamin precursors.
Adenosylcobinamide kinase/adenosylcobinamide phosphate guanylyltransferase: Essential for the formation of the cobalamin coenzyme.
url=https://www.uniprot.org/uniprot/?query=Cobalamin+biosynthetic+protein+CobS&sort=score]Cobalamin biosynthetic protein CobS[/url]: Crucial for the final steps of cobalamin biosynthesis.
Cobalamin biosynthetic protein CobU: Key enzyme in the cobalamin biosynthesis pathway.

Cobalamin recycling

Cob(I)alamin adenosyltransferase: Catalyzes the conversion of cob(I)alamin to adenosylcobalamin.
Cobalamin reductase: Converts cob(II)alamin to cob(I)alamin, which is crucial for the activation of cobalamin.
Methylcobalamin--homocysteine methyltransferase: Uses methylcobalamin as a cofactor to convert homocysteine to methionine, releasing cob(I)alamin.
Ribonucleotide triphosphate reductase: Uses adenosylcobalamin as a cofactor and is part of the cobalamin recycling process.
44


One-Carbon Metabolism

[size=12]One-Carbon Metabolism
R10243: Methylenetetrahydrofolate reductase
R07168: Methylenetetrahydrofolate reductase
R00943: 10-Formyltetrahydrofolate synthetase
R01655: 5,10-Methenyltetrahydrofolate cyclohydrolase
R01220: Methylenetetrahydrofolate dehydrogenase
R00134: Formate dehydrogenase
R07157: Carbonic anhydrase
7

Folate

C1-Compound and Folate Biosynthesis
R04325: Methenyltetrahydrofolate cyclohydrolase
R04559: Formate-tetrahydrofolate ligase
R06975: 10-Formyltetrahydrofolate synthetase
R07405: Methylenetetrahydrofolate reductase
R04560: Serine hydroxymethyltransferase
R04463: Glycinamide ribotide transformylase
6

Tetrahydrofolate and Folate Biosynthesis
R04620, 
R04638, 
R04639, 
R05046: GTP cyclohydrolase I
R03503, 
R03067: Dihydropteroate synthase
R01716: Anthranilate synthase
R11072: Dihydropteroate reductase
R02237: Dihydrofolate synthase
R04621: Dihydrofolate reductase
R00936, 
R11719: 7,8-Dihydroneopterin 3'-triphosphatase
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This list provides a comprehensive look into the core metabolic enzymes related to folate metabolism in chemolithoautotrophic organisms.

Folate Synthesis:

Dihydropteroate synthase (DHPS): Involved in the synthesis of 7,8-dihydropteroate from p-aminobenzoate and 6-hydroxymethyl-7,8-dihydropteroate.
Folylpolyglutamate synthase (FPGS): Catalyzes the addition of glutamate residues to folates.
Dihydrofolate synthase: Converts 7,8-dihydropteroate to dihydrofolate (DHF).

Utilization of Tetrahydrofolate (THF) Derivatives:

Methenyltetrahydrofolate cyclohydrolase (MTHFC): EC: 3.5.4.9 Converts 5,10-methenyltetrahydrofolate to 10-formyltetrahydrofolate.
Methylenetetrahydrofolate reductase (MTHFR): Converts 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate.
Methenyltetrahydrofolate synthetase (MTHFS): Converts 5,10-methylenetetrahydrofolate to 5,10-methenyltetrahydrofolate.
5,10-Methenyltetrahydrofolate cyclohydrolase: EC: 3.5.4.9 Converts 5,10-methenyltetrahydrofolate to 5,10-methylenetetrahydrofolate.

Recycling and Conversion of Tetrahydrofolate (THF):

Dihydrofolate reductase (DHFR): Converts dihydrofolate (DHF) to tetrahydrofolate (THF).
Serine hydroxymethyltransferase (SHMT): Catalyzes the conversion of serine and THF.
Methylene tetrahydrofolate dehydrogenase (MTHFD): Catalyzes the interconversion of forms of THF.

Other Related Enzymes in Folate Metabolism:

5,10-Methenyltetrahydrofolate cyclohydrolase / 5,10-methylenetetrahydrofolate dehydrogenase.
Glycinamide ribonucleotide formyltransferase (GARFT): Converts glycinamide ribonucleotide (GAR) to formylglycinamide ribonucleotide (FGAR).
10-formyltetrahydrofolate dehydrogenase: Converts 10-formyltetrahydrofolate to CO2, THF, and NADP+.
Methylene tetrahydrofolate dehydrogenase (NADP+).


