How Cellular Enzymatic and Metabolic networks point to design

How Cellular Enzymatic and Metabolic networks  point to design

https://reasonandscience.catsboard.com/t2371-how-cellular-enzymatic-and-metabolic-networks-point-to-design

The development of the metabolic system, which, as the primordial soup thinned, must have "learned" to mobilize chemical potential and to synthesize the cellular components, poses Herculean problems.
J.Monod Chance and Necessity: An Essay on the Natural Philosophy of Modern Biology 1972

1. Cells contain high information content that directs and controls integrated metabolic pathways which if altered are inevitably damaged or destroy their function. They also require regulation and are structured in a cascade manner, similar to electronic circuit boards.
2. There is always an observable consequence if a circuit is interrupted. Since these consequences are always catastrophically bad, flexibility is minimal, and since the circuits are all interconnected, the whole network partakes in the quality that there is only one way for things to work. ( Davidson)
3. Naturalistic mechanisms or undirected causes do not suffice to explain the origin and set up of information (instructional prescribing complex information), integrated complex circuits with little tolerance of change.
4. There is no way to write the code for all the enzymes unless one knows the 3D shapes of the substrates they act upon, and one can't know this unless one sees "the big picture" of the context within which and WHY they are needed for each life-essential product (or the final end products would not be produced), it becomes very clear that believing it could "evolve" without deliberate planning, foreknowledge, etc. stretches plausibility, reason, and logic, to say the least. Therefore, intelligent design constitutes the best explanation for the origin of these systems.


The argument of an intelligent designer required to set up the Metabolic Networks for the origin of life 

Observation: The existence of metabolic pathways is crucial for molecular and cellular function.  Although bacterial genomes differ vastly in their sizes and gene repertoires, no matter how small, they must contain all the information to allow the cell to perform many essential (housekeeping) functions that give the cell the ability to maintain metabolic homeostasis, reproduce, and evolve, the three main properties of living cells. Gil et al. (2004)  In fact, metabolism is one of the most conserved cellular processes. By integrating data from comparative genomics and large-scale deletion studies, the paper "Structural analyses of a hypothetical minimal metabolism" propose a minimal gene set comprising 206 protein-coding genes for a hypothetical minimal cell. The paper lists 50 enzymes/proteins required to create a metabolic network implemented by a hypothetical minimal genome for the hypothetical minimal cell. The  50 enzymes/proteins, and the metabolic network, must be fully implemented to permit a cell to keep its basic functions.
  
Hypothesis (Prediction): The origin of biological irreducible metabolic pathways that also require regulation and which are structured like a cascade, similar to electronic circuit boards,  are best explained by the creative action of an intelligent agent.

Experiment: Experimental investigations of metabolic networks indicate that they are full of nodes with enzymes/proteins, detectors, on/off switches, dimmer switches, relay switches, feedback loops etc. that require for their synthesis information-rich, language-based codes stored in DNA. Hierarchical structures have been proved to be best suited for capturing most of the features of metabolic networks (Ravasz et al, 2002). It has been found that metabolites can only be synthesized if carbon, nitrogen, phosphor, and sulfur and the basic building blocks generated from them in central metabolism are available.

 This implies that regulatory networks gear metabolic activities to the availability of these basic resources.  So one metabolic circuit depends on the product of other products, coming from other, central metabolic pathways, one depending on the other, like in a cascade.  Further noteworthy is that Feedback loops have been found to be required to regulate metabolic flux and the activities of many or all of the enzymes in a pathway.  In many cases, metabolic pathways are highly branched, in which case it is often necessary to alter fluxes through part of the network while leaving them unaltered or decreasing them in other parts of the network (Curien et al., 2009). These are interconnected in a functional way, resulting in a living cell. The biological metabolic networks are exquisitely integrated, so the significant alterations in inevitably damage or destroys the function. Changes in flux often require changes in the activities of multiple enzymes in a metabolic sequence. Synthesis of one metabolite typically requires the operation of many pathways.

Conclusion: Regardless of its initial complexity, self-maintaining chemical-based metabolic life could not have emerged in the absence of a genetic replicating mechanism ensuring the maintenance, stability, and diversification of its components. In the absence of any hereditary mechanisms, autotrophic reaction chains would have come and gone without leaving any direct descendants able to resurrect the process. Life as we know it consists of both chemistry and information.   If metabolic life ever did exist on the early Earth, to convert it to life as we know it would have required the emergence of some type of information system under conditions that are favorable for the survival and maintenance of genetic informational molecules. ( Ribas de Pouplana, Ph.D.)





Progress in dissecting signaling pathways has begun to layout a circuitry that will likely mimic electronic integrated circuits in complexity and finesse, where transistors are replaced by proteins (e.g., kinases and phosphatases) and the electrons by phosphates and lipids. […] Two decades from now, having fully charted the wiring diagrams of every cellular signaling pathway, it will be possible to layout the complete ‘integrated circuit of the cell’ upon its current outline. We will then be able to apply the tools of mathematical modeling to explain how specific genetic lesions serve to reprogram this integrated circuit in each of the constituent cell types so as to manifest cancer. ( Hanahan and Weinberg, 20 0 0 , p. 59, 67)



Intelligent agents have frequently end goals in mind and use high levels of instructional complex information to meet the goal. In our experience, systems storing large amounts of specified/instructional complex information through codes and languages -- invariably originate from an intelligent source.  Likewise, circuits or networks of coordinated interaction as for example of analog electronic devices can always be traced back to an intelligent causal agent. The operation of analog electronic devices maps very closely to the flow of information in chemical reactions of metabolic pathways (McAdams and Shapiro, 1995). A proposed mechanism to make metabolical networks  must be capable of construct de novo, not merely modifying, a minimal set of 50  enzymes, and complex integrated metabolic circuits with the end goal  to create life. A metabolic network that is not fully operational, will not permit life.  We know in our experience that intelligence is able to setup  circuit  boards, like discrete electronic boards, and is the  only known cause of irreducibly complex machines. Since evolution depends on metabolic circuits fully setup,  its excluded as possible mechanism. The only two alternatives, chance/luck or physical necessity have never been observed to be able to setup circuit boards and irreducible complex systems.  The origin of the basic metabolical network of the first cells is therefore best explained through the action of a intelligent agency. 

 
The existence of metabolic pathways is crucial for molecular and cellular function.   In fact, metabolism is one of the most conserved cellular processes; it is recognized that very little is known about how the chemistry of primitive enzymes arose (Perez-Jimenez et al, 2011) and which were the first enzymes appearing. Building a new living cell  requires not just new genes and proteins, but at least nine different metabolic networks which are essential, and irreducible In this paper, a minimum of 14 sets are mentioned :

https://repositorio-aberto.up.pt/bitstream/10216/62065/1/000149653.pdf

These are highly complex multibranched, noded anabolic, metabolic and catabolic systems, which are functionally critical, and  individually  not able to  turn a cell alive. Furthermore, metabolic networks support growth, the synthesis or turnover of storage compounds, or the accumulation of metabolites that have a role in coping with abiotic or biotic stress . Metabolism has been divided into discrete pathways, but we know now that it operates as a highly integrated network (Sweetlove et al., 2008). Metabolites are not synthesized in isolation from each other; rather, large sets of metabolites must be synthesized simultaneously. Hierarchical structures have been proved to be best suited for capturing most of the features of metabolic networks (Ravasz et al, 2002) Metabolites can only be synthesized if carbon, nitrogen, phosphor, and sulfur and the basic building blocks generated from them in central metabolism are available. This implies that regulatory networks gear metabolic activities to the availability of these basic resources.  So one metabolic circuit depends on the product of other products, coming from other, central metabolic pathways, one depending from the other, like in a casacade.  Further noteworthy is that Feedback loops are required to regulate metabolic flux, and the activities of many or all of the enzymes in a pathway.  In many cases, metabolic pathways are highly branched, in which case it is often necessary to alter fluxes through part of the network while leaving them unaltered or decreasing them in other parts of the network (Curien et al., 2009). One of the most basic principles of engineering is the principle of constraints. Engineers have long understood that the more functionally integrated a system is, the more difficult it is to change any part of it without damaging or destroying the system as a whole. The biological metabolic networks  are  exquisitely integrated, so the significant alterations in  inevitably damage or destroys the funcion. ( S.C.Meyer, Darwin's Doubt ) Changes in flux often require changes in the activities of multiple enzymes in a metabolic sequence. Synthesis of one metabolite typically requires the operation of many pathways. All of them have to be present in the first living cell,  correctly interconnected and noded to provide function, internal and external communication,  and the biosynthesis of various essential products and parts. These are circuits or networks of coordinated interaction, much like integrated circuits on a circuitboard. Metabolic networks work like electric circuits. The operation of analog electronic devices maps very closely to the flow of information in chemical reactions (McAdams and Shapiro, 1995). Life could not emerge without it. A proposed mechanism must be capable of constructing, not merely modifying, complex integrated metabolic circuits. The requirements for constructing the first living cells de novo cannot be done through evolution, since evolution depends on these basic initial networks,  fully operational. And since there is no function for a unfinished metabolic network, then how could it ever emerge ? The only two mechanisms that remain to explain its origin if intelligent design is excluded,  is chance/luck/self organisation, or physical necessity. We know of intelligence being able to construct electric circuits all the time, and even self replicating machines ( even if only experimentally , since extremely complex ). We do not know of lucky accidents with the same capacity, nor physical needs or physical/chemical laws. We can infer therefore confidently, that the origin of metabolic networks to create the first living cell was most probably designed.

