The pentose phosphate pathway consists of three stages, in which NADPH is produced, pentoses undergo isomerization a , and glycolytic intermediates are recovered. The pathway provides NADPH for reductive biosynthesis and ribose-5-phosphate b for nucleotide biosynthesis in the quantities that the cell requires. One role of the pentose phosphate pathway is production of pentoses, which are constituents of nucleotides. The second role of the pentose phosphate pathway is the production of metabolic (active) hydrogen, [H] in the form of NAD(P)H. This metabolic hydrogen is needed for many kinds of reductive syntheses. Each of the two major pathways of carbohydrate metabolism has a role in providing specific building blocks for cell synthesis . . . The Embden-Meyerhof pathway and the citric acid cycle not only furnish energy as ATP and reduced diphosphopyridine nucleotide (NADH), but also provide precursors of alanine, glutamic acid and the amino acids derived from it, and aspartic acid and its many metabolic products, including the purines and pyrimidines. The pentose phosphate pathway provides energy as reduced triphosphopyridine nucleotide (NADPH) as well as precursors for a number of aminoacids such as histidine, and aromatic amino acids. It also provides ribose and deoxyribose. Some of the reactions, in the reverse direction, are part of the Calvin cycle for- the assimilation of C02 by photosynthetic cells.
The pentose phosphate pathway.
The number of lines in an arrow represents the number of molecules reacting in one turn of the pathway so as to convert 3 G6P to 3 CO2, 2 F6P, and 1 GAP. For the sake of clarity, sugars from Reaction 3 onward are
shown in their linear forms. The carbon skeleton of R5P and the atoms derived from it are drawn in red, and those from Xu5P are drawn in green. The C2 units transferred by transketolase are shaded in green, and the C3 units transferred by transaldolase are shaded in blue. Double-headed arrows indicate reversible reactions.
The Pentose Phosphate Pathway Begins with Two Oxidative Steps
The pentose phosphate pathway
The glucose-6-phosphate dehydrogenase reaction is the first committed step in the pentose phosphate pathway. in step two, the the gluconolactonase reaction, and step three, the 6-phosphogluconate dehydrogenase reaction.
1. Glucose-6-Phosphate Dehydrogenase
The pentose phosphate pathway begins with the oxidation of glucose-6-phosphate. The products of the reaction are a cyclic ester (the lactone of phosphogluconic acid) and NADPH (Figure above). Glucose-6- phosphate dehydrogenase (G6PDH), which catalyzes this reaction, is highly specific for NADP1. As the first step of a major pathway, the reaction is irreversible and highly regulated. Glucose-6-phosphate dehydrogenase is strongly inhibited by the product coenzyme, NADPH, and also by fatty acid esters of coenzyme A (which are intermediates of fatty acid biosynthesis).
The gluconolactone produced in step 1 is hydrolytically unstable and readily undergoes a spontaneous ring-opening hydrolysis, although an enzyme, gluconolactonase, accelerates this reaction ( Step two, figure above ). The linear product, the sugar acid 6-phospho-d-gluconate, is further oxidized in step 3.
3. 6-Phosphogluconate Dehydrogenase
The oxidative decarboxylation of 6-phosphogluconate by Phosphogluconate dehydrogenase yields d-ribulose-5-phosphate and another equivalent of NADPH. There are two distinct steps in this reaction
( Step three, Figure above): The initial NADP1-dependent dehydrogenation yields a b-keto acid, 3-keto-6-phosphogluconate, which is very susceptible to decarboxylation (the second step). The resulting product, d-ribulose-5-P, is the substrate for the nonoxidative reactions composing the rest of this pathway.
There Are Four Nonoxidative Reactions in the Pentose Phosphate Pathway
This portion of the pathway begins with an isomerization and an epimerization c , and it leads to the formation of either d-ribose-5-phosphate or d-xylulose-5-phosphate. These intermediates can then be converted into glycolytic intermediates or directed to biosynthetic processes.
4. Phosphopentose Isomerase
Phosphopentose Isomerase interconverts ribulose-5-P and ribose- 5-P via an enediol intermediate (Figure below). The reaction (and mechanism) is quite similar to the phosphoglucoisomerase reaction of glycolysis, which interconverts glucose-6-P and fructose-6-P. The ribose-5-P produced in this reaction is utilized in the biosynthesis of coenzymes (including NADH, NADPH, FAD, and B12) nucleotides, and nucleic acids (DNA and RNA).
