Citric acid cycle

The citric acid cycle—also known as the Krebs cycle, Szent–Györgyi–Krebs cycle or the TCA cycle (tricarboxylic acid cycle)

aerobic respiration. In addition, the cycle provides precursors of certain amino acids, as well as the reducing agent NADH, that are used in numerous other reactions. Its central importance to many biochemical pathways suggests that it was one of the earliest components of metabolism.^[3]^[4] Even though it is branded as a "cycle", it is not necessary for metabolites to follow only one specific route; at least three alternative segments of the citric acid cycle have been recognized.^[5]

The name of this metabolic pathway is derived from the citric acid (a tricarboxylic acid, often called citrate, as the ionized form predominates at biological pH^[6]) that is consumed and then regenerated by this sequence of reactions to complete the cycle. The cycle consumes acetate (in the form of acetyl-CoA) and water, reduces NAD⁺ to NADH, releasing carbon dioxide. The NADH generated by the citric acid cycle is fed into the oxidative phosphorylation (electron transport) pathway. The net result of these two closely linked pathways is the oxidation of nutrients to produce usable chemical energy in the form of ATP.

In

inner membrane of the mitochondrion

.

For each pyruvate molecule (from glycolysis), the overall yield of energy-containing compounds from the citric acid cycle is three NADH, one FADH₂, and one GTP.^[7]

Discovery

Several of the components and reactions of the citric acid cycle were established in the 1930s by the research of

Nobel Prize for Physiology or Medicine in 1953, and for whom the cycle is sometimes named the "Krebs cycle".^[11]

Overview

acetyl group; the portion in black is coenzyme A

.

The citric acid cycle is a

enzymes that completely oxidize acetate (a two carbon molecule), in the form of acetyl-CoA, into two molecules each of carbon dioxide and water. Through catabolism of sugars, fats, and proteins, the two-carbon organic product acetyl-CoA is produced which enters the citric acid cycle. The reactions of the cycle also convert three equivalents of nicotinamide adenine dinucleotide (NAD⁺) into three equivalents of reduced NAD⁺ (NADH), one equivalent of flavin adenine dinucleotide (FAD) into one equivalent of FADH₂, and one equivalent each of guanosine diphosphate (GDP) and inorganic phosphate (P_i) into one equivalent of guanosine triphosphate (GTP). The NADH and FADH₂ generated by the citric acid cycle are, in turn, used by the oxidative phosphorylation

pathway to generate energy-rich ATP.

One of the primary sources of acetyl-CoA is from the breakdown of sugars by glycolysis which yield pyruvate that in turn is decarboxylated by the pyruvate dehydrogenase complex generating acetyl-CoA according to the following reaction scheme:

+ HSCoA + NAD⁺ → + NADH + CO₂

The product of this reaction, acetyl-CoA, is the starting point for the citric acid cycle. Acetyl-CoA may also be obtained from the oxidation of fatty acids. Below is a schematic outline of the cycle:

The
acetyl
group from acetyl-CoA to the four-carbon acceptor compound (oxaloacetate) to form a six-carbon compound (citrate).
The citrate then goes through a series of chemical transformations, losing two
anabolism, they might not be lost, since many citric acid cycle intermediates are also used as precursors for the biosynthesis of other molecules.^[12]

Most of the electrons made available by the oxidative steps of the cycle are transferred to NAD⁺, forming NADH. For each acetyl group that enters the citric acid cycle, three molecules of NADH are produced. The citric acid cycle includes a series of redox reactions in mitochondria.^[clarification needed]^[13]
In addition, electrons from the succinate oxidation step are transferred first to the
Complex III
.
For every NADH and FADH₂ that are produced in the citric acid cycle, 2.5 and 1.5 ATP molecules are generated in oxidative phosphorylation, respectively.
At the end of each cycle, the four-carbon oxaloacetate has been regenerated, and the cycle continues.