To setup of a cell metabolic network, many different proteins/enzymes are required, correctly interconnected to provide function. Yet the individual enzymes or physical/chemical laws  do not contain by themself the information  of how to  connect and interwine in the correct order that result in a functional metabolic circuit.   Furthermore, the mechanism must be capable of construct from zero, not merely modifying, complex integrated circuits. The requirements for constructing the first living cells  cannot be explained through evolution, since evolution depends on these networks fully operational.  These are circuits or networks of coordinated interaction, much like integrated circuits on a circuitboard. Metabolic networks work like electric circuits. The operation of analog electronic devices maps very closely to the flow of information in chemical reactions. We know intelligence is able to setup circuit boards.  There is no function for a unfinished metabolic network, which makes  it extremely unlikely that new metabolic and catabolic networks would arise naturally, in  non-guided manner. 

Strong Irreducible Complexity of Molecular Machines and Metabolic Pathways. 5 For certain enzymes (which are themselves highly complicated molecular structures) and metabolic pathways (i.e., systems of enzymes where one enzyme passes off its product to the next, as in a production line), simplification leads not to different functions but to the complete absence of all function. Systems with this feature exhibit a strengthened form of irreducible complexity. Strong irreducible complexity, as it may be called, entails that no Darwinian account can in principle be given for the emergence of such systems. Theodosius Dobzhansky, one of the founders of the neo-Darwinian synthesis, once remarked that to talk about prebiotic natural selection is a contradiction in terms—the idea being that selection could only select for things that are already functional. Research on strong irreducible complexity finds and analyzes biological systems that cannot in principle be grist for natural selection’s mill. For this research, which is only now beginning, to be completely successful would imply the unraveling of molecular Darwinism. 

The Implausibility of Metabolic Cycles on the Prebiotic Earth 3
Leslie E Orgel†
Although metabolism-first avoids the infeasibility of forming functional RNA by chance, "replication of compositional information is so inaccurate that fitter compositional genomes cannot be maintained by selection and, therefore, the system lacks evolvability (i.e., it cannot substantially depart from the asymptotic steady-state solution already built-in in the dynamical equations). We conclude that this fundamental limitation of ensemble replicators cautions against metabolism-first theories of the origin of life" [44]. Concerning the chemical cycles required, "These are chemically very difficult reactions ... One needs, therefore, to postulate highly specific catalysts for these reactions. It is likely that such catalysts could be constructed by a skilled synthetic chemist, but questionable that they could be found among naturally occurring minerals or prebiotic organic molecules. The lack of a supporting background in chemistry is even more evident in proposals that metabolic cycles can evolve to 'life-like' complexity. The most serious challenge to proponents of metabolic cycle theories—the problems presented by the lack of specificity of most non-enzymatic catalysts—has, in general, not been appreciated. If it has, it has been ignored. Theories of the origin of life based on metabolic cycles cannot be justified by the inadequacy of competing theories: they must stand on their own"

Hugh Ross , origin of life page 39
Metabolism first. 
Metabolism-first proponents maintain that mineral surfaces catalyzed the formation of a diverse collection of small molecules that, with time, evolved to form an interconnected series of chemical reactions. Once in place, these interrelated chemical reactions formed the basis for the cell’s metabolic systems.21 These chemical networks eventually became encapsulated to form protocells complete with a form of protometabolism. Some metabolism-first scenarios, like the iron-sulfur world, even suggest that minerals (for example, pyrite) became encapsulated along with the protometabolic networks and thereby served as life’s first catalysts. According to the metabolism-first idea, once protometabolic systems were established, they spawned self-replicating molecules.

The Genetic Code and the Origin of Life 
The metabolism theory claims that life, at least in its beginnings, was nothing more than a continuous chain of mineral surface-associated self-sustaining chemical reactions with no requirement for genetic information. A primitive type of reductive citric acid cycle is often cited as a model. There is some experimental support for the hypothesis, although the conditions for the various individual reaction steps are very different,  it remains to be established if the conditions used in these laboratory experiments are geophysically plausible and are therefore relevant to the origin of life. Regardless of its initial complexity, self-maintaining chemical-based metabolic life could not have evolved in the absence of a genetic replicating mechanism insuring the maintenance, stability, and diversification of its components. In the absence of any hereditary mechanisms, autotrophic reaction chains would have come and gone without leaving any direct descendants able to resurrect the process. Life as we know it consists of both chemistry and information.  Life as we know it consists of both chemistry and information. If metabolic life ever did exist on the early Earth, to convert it to life as we know it would have required the emergence of some type of information system under conditions that are favorable for the survival and maintenance of genetic informational molecules.

At a construction site, builders will make use of many materials: lumber, wires, nails, drywall, piping, and windows. Yet building materials do not determine the floor plan of the house or the arrangement of houses in a neighborhood. Similarly, electronic circuits are composed of many components, such as resistors, capacitors, and transistors. But such lower-level components do not determine their own arrangement in an integrated circuit (see Fig. 14.2).






In particular, the cause must be capable of constructing, not merely modifying, complex integrated metabolic circuits. The requirements for constructing the first living cells de novo cannot be accommodated by microevolutionary or macroevolutionary theory, since evolution depends on these networks fully operational. And since there is no function for a unfinished metabolic network, then how would new metabolic and catabolic networks ever arise?

Integrated circuits in electronics are systems of individually functional components such as transistors, resistors, and capacitors that are connected together to perform an overarching function. Likewise, the functional enzymes and proteins of metabolic and anabolic networks, also form an integrated circuit, one that contributes to accomplishing the overall function of producing a working functional cell.

Understanding complex signaling networks through models and metaphors 1

The operation of analog electronic devices maps very closely to the flowof information in chemical reactions (McAdams and Shapiro, 1995).

The buildup of charge, for example, is analogous to the accumulation of a particular molecule. Amplifiers, like enzymes, permit a small charge (or molecular concentration) to have a large effect on another. The identity of signals in an electronic circuit is maintained by distinct, insulated wires. In signaling circuits this identity is maintained by the fact that distinct molecules convey different signals. Even at a mathematical level, the equations describing equilibration of charge and amplifier function can faithfully mimic the equations describing chemical reactions.
















Following shows the minimal metabolic network that was required in the first supposed last universal common ancestor.  

The Enzymatic and Metabolic Capabilities of Early Life  

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0039912#pone.0039912-Srinivasan1

We reconstruct a representative metabolic network that may reflect the core metabolism of early life forms. Our results show that ten enzyme functions, four hydrolases, three transferases, one oxidoreductase, one lyase, and one ligase, are determined by metaconsensus to be present at least as late as the last universal common ancestor. Subnetworks within central metabolic processes related to sugar and starch metabolism, amino acid biosynthesis, phospholipid metabolism, and CoA biosynthesis, have high frequencies of these enzyme functions. 

Link to the respective Keggs database 

Sphingolipid metabolism
Pantothenate and CoA biosynthesis
Galactose metabolism
Drug metabolism - other enzymes
Starch and sucrose metabolism
fructose and mannose metabolism
pentose and glucuronate interconversions
Lipopolysaccaride biosynthesis
cyanoamino acid metabolism

#1 - http://religiopoliticaltalk.com/wp-content/uploads/2016/07/01-Sphingolipid.jpg

#2 - http://religiopoliticaltalk.com/wp-content/uploads/2016/07/02-Pantothenate.jpg

#3 - http://religiopoliticaltalk.com/wp-content/uploads/2016/07/03-Galactose.jpg

#4 - http://religiopoliticaltalk.com/wp-content/uploads/2016/07/04-Drug.jpg

#5 - http://religiopoliticaltalk.com/wp-content/uploads/2016/07/05-Starch.jpg

#6 - http://religiopoliticaltalk.com/wp-content/uploads/2016/07/06-Fructose.jpg 

#7 - http://religiopoliticaltalk.com/wp-content/uploads/2016/07/07-Fructose.jpg

#8 - http://religiopoliticaltalk.com/wp-content/uploads/2016/07/08-Lipopolysaccharide.jpg

#9 - http://religiopoliticaltalk.com/wp-content/uploads/2016/07/010-Cyanoamino.jpg






























1. http://www.nada.kth.se/kurser/kth/2D1436/2005/lasmaterial/f8c/Bhalla.pdf
2. http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0039912#pone.0039912-Srinivasan1
3. http://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.0060018
4. http://www.plantphysiol.org/content/152/2/428.full?sid=c0bd645e-881c-4bed-9f5b-0e4d595f140d
5. http://www.ideacenter.org/contentmgr/showdetails.php/id/1181