The phosphopentose isomerase reaction involves an enediol intermediate.
5. Phosphopentose Epimerase
This reaction converts ribulose-5-P to another ketose, namely, xylulose-5-P. This reaction also proceeds by an enediol intermediate but involves an inversion at C-3 (Figure below).
In the reaction, an acidic proton located a- to a carbonyl carbon is removed to generate the enediolate, but the proton is added back to the same carbon from the opposite side. Note the distinction in nomenclature here. Interchange of groups on a single carbon is an epimerization, and interchange of groups between carbons is an isomerization. To this point, the pathway has generated a pool of pentose phosphates. The three pentose-5-phosphates coexist at equilibrium. The pathway has also produced two molecules of NADPH for each glucose- 6-P converted to pentose-5-phosphate. The next three steps rearrange the five-carbon skeletons of the pentoses to produce three-, four-, six-, and seven-carbon units, which can be used for various metabolic purposes. Why should the cell do this? Very often, the cellular need for NADPH is considerably greater than the need for ribose-5-phosphate. The next three steps thus return some of the five-carbon units to glyceraldehyde-3-phosphate and fructose-6-phosphate, which can enter the glycolytic pathway. The advantage of this is that the cell has met its needs for NADPH and ribose-5-phosphate in a single pathway, yet at the same time it can return the excess carbon metabolites to glycolysis.
This is remarkable and raises the question: How did this arrangement emerge? We can observe, that a single pathway is less complex, and the metabolic pathways choice follows a logic and attends a specific distant demand, to produce the various metabolites in the right amount.
The PPP has gained recognition as being a central player in cellular biosynthetic metabolism and in controlling and maintaining the redox homeostasis of cells
The pentose phosphate pathway is the major source for the NADPH required for anabolic processes. There are three distinct phases each of which has a distinct outcome. Depending on the needs of the organism the metabolites of that outcome can be fed into many other pathways. Gluconeogenesis is directly connected to the pentose phosphate pathway. As the need for glucose-6-phosphate (the beginning metabolite in the pentose phosphate pathway) increases so does the activity of gluconeogenesis.3
The main molecule in the body that makes anabolic processes possible is NADPH. Because of the structure of this molecule it readily donates hydrogen ions to metabolites thus reducing them and making them available for energy harvest at a later time. The PPP is the main source of synthesis for NADPH. The pentose phosphate pathway (PPP) is also responsible for the production of Ribose-5-phosphate which is an important part of nucleic acids. Finally the PPP can also be used to produce glyceraldehyde-3-phosphate which can then be fed into the TCA and ETC cycles allowing for the harvest of energy. Depending on the needs of the cell certain enzymes can be regulated and thus increasing or decreasing the production of desired metabolites. The enzymes reasonable for catalyzing the steps of the PPP are found most abundantly in the liver (the major site of gluconeogenesis) more specifically in the cytosol. The cytosol is where fatty acid synthesis takes place which is a NADPH dependent process.
The beginning molecule for the PPP is glucose-6-P which is the second intermediate metabolite in glycolysis.
The PPP and glycolysis are therefore interdependent.
Glucose-6-P is oxidized in the presence of glucose-6-P dehydrogenase and NADP+. This step is irreversible and is highly regulated. NADPH and fatty acyl-CoA are strong negative inhibitors to this enzyme. The purpose of this is to decrease production of NADPH when concentrations are high or the synthesis of fatty acids is no longer necessary.
The metabolic product of this step is gluconolactone which is hydrolytrically unstable. Gluconolactonase causes gluconolactone to undergo a ring opening hydrolysis. The product of this reaction is the more stable sugar acid, 6-phospho-D-gluconate.
6-phospho-D-gluconate is oxidized by NADP+ in the presence of 6-phosphogluconate dehydrogenase which yields ribulose-5-phosphate.
The oxidation phase of the PPP is solely responsible for the production of the NADPH to be used in anabolic processes.
Ribulose-5-phosphate can then be isomerized by phosphopentose isomerase to produce ribose-5-phosphate. Ribose-5-phosphate is one of the main building blocks of nucleic acids and the PPP is the primary source of production of ribose-5-phosphate. If production of ribose-5-phosphate exceeds the needs of required ribose-5-phosphate in the organism, then phosphopentose epimerase catalyzes a chiralty rearrangement about the center carbon creating xylulose-5-phosphate. The products of these two reactions can then be rearranged to produce many different length carbon chains. These different length carbon chains have a variety of metabolic fates.