Steps

There are ten basic steps in the citric acid cycle, as outlined below. The cycle is continuously supplied with new carbon in the form of acetyl-CoA, entering at step 0 in the table.^[14]

	Reaction type	Substrates	Enzyme	Products	Comment
0 / 10	Aldol condensation	Acetyl CoA + H₂O	Citrate synthase	Citrate + CoA-SH	irreversible, extends the 4C oxaloacetate to a 6C molecule
1	Dehydration	Citrate	Aconitase	cis-Aconitate + H₂O	reversible isomerisation
2	Hydration	cis-Aconitate + H₂O	Aconitase	Isocitrate	reversible isomerisation
3	Oxidation	Isocitrate + NAD ⁺	Isocitrate dehydrogenase	Oxalosuccinate + NADH + H ⁺	generates NADH (equivalent of 2.5 ATP)
4	Decarboxylation	Oxalosuccinate	Isocitrate dehydrogenase	α-Ketoglutarate + CO₂	rate-limiting, irreversible stage, generates a 5C molecule
5	Oxidative decarboxylation	α-Ketoglutarate + NAD⁺ + CoA-SH	α-Ketoglutarate dehydrogenase, Thiamine pyrophosphate, Lipoic acid , Mg++,transsuccinytase	Succinyl-CoA + NADH + H ⁺ + CO₂	irreversible stage, generates NADH (equivalent of 2.5 ATP), regenerates the 4C chain (CoA excluded)
6	substrate-level phosphorylation	P_i	Succinyl-CoA synthetase	Succinate + CoA-SH + GTP	or P_i and hydrolysis of succinyl-CoA involve the H₂O needed for balanced equation.
7	Oxidation	ubiquinone (Q)	Succinate dehydrogenase	Fumarate + ubiquinol (QH₂)	uses FAD as a prosthetic group (FAD→FADH₂ in the first step of the reaction) in the enzyme.^[15] These two electrons are later transferred to QH₂ during Complex II of the ETC, where they generate the equivalent of 1.5 ATP
8	Hydration	Fumarate + H₂O	Fumarase	L-Malate	Hydration of C-C double bond
9	Oxidation	L-Malate + NAD⁺	Malate dehydrogenase	Oxaloacetate + NADH + H⁺	reversible (in fact, equilibrium favors malate), generates NADH (equivalent of 2.5 ATP)
10 / 0	Aldol condensation	Acetyl CoA + H₂O	Citrate synthase	Citrate + CoA-SH	This is the same as step 0 and restarts the cycle. The reaction is irreversible and extends the 4C oxaloacetate to a 6C molecule

Two

coenzyme Q, which is the final electron acceptor of the reaction catalyzed by the succinate:ubiquinone oxidoreductase complex, also acting as an intermediate in the electron transport chain.^[15]

Mitochondria in animals, including humans, possess two succinyl-CoA synthetases: one that produces GTP from GDP, and another that produces ATP from ADP.^[16] Plants have the type that produces ATP (ADP-forming succinyl-CoA synthetase).^[14] Several of the enzymes in the cycle may be loosely associated in a multienzyme protein complex within the mitochondrial matrix.^[17]

The GTP that is formed by GDP-forming succinyl-CoA synthetase may be utilized by nucleoside-diphosphate kinase to form ATP (the catalyzed reaction is GTP + ADP → GDP + ATP).^[15]

Products

Products of the first turn of the cycle are one GTP (or ATP), three NADH, one FADH₂ and two CO₂.

Because two acetyl-CoA

molecules are produced from each glucose molecule, two cycles are required per glucose molecule. Therefore, at the end of two cycles, the products are: two GTP, six NADH, two FADH₂, and four CO₂.^[18]