A few more challenges of origin of life scenarios

According to the  paper Structural analyses of a hypothetical minimal metabolism, a urancestor would require minimally 50 enzymatic steps in a minimal metabolic set. And following metabolic networks. glycolysis , phospholipid biosynthesis , nonoxidative pentose-phosphate pathway , nucleotide biosynthesis , synthesis of enzymatic cofactors (coenzyme metabolism ) , and synthesis of protein precursors, i.e., aminoacyl-tRNAs (aa-tRNA). These would have to be fully setup and present in a supposed Progenote, in order to give life a first go. How did that all emerge without evolution ? ( the setup had to precede DNA replication ) Even the simplest network would be ENORMOUSLY COMPLEX. What would have to be explained is 1. the origin of the information and mechanism to make the first minimal set of enzymes 2. the origin of the information to interconnect the network and interconnect the enzymes correctly 3. Set up the information for regulation, and start regulation 4. get all ingredients in high enough concentration at the cell building site. How could all that happen through unguided random chemical reactions ? Then : How could all that happen without a protecting membrane ? And even IF there were a protecting membrane : There was no oxygen in the atmosphere to protect from UV radiation yet ( that came only later in the supposed great oxygenation event ) nor could it have happened in water, since : In water, the assembly of nucleosides from component sugars and nucleobases, the assembly of nucleotides from nucleosides and phosphate, and the assembly of oligonucleotides from nucleotides are all thermodynamically uphill in water. Two amino acids do not spontaneously join in water. Rather, the opposite reaction is thermodynamically favored at any plausible concentrations: polypeptide chains spontaneously hydrolyze in water, yielding their constituent amino acids,” (Luskin). Physicist Richard Morris concurs, “… water tends to break chains of amino acids. If any proteins had formed in the ocean 3.5 billion years ago, they would have quickly disintegrated,” (Morris, 167). Additionally, the cytoplasm of living cells contain essential minerals of potassium, zinc, manganese and phosphate ions. If cells manifested naturally, these minerals would need to be present nearby. But marine environments do not have widespread concentrations of these minerals (Switek). Thus, it is clear, life could not have formed in the ocean.

http://reasonandscience.heavenforum.org/t2371-how-cellular-enzymatic-and-metabolic-networks-point-to-design#5137



Frontiers of Astrobiology page 60

Metabolism in the LUCA
The core metabolic network of the LUCA was in many ways strikingly similar to those found in extant life. This assertion is based upon two lines of evidence. First, as mentioned above, pathways for synthesis of amino acids and nucleotides are identical or nearly identical in Archaea, bacteria, and eukaryotes. The TCA, or citric acid, cycle is present in representatives of all domains of life, although in some organisms only parts of the cycle are present, and in others the cycle runs in reverse. It is extremely unlikely that the same sequences of reactions would have been invented independently in different lineages. ( Unless a designer did it ) The second line of evidence is based upon the predicted gene content of the LUCA. Assessing the metabolic capabilities of the LUCA is challenging because the content of metabolic enzymes in extant organisms has been shaped by multiple processes. Genes encoding metabolic enzymes can be inherited vertically from direct progenitors. They can also be gained by duplication of pre-existing genes and divergence of function between the resulting homologs, as well as by horizontal gene transfer between microbes, which has been rampant throughout the entire history of life. To further complicate the picture, genes encoding metabolic enzymes are often lost when they are not needed in particular environmental niches. As a consequence, few genes encoding metabolic enzymes are found in 100% of taxa in any domain of life. (Note the contrast between this situation and the universal conservation of ribosomes; protein synthesis is necessary in every environmental niche, so genes encoding ribosomal RNA are never lost.) A gene that is found in 40% of all taxa might have been present in the LUCA and subsequently lost in many lineages, or may have originated in one lineage and then appeared in other lineages via horizontal gene transfer. A decision between these alternative explanations requires assumptions about the relative frequencies of horizontal gene transfer and gene loss. Careful analyses that take these uncertainties into account suggest that the LUCA contained a few hundred genes; Mirkin et al. (2003) estimated that the LUCA contained 572 genes. In a later study with a larger data set, Ouzounis et al. (2006) estimated that the LUCA contained 669 genes. Notably, genes encoding enzymes for synthesis of amino acids and nucleotides, for the TCA cycle, and for degradation of glucose, are predicted to have been present in the LUCA in both studies. Thus, we can be reasonably confident that, by the LUCA, many core metabolic pathways were firmly in place. Furthermore, a functional electron transport chain had emerged by the LUCA, as genes encoding subunits of the enzymes NADH dehydrogenase, succinate dehydrogenase, and the cytochrome b subunit of the cytochrome bc complex are predicted to have been present. The electron transport chain likely carried out its current function of generating an ion gradient across the membrane, since the reconstructed genome of the LUCA encodes several of the subunits of the F0F1 ATP synthase enzyme that uses the energy stored in an ion gradient to drive the synthesis of ATP. Clearly the LUCA captured energy from redox processes, but the specific types of electron donors and acceptors that were used cannot be determined. Although the core of modern metabolism had emerged by the time of the LUCA, a considerable amount of innovation occurred as microbes proliferated on Earth, adapted to diverse habitats, and established ecosystems characterized by both syntrophic and competitive interactions between species. Existing free-living bacteria typically have 1000–2000 enzymes; Streptomyces coelicolor is predicted to have over 2800 enzymes (Freilich et al. 2005). This dramatic expansion of metabolic capabilities occurred by both acquisition of new protein folds and by gene duplication and divergence that allowed novel uses of existing protein folds.

Getting to the LUCA
It is remarkable that we can infer many of the characteristics of a life form that existed 3.8 billion years ago. The evidence  suggests that the LUCA was a sophisticated life form, capable of replicating its genome (which may have consisted of RNA), synthesizing genetically encoded proteins using ribosomes, and synthesizing the nucleotide and amino acid building blocks of macromolecules. Unfortunately, the most intriguing part of the origin-of-life story, the processes that led to the origin of the complex metabolic and genetic systems of the LUCA, is beyond the reach of any hard physical or bioinformatic evidence. We can conjecture about these processes, but in this realm of speculation there is much more controversy. An elegant hypothesis about the progenitor of the LUCA was put forward by Carl Woese (Woese 1998). Woese defined the “progenote” as an entity in which translation had just emerged but “had not developed to the point that proteins of the modern type could arise.” The progenote, as the progenitor of the LUCA, is also a universal ancestor of life, but we distinguish it from the LUCA in this discussion because it lacked the accurate translation process required for reliable production of large proteins that are needed for faithful genome replication and efficient catalysis of metabolic reactions. Woese proposed that the progenote was a communal organism in which genetic information was extensively shared. Strategies for replication, transcription, translation, and metabolism would have been explored, refined, and shared within the entire community. The proposal that the progenote was a communal organism dovetails nicely with the proposition mentioned above that compartmentalization at the earliest stages of life was provided by the porous walls of hydrothermal vents, rather than by lipid membranes that would have provided a substantial barrier to transfer of genetic information. Woese suggested that genome replication and translation in the progenote were rudimentary and inaccurate, a reasonable hypothesis since replication and translation could not have sprung into existence in their present sophisticated forms. Inaccurate replication would likely have limited the size of the progenote genome due to the risk of “error catastrophe,” the accumulation of so many genetic mistakes that the organism is no longer viable. To illustrate this point, consider the problem of replicating a genome of one million bases, which is sufficient to encode a few hundred RNAs and proteins. (The smallest known genome for an extant free-living bacterium is that of Pelagibacter ubique, which consists of 1.3 million bases.) If replication were even modestly faithful, with an error frequency of 0.1%, every replication of a genome consisting of 1 million bases would result in 1000 errors, approximately one or two in every gene. Some of those errors would have been harmless, and a few might have been beneficial, but many would have been detrimental, leading to macromolecules with impaired functions. Inaccurate replication may have required the progenote to maintain multiple copies of each chromosome to provide genetic redundancy. An important consequence – and a favorable one – of high error rates coupled with high genetic redundancy would have been an enhanced ability to explore sequence space and consequently a high rate of evolutionary innovation. The redundancy provided by multiple copies of chromosomes would mean that a functional copy of a gene was always available as a backup, even as the high mutation rate allowed a great deal of experimentation. When a gene encoding an improved macromolecule was discovered, it could replace the previous version and serve as the starting point for subsequent experimentation. This process would likely have resulted in fairly efficient testing of a variety of solutions to the problems of replicating the genome, producing proteins, harnessing energy from the environment, and synthesizing the building blocks of macromolecules.

The metabolic pathways that were present in the LUCA evolved as the progenote learned to synthesize the building blocks of macromolecules that initially were provided by the environment, either by delivery from the atmosphere or space or by geochemical processes. Thats a perfect example of pseudo-scientific just so claim made without evidence.  Early metabolic pathways probably relied on “generalist” enzymes that catalyzed certain generic reactions (for example, reduction of a carbonyl or phosphorylation of a carboxylate), probably with relatively low efficiency and low substrate specificity. Thus, the number of reactions that were included in an early metabolic network would have been much higher than the actual number of catalysts. As the progenote evolved toward the LUCA, both the number of enzymes and their specificity would likely have increased. More specific enzymes are advantageous for several reasons. First, an increase in specificity can increase catalytic power because a substrate can be oriented more precisely with respect to the active site machinery. Increased specificity also decreases the potential for catalysis of undesirable side reactions when certain substrates cannot be excluded from the active site. Finally, catalysis of reactions in more than one pathway by a generalist enzyme makes it difficult to optimize fluxes toward products that may be needed in very different quantities.