Methanogenesis (relevant for archaea):

Methyl-coenzyme M reductase: EC: 2.8.4.1 Key enzyme in methane production in certain archaea.
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S-Adenosylmethionine (SAM) Metabolism

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Synthesis of S-Adenosylmethionine (SAM):

Methionine adenosyltransferase (MAT): EC: 2.5.1.6 Converts methionine and ATP to S-adenosylmethionine (SAM).
Methylenetetrahydrofolate reductase (MTHFR): Converts 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, which donates a methyl group to homocysteine in the synthesis of methionine.
Betaine-homocysteine methyltransferase (BHMT): EC: 2.1.1.5 Utilizes betaine as a methyl donor to convert homocysteine to methionine.
Cystathionine β-synthase (CBS): EC: 4.2.1.22 Converts homocysteine to cystathionine as part of the transsulfuration pathway.

Utilization of Tetrahydrofolate (THF) Derivatives:

Methenyltetrahydrofolate cyclohydrolase (MTHFC): Converts 5,10-methenyltetrahydrofolate to 10-formyltetrahydrofolate.
Methylenetetrahydrofolate reductase (MTHFR): As mentioned above.
Methenyltetrahydrofolate synthetase (MTHFS): Converts 5,10-methylenetetrahydrofolate to 5,10-methenyltetrahydrofolate.
5,10-Methenyltetrahydrofolate cyclohydrolase: Converts 5,10-methenyltetrahydrofolate to 5,10-methylenetetrahydrofolate.

Recycling and Conversion of Tetrahydrofolate (THF):

Dihydrofolate reductase (DHFR): Converts dihydrofolate (DHF) to tetrahydrofolate (THF).
Serine hydroxymethyltransferase (SHMT): Catalyzes the conversion of serine and THF.
Folylpolyglutamate synthase (FPGS): Adds glutamate residues to folates.
Methylenetetrahydrofolate reductase (MTHFR): As mentioned above.
Methylene tetrahydrofolate dehydrogenase (MTHFD): Catalyzes the interconversion of forms of THF.

Central enzymes and transporters related to the methionine cycle and SAM/SAH metabolism:

Methionine adenosyltransferase (MAT) (EC 2.5.1.6): Converts methionine and ATP to SAM.
S-adenosylhomocysteine hydrolase (SAHH) (EC 3.3.1.1): Hydrolyzes S-adenosylhomocysteine to adenosine and homocysteine.
Methionine synthase (MS) (EC 2.1.1.13): Uses a methyl group from 5-methyltetrahydrofolate to convert homocysteine to methionine.

Methyl transfer with S-adenosylmethionine (SAM):

S-adenosylmethionine (SAM): Principal methyl donor in the cell.
S-adenosylhomocysteine hydrolase: EC: 3.3.1.1 Regenerates homocysteine and adenosine from S-adenosylhomocysteine.
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Carbon Monoxide Dehydrogenase (CODH)


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Synthesis:
CO Dehydrogenase/Acetyl-CoA Synthase (CODH/ACS): EC: 1.2.7.4 Involved in the Wood-Ljungdahl pathway, fixes CO and CO2 to produce acetyl-CoA, crucial for autotrophic growth.
Recycling and Conversion:
Carbon Monoxide Dehydrogenase (CODH): EC: 1.2.99.2 Oxidizes CO to CO2, playing a significant role in carbon cycling.
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Formate

Formate Biosynthesis
RMAN4: Formate dehydrogenase
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Synthesis and Utilization:

Formate--tetrahydrofolate ligase: EC: 6.3.4.3 Catalyzes the reversible conversion of formate and tetrahydrofolate to 10-formyltetrahydrofolate, an essential intermediate in purine biosynthesis.
Methenyltetrahydrofolate cyclohydrolase: EC: 3.5.4.9 Involved in the biosynthesis of 5,10-methylenetetrahydrofolate, a critical coenzyme in various one-carbon transfer reactions.
Methenyltetrahydrofolate synthetase: EC: 6.3.4.3 Converts formyltetrahydrofolate to methenyltetrahydrofolate in the folate biosynthesis pathway.
10-Formyltetrahydrofolate synthetase: EC: 6.3.4.3 Catalyzes the conversion of formate and tetrahydrofolate to 10-formyltetrahydrofolate, a crucial step in purine biosynthesis.
Formate dehydrogenase: EC: 1.2.1.2 Catalyzes the oxidation of formate to carbon dioxide and couples it with the reduction of an electron acceptor (e.g., NAD+).

Recycling and Conversion:

Formate dehydrogenase: EC: 1.2.1.2 Also involved in the reverse reaction, converting carbon dioxide to formate during anaerobic respiration.[/size]
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