Description	Reactants	Products
The sum of all reactions in the citric acid cycle is:	Acetyl-CoA + 3 NAD⁺ + FAD + GDP + P_i + 2 H₂O	→ CoA-SH + 3 NADH + FADH₂ + 3 H⁺ + GTP + 2 CO₂
Combining the reactions occurring during the pyruvate oxidation with those occurring during the citric acid cycle, the following overall pyruvate oxidation reaction is obtained:	Pyruvate ion + 4 NAD⁺ + FAD + GDP + P_i + 2 H₂O	→ 4 NADH + FADH₂ + 4 H⁺ + GTP + 3 CO₂
Combining the above reaction with the ones occurring in the course of glycolysis, the following overall glucose oxidation reaction (excluding reactions in the respiratory chain) is obtained:	Glucose + 10 NAD⁺ + 2 FAD + 2 ADP + 2 GDP + 4 P_i + 2 H₂O	→ 10 NADH + 2 FADH₂ + 10 H⁺ + 2 ATP + 2 GTP + 6 CO₂

The above reactions are balanced if P_i represents the H₂PO₄⁻ ion, ADP and GDP the ADP²⁻ and GDP²⁻ ions, respectively, and ATP and GTP the ATP³⁻ and GTP³⁻ ions, respectively.

The total number of ATP molecules obtained after complete oxidation of one glucose in glycolysis, citric acid cycle, and oxidative phosphorylation is estimated to be between 30 and 38.^[19]

Efficiency

The theoretical maximum yield of

malate-aspartate shuttle, transport of two of these equivalents of NADH into the mitochondria effectively consumes two equivalents of ATP, thus reducing the net production of ATP to 36. Furthermore, inefficiencies in oxidative phosphorylation due to leakage of protons across the mitochondrial membrane and slippage of the ATP synthase/proton pump commonly reduces the ATP yield from NADH and FADH₂ to less than the theoretical maximum yield.^[19] The observed yields are, therefore, closer to ~2.5 ATP per NADH and ~1.5 ATP per FADH₂, further reducing the total net production of ATP to approximately 30.^[20] An assessment of the total ATP yield with newly revised proton-to-ATP ratios provides an estimate of 29.85 ATP per glucose molecule.^[21]

Variation

While the citric acid cycle is in general highly conserved, there is significant variability in the enzymes found in different taxa [22] (note that the diagrams on this page are specific to the mammalian pathway variant).

Some differences exist between eukaryotes and prokaryotes. The conversion of D-threo-isocitrate to 2-oxoglutarate is catalyzed in eukaryotes by the NAD⁺-dependent EC 1.1.1.41, while prokaryotes employ the NADP⁺-dependent EC 1.1.1.42.^[23] Similarly, the conversion of (S)-malate to oxaloacetate is catalyzed in eukaryotes by the NAD⁺-dependent EC 1.1.1.37, while most prokaryotes utilize a quinone-dependent enzyme, EC 1.1.5.4.^[24]

A step with significant variability is the conversion of succinyl-CoA to succinate. Most organisms utilize EC 6.2.1.5, succinate–CoA ligase (ADP-forming) (despite its name, the enzyme operates in the pathway in the direction of ATP formation). In mammals a GTP-forming enzyme, succinate–CoA ligase (GDP-forming) (EC 6.2.1.4) also operates. The level of utilization of each isoform is tissue dependent.^[25] In some acetate-producing bacteria, such as Acetobacter aceti, an entirely different enzyme catalyzes this conversion – EC 2.8.3.18, succinyl-CoA:acetate CoA-transferase. This specialized enzyme links the TCA cycle with acetate metabolism in these organisms.^[26] Some bacteria, such as Helicobacter pylori, employ yet another enzyme for this conversion – succinyl-CoA:acetoacetate CoA-transferase (EC 2.8.3.5).^[27]

Some variability also exists at the previous step – the conversion of 2-oxoglutarate to succinyl-CoA. While most organisms utilize the ubiquitous NAD⁺-dependent 2-oxoglutarate dehydrogenase, some bacteria utilize a ferredoxin-dependent 2-oxoglutarate synthase (EC 1.2.7.3).^[28] Other organisms, including obligately autotrophic and methanotrophic bacteria and archaea, bypass succinyl-CoA entirely, and convert 2-oxoglutarate to succinate via

succinate semialdehyde, using EC 4.1.1.71, 2-oxoglutarate decarboxylase, and EC 1.2.1.79, succinate-semialdehyde dehydrogenase.^[29]