Metabolism in an “RNA” world
The progenote described by Woese is defined as an organism in which translation had just emerged. An even more primitive form of life must have existed before the progenote. This life form may have had an RNA genome, a metabolic network, and possibly small peptides, but no protein enzymes since translation had yet been invented. (!) (The term “protein” is typically reserved for genetically encoded polypeptides that are produced by the ribosome.) In this life form, RNA molecules (or a similar nucleic acid) may have served as both the genetic material and as catalysts for genome replication as well as metabolic reactions. Numerous examples of RNA viruses that have RNA genomes and copy RNA directly into RNA (without a DNA intermediate) support the idea that a genome need not consist of DNA. The idea that nucleic acids were the earliest macromolecular catalysts was first proposed in the 1960s, and gained credence from the demonstration of catalysis by RNA molecules in the labs of Cech and Altman in the early 1980s (Kruger et al. 1982, Guerrier-Takada et al. 1983). Since then, ribozymes (catalytic RNA molecules) generated by in vitro evolution methods have been shown to catalyze a wide range of reactions involved in metabolism, including amino acid activation (Kumar and Yarus 2001), formation of coenzyme A (CoA), nicotinamide adenine dinucleotide (NAD), and flavin adenine dinucleotide (FAD) from 4-phosphopantetheine, nicotinamide mononucleotide (NMN), and flavin mononucleotide (FMN), respectively (Huang et al. 2000), peptide bond synthesis (Illangasekare and Yarus 1999), and aldol condensation (Fusz et al. 2005). Thus, it appears that RNA molecules could have catalyzed all of the reactions needed to sustain life. The first nucleic acid catalysts may not have actually been ribonucleic acid, which has a backbone based on the sugar ribose. Nucleic acids with intriguing alternative backbone structures include threonucleic acid (TNA) (Eschenmoser 1999, Schoning et al. 2000), peptide nucleic acid (PNA) (Nielsen 2007), and glycol nucleic acid (GNA) (Zhang et al. 2005). (This uncertainty is the reason for the inclusion of RNA in quotation marks in the title of this section.) Further, early nucleic acids may well have contained bases other than the four canonical bases found in RNA today. Although catalysis by nucleic acids has only been demonstrated for RNA and DNA, it is likely that alternative kinds of nucleic acids can catalyze chemical reactions, as well. Although ribozymes have been shown to catalyze an impressive range of reactions, catalysis in the “RNA” world was likely not the exclusive purview of nucleic acids. Mineral surfaces, soluble metal ions, and small molecules, including amino acids and peptides, can also catalyze chemical reactions. These components presumably catalyzed reactions before the advent of macromolecular nucleic acids. Even after nucleic acid catalysts arose, metal ions and small molecules might have enhanced their catalytic abilities, either by stabilizing structures required for catalysis or by directly participating in catalysis (Copley et al. 2007, Cech 2009).

Does extant metabolism resemble early proto-metabolic networks?
The structure of the metabolic network in extant life is dictated by the availability of catalysts, and this would have been true during all of the stages of the emergence of life, as well. Catalysts define the structure of metabolic networks by accelerating flux through certain reactions at the expense of slower competing reactions. For example, a catalyst that accelerates the rate of one of the possible reactions of a molecule by a relatively modest 50-fold alters the distribution of products to the point at which one product predominates and the others are formed in only very small quantities . Figure 3.6 extends this idea to the effect of multiple catalysts on a more complicated chemical network, and illustrates how the availability of different sets of catalysts results in different network topologies and formation of different final products. As discussed above, biosynthetic pathways in extant organisms clearly resemble those in the LUCA. A more difficult question is whether metabolism in the LUCA reflected the structure of a pre-existing proto-metabolic reaction network,



or replaced a pre-existing proto-metabolic reaction network. In the first scenario, metabolic pathways might have remained largely the same while ever more efficient catalysts were recruited ( how should they have become more efficient ? trial and error ? ) to facilitate individual reactions, leading to a smooth transition from the earliest stages of mineral and small-molecule catalysis, through an intermediate stage involving proto-RNA and RNA catalysts (likely with catalytic auxiliaries provided by amino acids, peptides, and cofactors), and finally to protein enzymes. A point in favor of this argument is that it is undoubtedly easier to patch a single catalyst into a functioning pathway than to invent de novo an entirely different pathway whose efficiency surpasses that of a previously existing pathway. A second hypothesis is that modern metabolic pathways have completely replaced primordial pathways due to the advent of more effective catalysts, probably at the stage of the RNA world (Benner et al. 1989). This viewpoint is based upon the assumption that a large number of highly effective catalysts arose in the RNA world, or at least by the LUCA, which together allowed flux through pathways that had never before been accessible. ( These are assumptions that cannot be backed up with evidence )  In the context of Figure 3.6, this would correspond to a switching between sets of catalysts with consequent reconstruction of the topology of the network. The answer to this question most likely lies somewhere between these two opposing theories. The idea that modern metabolism runs along pathways that were laid down before the emergence of the LUCA is appealing from the standpoint of continuity between pre-life and life, and because recruitment of catalysts one at a time is more likely than recruitment of several catalysts simultaneously to enable an entirely new pathway. However, recruitment of several catalysts simultaneously to enable a novel pathway can certainly occur once there is a sufficient collection of catalysts.


This is all in all a admission of helplessness , and avoiding to go further into detail, how exactly these metabolic networks could have emerged. The answers and explanations are superficial, without experimental knowledge that could give credence that complex enzymes and catalysts could become more complex over time, and form complex multibranched metabolic networks. 

The living cell is a chemical industry in miniature, where thousands of reactions  occur within a microscopic space.  Metabolism is an emergent property of life that  arises from specific interactions between molecules within the orderly environment  of the cell.  Sugars are converted into amino acids, and vice versa. Small molecules  are assembled into polymers, which may later be hydrolyzed as the needs of cell  change.  One of the unique property living things is to create and maintain the order.



In order to create and maintain order cells perform many different chemical reactions, which are  small organic molecules like sugars, fatty acids, nucleotides are taken up and modified  within cells by chemical reactions through a series of reactions The chemical reactions occur in every cells require boost in reactivity and precise  chemical control.  These are achieved by specialized protein called enzymes. Each  enzyme accelerates or catalyzes a specific reaction.  Enzyme-catalyzed reactions are  usually under connected in a series, so that the product of one reaction becomes the  starting material or substrate for the next



As a whole, metabolism is concerned with managing the material and energy  resources of the cell.  Some metabolic pathways release energy by breaking down  complex molecules into simpler compounds.  These degradative processes are called  catabolic pathways. A major example of catabolism is cellular respiration, in which  sugar glucose and other and other organic fuels are broken down to carbon dioxide  and water.   There are also anabolic pathways or biosynthesis, which consumes  energy to build complicated molecules from simpler ones.  An example of anabolism  is the synthesis of protein from amino acids



Schematic representation of the relationship between catabolic and anabolic  pathways in metabolism.

As suggested here, since a major portion of the energy stored in the chemical bonds of food molecules is dissipated as heat, the mass of food required by any organism  that derives all of its energy from catabolism is much greater than the mass of the  molecules that can be produced by anabolism

The Metabolic Map

Metabolism is the totality of an organism’s chemical processes.  We can think of a  cell’s metabolism as an elaborate road map of the thousands of reactions in that cell.  These longer linear reaction pathways, or metabolic pathways, are in turn linked to  one another, forming a complex web interconnected reactions that enable to the cell  to survive, grow, and reproduce.

Biological Order Is Made Possible by the Release of Heat Energy from Cells

Living cells-by surviving, growing, and forming complex organisms-are generating order  and thus might appear to defy the second low of thermodynamics. But this is not the  case.  A cell is not isolated system.  It takes energy form as food or photons from the  sun and it then use this energy to generate order within itself.  In the course of performing  the chemical reactions that generate order, chemical and bond energy is converted into  heat. Why would natural non guided, non intelligent chemical processes generate thermodynamically uphill reactions, rather than downhill reactions ? 

A simple thermodynamic analysis of a living cell.

In the diagram on the left the molecules of both the cell and the rest of the  universe (the sea of matter) are depicted in a relatively disordered state. In the diagram on the right the cell has taken in energy from food molecules  and released heat by a reaction that orders the molecules the cell contains.  Because the heat increases the disorder in the environment around the cell  (depicted by the jagged arrows and distorted molecules, indicating increased  molecular motions), the second law of thermodynamics, which states that the  amount of disorder in the universe must always increase, is satisfied as the cell  grows and divides.

In his article Metabolism First and the Origin of Life, Larry Moran mentions the article The Origin of Life as science writing at its best. Lets have a look at what the article says, and how it witholds scrutiny, and if the compliment and praise is justified.

As the frontiers of knowledge have advanced, scientists have resolved one creation question after another.
No, they have not, as i write at the article Open questions in biology, biochemistry, and evolution. 

the early steps on the way to life are an inevitable, incremental result of the operation of the laws of chemistry and physics operating under the conditions that existed on the early Earth, a result that can be understood in terms of known (or at least knowable) laws of nature.
The author only forgets to mention that instructional information does not arise through laws of nature or chemistry, but are exclusively the product of intelligent intervention.