There are two main classes of enzymes responsible for the rearrangement and synthesis of the different length carbon chain molecules. These are transketolase and transaldolase. Transketolase is responsible for the cleaving of a two carbon unit from xylulose-5-P and adding that two carbon unit to ribose-5-P thus resulting in glyceraldehyde-3-P and sedoheptulose-7-P. Transketolase is also responsible for the cleaving of a two carbon unit from xylulose-5-P and adding that two carbon unit to erythrose-4-P resulting in glyceraldehyde-3-P and fructose-6-P. Transaldolase is responsible for cleaving the three carbon unit from sedoheptulose-7-P and adding that three carbon unit to glyceraldehyde-3-P thus resulting in erythrose-4-P and fructose-6-P. The end results of the rearrangement phase is a variety of different length sugars which can be fed into many other metabolic processes. For example, fructose-6-P is a key intermediate of glycolysis as well as glyceraldehyde-3-P.
Pentose Phosphate Pathway of Glucose Oxidation 2
In most animal tissues, the major catabolic fate of glucose 6-phosphate is glycolytic breakdown to pyruvate, much of which is then oxidized via the citric acid cycle, ultimately leading to the formation of ATP. Glucose 6-phosphate does have other catabolic fates, however, which lead to specialized products needed by the cell. Of particular importance in some tissues is the oxidation of glucose 6-phosphate to pentose phosphates by the pentose phosphate pathway (also called the phosphogluconate pathway or the hexose monophosphate pathway;
In this oxidative pathway, NADP is the electron acceptor, yielding NADPH. Rapidly dividing cells, such as those of bone marrow, skin, and intestinal mucosa, and those of tumors, use the pentose ribose 5-phosphate to make RNA, DNA, and such coenzymes as ATP, NADH, FADH2, and coenzyme A. In other tissues, the essential product of the pentose phosphate pathway is not the pentoses but the electron donor NADPH, needed for reductive biosynthesis or to counter the damaging effects of oxygen radicals. Tissues that carry out extensive fatty acid synthesis (liver, adipose, lactating mammary gland) or very active synthesis of cholesterol and steroid hormones (liver, adrenal glands, gonads) require the NADPH provided by this pathway. Erythrocytes and the cells of the lens and cornea are directly exposed to oxygen and thus to the damaging free radicals generated by oxygen. By maintaining a reducing atmosphere (a high ratio of NADPH to NADP and a high ratio of reduced to oxidized glutathione), such cells can prevent or undo oxidative damage
to proteins, lipids, and other sensitive molecules.
a In chemistry isomerization (also isomerisation) is the process by which one molecule is transformed into another molecule which has exactly the same atoms, but the atoms have a different arrangement e.g. A-B-C → B-A-C (these related molecules are known as isomers ). 4
b The starting material for purine biosynthesis is α-D-ribose-5-phosphate, a product of the pentose phosphate pathway. IMP is synthesized through the assembly of a purine base on ribose-5-phosphate. Ribose 5-phosphate (R5P) is both a product and an intermediate of the pentose phosphate pathway. The last step of the oxidative reactions in the pentose phosphate pathway is the production of ribulose 5-phosphate. Depending on the body's state, ribulose 5-phosphate can reversibly isomerize to ribose 5-phosphate. Ribulose 5-phosphate can alternatively undergo a series of isomerizations as well as transaldolations and transketolations that result in the production of other pentose phosphates as well as fructose 6-phosphate and glyceraldehyde 3-phosphate (both intermediates in glycolysis). 5 Ribose-5-phosphate is also an essential component of ATP, NAD1, FAD, coenzyme A, and particularly DNA and RNA. 6
c The process of forming an epimer by changing one asymmetric centre in a compound that has more than one. Epimerization is a chemical process where an epimer is made to transform into its chiral counterpart. It can happen in condensed tannins depolymerisation reactions. Epimerisation can be spontaneous (generally a slow process), or catalyzed by enzymes, e.g. the epimerization between the sugars N-acetylglucosamine and N-acetylmannosamine, which is catalyzed by renin-binding protein. 7
2) Lehninger Principles of Biochemistry fifth edition pg.558
6. Biochemistry, 6th ed. Garrett, page 756
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