We believe this early version of metabolism consisted of a series of simple chemical reactions running without the aid of complex enzymes, via the catalytic action of networks of small molecules, perhaps aided by naturally occurring minerals. If the network generated its own constituents—if it was recursive—it could serve as the core of a self-amplifying chemical system subject to selection. We propose that such a system arose and that much of that early core remains as the universal part of modern biochemistry, the reaction sequences shared by all living beings. Further elaborations would have been added to it as cells formed and came under RNA control, and as organisms specialized as participants in more complex ecosystems.


The author believes that natural selection could act, when there was no replication. So this mechanism falls apart. Remains chance. We do not know of chance being able to produce complex circuit board like connections which provide function. 


Furthermore, ALL these metabolic pathways had to be fully operational. A stepwise evolutionary manner is not possible:

Several independent studies have used comparative bioinformatics methods to identify taxonomically broad features of genomic sequence data, protein structure data, and metabolic pathway data in order to predict physiological features that were present in early, ancestral life forms.

#1 - http://religiopoliticaltalk.com/.../07/01-Sphingolipid.jpg

#2 - http://religiopoliticaltalk.com/.../07/02-Pantothenate.jpg

#3 - http://religiopoliticaltalk.com/.../2016/07/03-Galactose.jpg

#4 - http://religiopoliticaltalk.com/.../2016/07/04-Drug.jpg

#5 - http://religiopoliticaltalk.com/.../2016/07/05-Starch.jpg

#6 - http://religiopoliticaltalk.com/.../2016/07/06-Fructose.jpg 

#7 - http://religiopoliticaltalk.com/.../2016/07/07-Fructose.jpg

#8 - http://religiopoliticaltalk.com/.../08-Lipopolysaccharide...

#9 - http://religiopoliticaltalk.com/.../07/010-Cyanoamino.jpg

Here’s an analogy that will provide an outline for the argument we make: Consider the requirements of the U.S. Interstate highway system. The system includes an enormously complex network of roads; major infrastructure devoted to extracting oil from the Earth, refining oil into gasoline and distributing gasoline along the highways, a major industry devoted to producing automobiles; and so on. If we wanted to explain this system in all of its complexity, we would not ask whether cars led to roads or roads led to cars, nor would we suspect that the entire system had been created from scratch as a giant public works project. It would be more productive to consider the state of transport in preindustrial America and ask how the primitive foot trails that must certainly have existed had developed into wagon roads, then paved roads and so on. By following this evolutionary line of argument, we would eventually account for the present system in all its complexity without needing recourse to highly improbable chance events.

Why would have there began a thermodynamically upward metabolic network AT ALL ? 


http://reasonandscience.heavenforum.org/t2174-the-enzymatic-and-metabolic-capabilities-of-early-life

Analysis of minimal metabolic networks through whole-cell in silico modelling of prokaryotes 1

One simple prokaryotic cell can be viewed as a highly complex dynamic bionanomachine that bioengineers cannot assemble from its parts. Escherichia coli, for example, has millions of proteins, thousands of RNA molecules, millions of lipids, etc., all of them working together in subsystems and complexes. However, for each cell, there is only one circular double helix DNA genome

Table 1 – Number of molecules in a single Escherichia coli cell Adapted from (Deamer, 2009) .
Molecular component Number of molecules



 minimal cells have been studied mostly as minimal genome-containing cells. With Systems Biology affirmation in the several new omics datasets (proteomics, metabolomics, lipidomics, etc) cells are starting to be looked at as a whole, and the approach of this new discipline appears to be very appropriate to conceive minimal cells. The identification and interconnection of cellular parts in dynamic systems and ultimately, the construction of models are the goals of Systems Biology. In fact, the old approaches to minimal cells – Top down and Bottom up - are general terms for two strategies of information processing and knowledge ordering in any systems science, or philosophy. Therefore, systems biology has always been the approach in the search for the minimal cell. 


 The study of minimal metabolism in silico A minimal gene-set obtained from the comparison of two small genomes (Haemophylus influenzae and Mycoplasma genitalium (Mushegian & Koonin, 1996)) motivated one dynamic, in silico study of metabolic viability of a minimal cell (Chiarugi et al, 2007). The authors refined the gene set to obtain a virtual cell that was proven to live in silico (ViCe) although they make the reservation that it remains to be tested experimentally. ViCe includes: a complete glycolytic pathway coupled with the synthesis of ATP through the ATP synthase/ATPase transmembrane system; a Pentose Phosphate Pathway; enzymes for glycerol-fatty acids condensation (but no pathways for fatty acids synthesis that need to be taken from the outside); ‘‘salvage pathways’’ for nucleotide biosynthesis (thymine is the only nucleotide the cell is able to synthesize de novo); a proper set of carriers for metabolites uptake; the necessary enzymes for protein synthesis, and the whole machinery necessary for DNA synthesis is also included in ViCe. Notoriously, this is an attempt to build a true minimal cell that is totally dependent on a rich medium.

Evolution of metabolism
A globally heterotrophic, and microaerobic LUCA community

There are two basically different types of metabolism -autotrophic and heterotrophic- and, consequently, two opposite views for the origin of the first living cells; when the generation of metabolic energy is taken into account, these views are however not as irreconcilable as used to be considered [115]. At any rate, LUCA was not an immediate descendant of these primeval cells and its metabolic status is not expected to bear a direct relationship to their origin. In its present state, and whatever the exact branching order of the three Domains, the universal tree of life, with many deep-branching chemoorganotrophic types of microorganisms, is not adverse to the notion of a heterotrophic LUCA (or to the presence of heterotrophs in a LUCA community of diverse metabolic types). This contrasts with earlier emphasis on autotrophic (and hyperthermophilic) metabolism in alleged primeval cell lines at a time the tree of life featured many such organisms close to the root[116]. Actually, even if the primeval cells that preceded the LUCA had been autotrophic, evolutionary pressure from an environment containing organic substances, whether of living or still from prebiotic origin, would have promoted the advent of heterotrophic cells. A penetrating analysis of the phylogeny of gene families involved in energetic metabolism [113] further suggests that LUCA (or the LUCA community [9,114]) was endowed with a wide spectrum of bioenergetic capacities, including the paraphernalia of respiration and even a superoxide dismutase [91]); oxygen may thus have become an electron acceptor at a very early time, though its concentration would have remained very low (but perhaps already compatible with a micro- or nanoaerophilic metabolism [94,113]) before the massive increase progressively brought about by oxygenic photosynthesis and other processes [117]. It is usually assumed that oxygen is necessary for sterol biosynthesis (oxidation of squalene) but the possibility of an anaerobic pathway for squalene biosynthesis should be kept in mind [118]. Should this be the case, and despite indications for early participation of oxygen in metabolism, the protoeukaryote could have emerged in a totally anaerobic environment, perhaps still at the progenote stage.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2478661/

Bacteria Metabolisms Are Like Computer Circuit Boards 1

Bacteria sometimes face a rough life. At about a tenth the size of most plant and animal cells, they have no layer of skin to protect them. Environments can change quickly and if microbes don't have the right tools to adapt, they won't last long. Bioengineers modeled three interdependent aspects of a metabolic system that bacteria use to thrive in ever-changing environments, revealing an underlying array of interrelated parts that they described as "underappreciated."1
When biologists seed a fresh batch of sugary broth with C. acetobutylicum bacteria, the first thing those microbes do is harvest the sugar's energy and multiply—their simple method of reproduction. Since no sewage treatment system exists nearby, their organic acid wastes build up around them. But that's no problem for well-equipped bacteria.
When acids mount up, the bacteria switch on a different internal factory that assimilates those wastes and actually converts them into something useful. Sounds simple from a birds-eye view, but when top scientific minds try to make such a system, they discover that bacterial metabolism is far from simple.
The bacteria use detectors, on/off switches, dimmer switches, relay switches, feedback loops, and a lot of precise engineering to properly connect them—like a complicated computer circuit board. How complicated is it? Just ask the bioengineers who designed a digital version of just one corner of C. acetobutylicum'smetabolism. They published their model, which they tested against real bacterial cultures, in Proceedings of the National Academy of Sciences.1





University of Illinois Engineering News wrote, "Researchers from the University of Illinois at Urbana-Champaign have, for the first time, uncovered the complex interdependence and orchestration of metabolic reactions, gene regulation, and environmental cues of clostridial metabolism."2
Inside the bacteria, a set of uniquely tailored enzymes (protein machines) facilitates each chemical reaction in a chain of essential metabolic events. Increasing levels of byproducts from this activity makes a toxic and acidic world outside the cell. A second metabolic system saves the bacteria from these potentially lethal byproducts by reconfiguring them.
How does the cell know what its environment contains and what turns on this second metabolic gear? It turns out that tiny machines compare the acidity inside the cell to that outside the cell, and protocols communicate that information to other machines that manage its genes. This is when gene regulation comes into play. This interdependent aspect of the system activates certain genes at just the right time and for just the right durations for the cells to begin converting poisonous organic acids into solvents.
Eventually, the environment becomes too hostile even for these remarkable tactics, at which point the cells switch into preservation mode. Some cells convert themselves into resistant spores that wait until conditions improve before kick starting another growth phase.
At the University of Illinois, bioengineers digitally mimicked subsets of these real-world bacterial systems. They wrote, "The complexity and systems nature of the process have [sic] been largely underappreciated."2Nothing like reverse-engineering to gain an appreciation for the intricacies built into a real-live system. Reverse-engineering requires intense analysis.
For example, in describing one aspect of building their digital version of the bacteria's gene regulation module, the researchers wrote, "Here, the concentrations of the four key molecules (Spo0A, Spo0A∼P, σF, and σK) were adopted as the main model variables, and their kinetics were described using differential equations."1
Did evolutionary processes really have the ability or forward-thinking insight to construct the metabolism in C. acetobutylicum? Which natural process understood enough basic calculus to integrate differential equations into an essential, dynamic network of interdependent parts and modules? Was it mutations, death of the unfit, or population dynamics?
Since no combination of natural processes fits the bill, an intelligent source must have made bacterial metabolism's interdependent aspects. And that intelligent source must have been even brighter than the excellent engineers who discovered and tried to replicate them. They made a mere digital copy, but He made the real living thing.

Integrated, systems metabolic picture of acetone-butanol-ethanol fermentation by Clostridium acetobutylicum 2

University of Illinois Engineering News wrote, "Researchers from the University of Illinois at Urbana-Champaign have, for the first time, uncovered the complex interdependence and orchestration of metabolic reactions, gene regulation, and environmental cues of clostridial metabolism."

1. http://www.icr.org/article/bacteria-metabolisms-are-like-computer/
2. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4500237/

The evolution of modularity in bacterial metabolic networks

The origin and evolution of modern metabolism
Metabolism is very ancient and parts of the metabolic network probably evolved prior to the origin of cellular life from reactions that could have proceeded without catalysis or with inorganic catalysts (Maden, 1995). This view is supported by in vitro experiments that try to simulate pre-biotic chemistry. Ribozymic catalysts may also have preceded modern metabolic reactions. In an extreme scenario, the only palimpsest that is required relates to the pre-biotic creation of nucleotides (Orgel, 2000, 2003). It is highly likely that polypeptides became metabolic catalysts through takeover from pre-biotic reactions and ribozymes (Kacser and Beeby, 1984). The earliest enzymes were probably weakly catalytic and multifunctional with broad specificities. Gradually, more numerous, effective, and specific enzymes evolved from the multifunctional enzymes through gene duplication, mutation and divergence (Lazcano and Miller, 1996). As enzymatic pathways became more complex, new enzymatic functions and metabolic pathways were generated by recruitment of individual enzymes from the same or different pathways in groups, thanks to the dynamic interplay between functional (catalytic and structural) promiscuity and structural canalization tendencies that enhance specificity and metabolic efficiency.

How Life Began:  The Emergence of Sparse Metabolic Networks 1

A consideration of the mechanisms by which the sparse metabolic network characteristic of extant life emerged is complicated because molecules in a proto-metabolic or metabolic network must have satisfied multiple criteria simultaneously over the entire course of the emergence of life, even as these criteria were constantly changing. Initially, they must have been accessible from geochemical or astrophysical precursors by pathways that used reliably available catalysts or facile un-catalyzed reactions. If catalysts were compounds within the network (such as small molecules, metal ions chelated by small molecules, peptides or oligonucleotides (Copley et al., 2007), they must have been produced at sufficient rates relative to dilution or degradation to participate reliably in the network. It is a truism that evolution cannot anticipate the future usefulness of particular phenotypes. Thus, the earliest constituents of a proto-metabolic network must have provided some potential for the emergence of further complexity, or else life would not have emerged. Further, reasonable concentrations of at least a minimal set of building blocks must have been available before the emergence of macromolecules that were able to exert feedback on the system by catalyzing the synthesis of their own building blocks. Different processes would have influenced the sparse network of metabolism after the advent of macromolecules. At this stage, components that enhanced the functions of proto-RNA, RNA and, later, proteins would have been favored, but this more complex world would still have relied ultimately upon materials available from the environment. Thus, it is probably a false prejudice to cast the emergence of the sparse metabolic network of extant life as either a consequence of selection due to adsorption onto surfaces and kinetic effects before the emergence of life, or by selection in the Darwinian era, as discrete alternatives. A more nuanced picture of the emergence of metabolism must address how selective pressures varied over time and under changes in the complexity of the metabolic network, and which aspects of the composition and topology of extant metabolic networks arose by which mechanisms.

Molecules in a proto-metabolic or metabolic network must have satisfied multiple criteria simultaneously over the entire course of the emergence of life.
They must have been produced at sufficient rates relative to dilution or degradation to participate reliably in the network.
Evolution cannot anticipate the future usefulness of particular phenotypes. Thus, the earliest constituents of a proto-metabolic network must have provided some potential for the emergence of further complexity, or else life would not have emerged.
Reasonable concentrations of at least a minimal set of building blocks must have been available before the emergence of macromolecules that were able to exert feedback on the system by catalyzing the synthesis of their own building blocks.

Structural analyses of a hypothetical minimal metabolism 2

According to the  paper Structural analyses of a hypothetical minimal metabolism, a urancestor would require minimally 50 enzymatic steps in a minimal metabolic set. And following metabolic networks. glycolysis , phospholipid biosynthesis , nonoxidative pentose-phosphate pathway , nucleotide biosynthesis , synthesis of enzymatic cofactors (coenzyme metabolism ) , and synthesis of protein precursors, i.e., aminoacyl-tRNAs (aa-tRNA). These would have to be fully setup and present in a supposed Progenote, in order to give life a first go. How did that all emerge without evolution ? Even the simplest network would be ENORMOUSLY COMPLEX. What would have to be explained is 1. the origin of the information and mechanism to make the first minimal set of enzymes 2. interconnect the network 3. regulate it 4. get all ingredients in high enough concentration at the site. How could all that happen through unguided random chemical reactions ? Then : How could all that happen without a protecting membrane ?

pathways                                          genes   enzymatic steps
glycolysis from glucose to lactate              13           11
pentose phosphate pathway                       5            7
phospholipid biosynthesis                          6            6
biosynthesis of nucleotides                        15          26
total                                                     39          50

By integrating data from comparative genomics and large-scale deletion studies, the paper "Structural analyses of a hypothetical minimal metabolism"   proposes a minimal gene set comprising 206 protein-coding genes for the hypothetical minimal cell. As they explain, variations in the hypothetical set of substrates provided by the environment could lead to alternative, perhaps smaller, minimal metabolism set. 


glycolysis 
phospholipid biosynthesis 
nonoxidative pentose-phosphate pathway 
nucleotide biosynthesis 
synthesis of enzymatic cofactors (coenzyme metabolism ) 
and synthesis of protein precursors, i.e., aminoacyl-tRNAs (aa-tRNA). 





Even if this hypothetical minimal set could  be  reduced further, there is a threshold that cannot be surpassed.  Listed below are 50 enzymes/proteins required to create a metabolic network implemented  for the hypothetical minimal cell. 




Figure 1. 
A simplified overview of the metabolic network implemented by a hypothetical minimal genome of 208 protein-coding genes derived by an integrated approach (modified from Gil et al. 2004). 
Names of substrates freely available for the hypothetical minimal cell are represented inside a frame. Two sink metabolites are labelled in grey. Coenzyme metabolism (except the folate metabolism linked to TTP biosynthesis) is shown in the inset and was not considered in the stoichiometric analysis. Wider arrows in the glycolytic pathway indicate the two steps where ATP is synthesized by substrate-level

2.7.1.69	phosphotransferase system	PTS	glc+pep→g6p+pyr	MG041, 069, 429
5.3.1.9	glucose-6-phosphate isomerase	PGI	g6p↔f6p	MG111
2.7.1.11	6-phosphofructokinase	PFK	f6p+atp →fbp+adp	MG215
4.1.2.13	fructose-1,6-bisphosphate aldolase	FBA	fbp↔gdp+dhp	MG023
5.3.1.1	triose-phosphate isomerase	TPI	gdp↔dhp	MG431
1.2.1.12	glyceraldehyde-3-phosphate dehydrogenase	GAP	gdp+nad+p↔bpg+nadh	MG301
2.7.2.3	phosphoglycerate kinase	PGK	bpg+adp↔3pg+atp	MG300
5.4.2.1	phosphoglycerate mutase	GPM	3pg↔2pg	MG430
4.2.1.11	enolase	ENO	2pg↔pep	MG407
2.7.1.40	pyruvate kinase	PYK	pep+adp→pyr+atp	MG216
1.1.1.27	lactate dehydrogenase	LDH	pyr+nadh↔lac+nad	MG460
1.1.1.94	sn-glycerol-3-phosphate dehydrogenase	GPS	dhp+nadh→g3p+nad	n.i.a
2.3.1.15	sn-glycerol-3-phosphate acyltransferase	PLSb	g3p+pal→mag	n.i.
2.3.1.51	1-acyl-sn-glycerol-3-phosphate acyltransferase	PLSc	mag+pal→dag	MG212
2.7.7.41	phosphatidate cytidyltransferase	CDS	dag+ctp→cdp-dag+pp	MG437
2.7.8.8	phosphatidylserine synthase	PSS	cdp-dag+ser→pser+cmp	n.i.
4.1.1.65	phosphatidylserine decarboxylase	PSD	pser→peta	n.i.
4.1.2.13	fructose-1,6-bisphosphate aldolase	FBA2	gdp+e4p↔sbp	MG023
3.1.3.37b	sedoheptulose-1,7-bisphosphatase	SPH	sbp→s7p+p	n.i.
2.2.1.1	transketolase	TKT	gdp+s7p↔rip+xip	MG066
2.2.1.1	transketolase	TKT2	e4p+xip↔f6p+gdp	MG066
5.1.3.1	ribulose-phosphate 3-epimerase	RPE	xip↔rup	MG112
5.3.1.6	ribose-5-phosphate isomerase	RPI	rup↔rip	MG396
2.7.6.1	phosphoribosylpyrophosphate synthase	PRS	rip+atp→prpp+amp	MG058
2.4.2.8	hypoxanthine phosphoribosyltransferase	HPT	prpp+ade→amp+pp	MG276
2.4.2.8	hypoxanthine phosphoribosyltransferase	HPT2	prpp+gua→gmp+pp	MG458
2.4.2.9	uracil phosphoribosyltransferase	UPP	prpp+ura→ump+pp	MG030
3.6.1.1	inorganic pyrophosphatase	PPA	pp→2p	MG351
2.7.4.3	adenylate kinase	ADK	amp+atp→2adp	MG171
2.7.4.8	guanylate kinase	GMK	gmp+atp→gdp+adp	MG107
2.7.4.14b	cytidylate kinase	CMK	ump+atp→udp+adp	MG330
2.7.4.14	cytidylate kinase	CMK2	cmp+atp→cdp+adp	MG330
2.7.4.6	nucleoside diphosphate kinase	NDK	gdp+atp↔gtp+adp	MG216c
2.7.4.6	nucleoside diphosphate kinase	NDK2	udp+atp↔utp+adp	d
2.7.4.6	nucleoside diphosphate kinase	NDK3	dadp+atp↔datp+adp	MG216c
2.7.4.6	nucleoside diphosphate kinase	NDK4	dgdp+atp↔dgtp+adp	MG216c
2.7.4.6	nucleoside diphosphate kinase	NDK5	ctp+adp↔cdp+atp	d
2.7.4.6	nucleoside diphosphate kinase	NDK6	dcdp+atp↔dctp+adp	d
2.7.4.6	nucleoside diphosphate kinase	NDK7	dutp+adp↔dudp+atp	d
2.7.4.6	nucleoside diphosphate kinase	NDK8	tdp+adp↔ttp+adp	MG034
1.17.4.1	ribonucleoside diphosphate reductase	NRD	adp+nadh→dadp+nad	MG229–MG231
1.17.4.1	ribonucleoside diphosphate reductase	NRD2	gdp+nadh→dgdp+nad	MG229–MG231
1.17.4.1	ribonucleoside diphosphate reductase	NRD3	cdp+nadh→dcdp+nad	MG229–MG231
6.3.4.2	CTP synthase	PYR	utp→ctp	n.i.
3.5.4.13	dCTP deaminase	DCD	dctp→dutp	n.i.
2.7.4.9	thymidylate kinase	TMK	dudp+adp↔dump+atp	MG006
2.7.4.9	thymidylate kinase	TMK2	tmp+atp↔tdp+adp	MG006
2.1.1.45	thymidylate synthase	THY	dump+mthf→dhf+tmp	MG227
1.5.1.3	dihydrofolate reductase	DFR	dhf+nadh↔thf+nad	MG228
2.1.2.1	glycine hydroxymethyltransferase	GHT	ser+thf↔gly+mthf	MG394

Table 2
Metabolite and reaction input for the network shown in figure 1. (Metabolite abbreviations are the usual in biochemistry, except for pal (palmitoyl CoA), peta (phosphatidylethanolamine), pser (phosphatidylserine), mthf (5,10-methylene-tetrahydrofolate). Input fluxes (for k source substrate) and output fluxes (for k sink product) are indicated by Jik and Jok, respectively. For redox coenzyme NAD+/NADH, a reversible flux Jk is defined. Reversible and irreversible reactions are indicated, in the reaction equations, by the symbols ↔ and →, respectively. Last column shows the corresponding Mycoplasma genitalium genes considered as essential by Glass et al. (2006). The four cases in boldface correspond to non-essential genes. n.i., non-identified in M. genitalium. Input file for metatool is available upon request to the corresponding author.)



Determination of the Core of a Minimal Bacterial Gene Set 3



A minimal metabolism. The minimal cell can obtain its more basic components from the environment: glucose, fatty acids, amino acids, adenine, guanine, uracil, and coenzyme precursors (nicotinamide, riboflavin, folate, pantothenate, and pyridoxal). Each box includes the metabolic transformations classified in major groups of pathways:

glycolysis
phospholipid biosynthesis
nonoxidative pentose-phosphate pathway
nucleotide biosynthesis
synthesis of enzymatic cofactors
and synthesis of protein precursors, i.e., aminoacyl-tRNAs (aa-tRNA).

Products:

Glycolysis:
glycerol that combines with fatty acids to form fat
two molecules of pyruvate
two molecules of NADH
two molecules of adenosine triphosphate
hydrogen ions
water

Glycolysis is one of the most fundamental processes used by living organisms to break down sugar to produce energy stored in its chemical bonds.

Phospholipid biosynthesis
Arrows with discontinuous lines represent incorporation from the environment. Single continuous arrows represent single enzymatic steps, whereas wide arrows represent several enzymatic steps (the number within the arrow indicates the number of steps). Lines with a final black point indicate the necessity of metabolites for some of the transformations inside the corresponding box. Metabolic intermediates and final pathway products are in green boxes. Metabolites acting as a source of chemical energy are in red boxes. Reducing-power cofactors are in light blue boxes. Abbreviations (besides the accepted symbols and those defined in the text): PEP, phosphoenolpyruvate; G6P, glucose-6-phosphate; Gd3P, glyceraldehyde-3-phosphate; DHAP, dihydroxyacetonephosphate; G3P, sn-glycerol-3-phosphate; CDP-DAG, CDP-diacylglycerol; SAM, S-adenosylmethionine; THF, tetrahydrofolate. Metabolic precursors of external origin are in gray boxes.

1. http://cosmology.com/Abiogenesis113.html
2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2442391/
3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC515251/

The origin and evolution of modern metabolism

Metabolic networks analogous to electronic circuits point to design.

In the following topic, I have reported

The interdependent and irreducible structures required to make proteins
https://reasonandscience.catsboard.com/t2039-the-interdependent-and-irreducible-structures-required-to-make-proteins

Lets have a look, how secular science tries to explain the origin of the primordial metabolic network to make amino acids:

The primordial metabolism: an ancestral interconnection between leucine, arginine, and lysine biosynthesis

It is generally assumed that primordial cells had small genomes with simple genes coding for enzymes able to react with a wide range of chemically related substrates, interconnecting different metabolic routes. New genes coding for enzymes with a narrowed substrate specificity arose by paralogous duplication(s) of ancestral ones and evolutionary divergence.

Can you believe this? how did this interconnection of metabolic routes occur? Imagine you have to create an electronic circuit. Have you EVER imagined or thought that it could emerge randomly, interconnecting the right parts by a lucky accident? That is precisely what the above science papers want us to believe. Does that make sense?

The comparison is not far-fetched:

Conceptual comparison of metabolic pathways with electronic circuits
https://link.springer.com/article/10.1007/BF03399473

An electronic circuit has been designed to mimic glycolysis, the Citric Acid (TCA) cycle and the electron transport chain. Enzymes play a vital role in metabolic pathways; similarly, transistors play a vital role in electronic circuits; the characteristics of enzymes in comparison with those of transistors suggests that the properties are analogous.

Tell me if this is not AMAZING ??!!

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In Narnia, we are transported to fantasy land. I feel sometimes, that God is taking my hands, and takes me to a walk to see what he has done to make life possible, to a reality which is more bewildering than in someone’s wildest dreams. When i move forward in my investigation, I step into new territory, and what i discover, makes me speechless.

The ability of transfer of just ONE SINGLE CARBON atom is absolutely essential for the metabolism of the amino acids glycine, serine, methionine, and histidine, and the biosynthesis of purines and pyrimidines - which constitute DNA molecules, the information carriers of cells.

And in order for biological cells to achieve this transfer, they require tetrahydrofolate cofactors, consisting of three moieties. Folates are among the most complex pterin coenzymes. The folate pathway is central to any study related to DNA methylation, dTMP synthesis or purine synthesis, and as such, to the origin of life itself, since without amino acids, and DNA - no life.

Annexed below, you can see the Folate biosynthesis pathway - at each branch point, there is a ramification of a web of complex enzymes which work in a coordinated, orchestrated, and interconnected way together to produce just this Tetrahydrofolate cofactor. To make things even more complex, the two essential precursors of folate biosynthesis are 4-aminobenzoate (a product of shikimate biosynthesis pathway) and GTP. To give you an idea about the complexity of the shikimate metabolic pathway, you can have a look here:

http://www.genome.jp/kegg-bin/show_pathway?map01063

The central pathway uses six extremely complex enzymes, which I describe in detail in the article below. Moral of the story: These metabolic networks, enzymes, and co-factors are upon which life depends, and could hardly be explained with any other causal mechanism, besides a super intelligent creator.

https://reasonandscience.catsboard.com/t2590p25-origins-what-cause-explains-best-our-existence-and-why#5938

William Martin and colleagues from University Düsseldorf’s Institute of Molecular Evolution give us also an interesting number:

The metabolism of cells contains evidence reflecting the process by which they arose. Here, we have identified the ancient core of autotrophic metabolism encompassing 404 reactions that comprise the reaction network from H2, CO2, and ammonia (NH3) to amino acids, nucleic acid monomers, and the 19 cofactors required for their synthesis. Water is the most common reactant in the autotrophic core, indicating that the core arose in an aqueous environment. Seventy-seven core reactions involve the hydrolysis of high-energy phosphate bonds, furthermore suggesting the presence of a non-enzymatic and highly exergonic chemical reaction capable of continuously synthesizing activated phosphate bonds. CO2 is the most common carbon-containing compound in the core. An abundance of NADH and NADPH-dependent redox reactions in the autotrophic core, the central role of CO2, and the circumstance that the core’s main products are far more reduced than CO2 indicate that the core arose in a highly reducing environment. The chemical reactions of the autotrophic core suggest that it arose from H2, inorganic carbon, and NH3 in an aqueous environment marked by highly reducing and continuously far from equilibrium conditions. 54 55

Eight fundamental problems in the emergence of the first metabolic network of the universal common ancestor

https://reasonandscience.catsboard.com/t2371-how-cellular-enzymatic-and-metabolic-networks-point-to-design#9336

John D. Sutherland: Provisioning the origin and early evolution of life 2019 Nov 11

1. There is no alternative to enzymatic catalysts
The degree of catalysis by enzymes can be remarkable, for example, orotidine monophosphate decarboxylase accelerates the uncatalyzed reaction, which has a half-life of seventy-eight million years, ∼10^17-fold. Without this single reaction, there would be no pyrimidine ribonucleotides produced by the (proto)biological network, no functional RNA, and no prospects of translation ever emerging. Catalysis of almost all of the reactions of the network would thus be necessary for the network to operate with any degree of efficiency.

2. Negative aspects of catalysis.
Metal ion cofactors catalyze deleterious as well as desired reactions. It has been known for decades that metal ions, particularly divalent ones, can catalyze certain biological reactions, albeit modestly, but without shepherding by enzymes they also catalyze unwanted reactions. An essential reaction of the partial gluconeogenesis branch is the enolase-catalyzed conjugate addition of water to phosphoenolpyruvate (PEP), giving 2-phosphoglycerate (2-PG), but divalent metal ions instead catalyze the attack of water at the phosphate group of PEP resulting in hydrolysis back to pyruvate. Certain ions are particularly effective at this, the hydrolysis being ‘strongly accelerated’ by ferrous ions, for example. Likewise, the decarboxylation of oxaloacetate back to pyruvate is catalyzed by divalent metal ions, as is the aldol dimerization of pyruvate which would compete with its conversion to acetolactate — even if that could ever be achieved without TPP — and thence valine and leucine.

3. Flux control from branch points and regulation.
Flux through the different branches emanating from branch points has to be controlled such that all the branches are productive. Thus, if any of the reactions leading away from pyruvate is significantly faster than the others, the others suffer, yet all are crucial. This problem is compounded by the divalent metal ion problem outlined above. Biology catalyzes reactions differentially such that most are brought up to a similar speed, thus avoiding bottlenecks, but the background reactions have widely differing rates. Thus, even if prebiotically plausible catalysts for all 75 or so reactions could be found, it would not be enough, as they would additionally need to accelerate the individual reactions in the same differential way as do the enzymes used in biology, for the network to operate with the efficiency needed.

4. Instability of intermediates.
Metabolic networks are able to handle some extremely unstable intermediates, which decompose in the absence of enzymes. Thus, for example, phosphoribosylamine, produced by ammonolysis of PRPP, hydrolyses to ribose-5-phosphate with a half-life of 38 seconds under physiological conditions and it anomerises even faster. Any non-enzymatic catalyst for the subsequent glycosylation step would have to outcompete these rapid reactions or there would be no purine ribonucleotides.

5. Oxidation in a reducing environment.
Biology plays redox chemistry really well, but achieving this at a network level without enzymes and redox cofactors would be extremely tricky. For sure, oxidation and reduction reactions can operate simultaneously in chemistry, but oxidizing the hydroxyl group of 3-isopropylmalate, en route to leucine, would be challenging in the presence of other alcohols, particularly whilst simultaneously reducing dihydroxyacetone phosphate to glycerol-3-phosphate. Dehydrogenating dihydroorotate and inosine monophosphate during ribonucleotide synthesis would be similarly difficult whilst hydrogenating enoyl derivatives in fatty acid synthesis.

6. Substrate selectivity.
By employing enzymes with concave active sites, biology is capable of discriminating between chemically similar compounds of different shapes and sizes. Without such discrimination, it would not be possible to control selectivity in the network. Thus, for example, any non-enzymatic phosphatase mimic that could hydrolyse fructose-1,6-bisphosphate, and mitigate the triose phosphate instability problem alluded to above, would be hard-pressed not to dephosphorylate any of the many monophosphates in the network, especially dihydroxyacetone phosphate. Similarly, in purine ribonucleotide synthesis any simple catalyst that happened to be able to formylate the amino group of aminoimidazolecarboxamide ribonucleotide (AICAR) would have a hard job in not formylating the more nucleophilic amino group of the closely related aminoimidazole ribonucleotide (AIR). Formylation of the latter intermediate would block purine ribonucleotide synthesis and thus prevent the formation of functional RNA.

7. The ammonia problem.
Ammonia is needed throughout the network, but there are many intermediates that are destroyed by this potent nucleophile. Biology gets around this by storing ammonia in compounds such as glutamate and glutamine and then releasing it at the enzyme active sites, or at the entrances to tunnels to other active sites, where it is needed. Absent this trick, it would be highly difficult to reductively aminate pyruvate to alanine, for example, without ammonolysing the various thioesters and acyl phosphates of the network. Ammonolysis of acetyl-CoA to give acetamide would shut down the synthesis of pyruvate. Ammonolysis of acyl phosphates, or thioesters derived therefrom, would prevent the reduction of carboxylate groups to aldehydes that occurs throughout the network.

8.Energy coupling
Expenditure of ATP (or GTP) is required to drive many of the reactions of the network, which would otherwise be energetically unfavorable. Proponents of building block synthesis by nascent life have gradually moved away from the idea that some sort of primitive chemiosmosis could regenerate ATP (and thence GTP). They have even moved away from nucleoside triphosphates as an energy currency because of their kinetic inertness and currently seem to favor acetyl phosphate as a source of energy, even though its hydrolysis is catalyzed by metal ions. Granted, acetyl phosphate has the potential to phosphorylate homoserine, for example, — though it would have to be a very selective catalyst that managed to discriminate between the hydroxyl group of this alcohol and 55 M water — but what about the crucial phosphorylation of pyruvate to PEP? This latter reaction needs two high-energy phosphate bonds of ATP to be spent to drive it and the enzyme that catalyzes the transformation does so using some pretty spectacular enzymology. It is an almost inconceivable transformation using acetyl phosphate and prebiotically plausible non-enzymatic catalysts. Even if it was possible, it would have to compete with the divalent metal ion-catalyzed hydrolysis back to pyruvate.

Are there any ways to escape from these eight fundamental problems?
If the mantra is strictly adhered to, no. So, what is now happening is that people who insist on synthesis in cellulo as biology emerges are opting for reactions that are increasingly different from those in extant biology. But the eight problems are irredeemable even by this shifting of the goal posts. Thus, one cannot invoke iron-nickel sulfide catalyzed synthesis of acetyl thioesters at the same time and place as the ferrous–ferric iron-mediated reductive amination of pyruvate to alanine with 0.375 M ammonia because of the ammonia problem. It is not possible to have a formose reaction of formaldehyde to generate pentoses at the same time as ferrous iron-mediated aldolization chemistry of pyruvate because of myriad deleterious crossed aldolisations between oxoacids, formaldehyde, and sugars. One cannot rely on metallic iron and hydroxylamine as a way of converting pyruvate to alanine  because the same conditions will destroy key intermediates in the network, for example by converting all acyl phosphates and thioesters to hydroxamates. No amount of hard selling can resurrect this dead parrot of an idea — caveat emptor.

Summary
Synthesizing life's building blocks using the same pathways and intermediates as extant biology is a near-impossible task without enzymes.
However, the building blocks can be synthesized from hydrogen cyanide and its derivatives under prebiotically plausible conditions, but some of these conditions are incompatible with life.
Therefore, it is proposed that the origin and early evolution of life took place in an environment containing previously synthesized building blocks.
The pathways and intermediates of extant biology could then have been introduced in a patchwork fashion as environmental supplies of building blocks became depleted and early organisms adapted to their changing conditions.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6992421/