In

ten-eleven translocation (TET) enzymes; ordinarily TETs hydroxylate 5-methylcytosines to prime them for demethylation. However, in the absence of alpha-ketoglutarate this cannot be done and there is hence hypermethylation of the cell's DNA, serving to promote epithelial-mesenchymal transition (EMT) and inhibit cellular differentiation. A similar phenomenon is observed for the Jumonji C family of KDMs which require a hydroxylation to perform demethylation at the epsilon-amino methyl group.^[33] Additionally, the inability of prolyl hydroxylases to catalyze reactions results in stabilization of hypoxia-inducible factor alpha, which is necessary to promote degradation of the latter (as under conditions of low oxygen there will not be adequate substrate for hydroxylation). This results in a pseudohypoxic phenotype in the cancer cell that promotes angiogenesis, metabolic reprogramming, cell growth, and migration.^{[citation needed}

]

Regulation

Allosteric regulation by metabolites. The regulation of the citric acid cycle is largely determined by product inhibition and substrate availability. If the cycle were permitted to run unchecked, large amounts of

allosteric mechanism that can account for large changes in reaction rate from an allosteric effector whose concentration changes less than 10%.^[6]

Citrate is used for feedback inhibition, as it inhibits phosphofructokinase, an enzyme involved in glycolysis that catalyses formation of fructose 1,6-bisphosphate, a precursor of pyruvate. This prevents a constant high rate of flux when there is an accumulation of citrate and a decrease in substrate for the enzyme.^[34]

Regulation by calcium. Calcium is also used as a regulator in the citric acid cycle. Calcium levels in the mitochondrial matrix can reach up to the tens of micromolar levels during cellular activation.

α-ketoglutarate dehydrogenase.^[36] This increases the reaction rate of many of the steps in the cycle, and therefore increases flux throughout the pathway.^{[citation needed}

]

Transcriptional regulation. There is a link between intermediates of the citric acid cycle and the regulation of

prolyl 4-hydroxylases. Fumarate and succinate have been identified as potent inhibitors of prolyl hydroxylases, thus leading to the stabilisation of HIF.^[37]

Major metabolic pathways converging on the citric acid cycle

Several

catabolic pathways converge on the citric acid cycle. Most of these reactions add intermediates to the citric acid cycle, and are therefore known as anaplerotic reactions, from the Greek meaning to "fill up". These increase the amount of acetyl CoA that the cycle is able to carry, increasing the mitochondrion's capability to carry out respiration if this is otherwise a limiting factor. Processes that remove intermediates from the cycle are termed "cataplerotic" reactions.^[38]

In this section and in the next, the citric acid cycle intermediates are indicated in italics to distinguish them from other substrates and end-products.

NADH, as in the normal cycle.^[39]

However, it is also possible for pyruvate to be

carboxylated by pyruvate carboxylase to form oxaloacetate. This latter reaction "fills up" the amount of oxaloacetate in the citric acid cycle, and is therefore an anaplerotic reaction, increasing the cycle's capacity to metabolize acetyl-CoA when the tissue's energy needs (e.g. in muscle) are suddenly increased by activity.^[40]

In the citric acid cycle all the intermediates (e.g.

alpha-ketoglutarate, succinate, fumarate, malate, and oxaloacetate) are regenerated during each turn of the cycle. Adding more of any of these intermediates to the mitochondrion therefore means that that additional amount is retained within the cycle, increasing all the other intermediates as one is converted into the other. Hence the addition of any one of them to the cycle has an anaplerotic effect, and its removal has a cataplerotic effect. These anaplerotic and cataplerotic reactions will, during the course of the cycle, increase or decrease the amount of oxaloacetate available to combine with acetyl-CoA to form citric acid. This in turn increases or decreases the rate of ATP production by the mitochondrion, and thus the availability of ATP to the cell.^[40]

fatty acids, is the only fuel to enter the citric acid cycle. With each turn of the cycle one molecule of acetyl-CoA is consumed for every molecule of oxaloacetate present in the mitochondrial matrix, and is never regenerated. It is the oxidation of the acetate portion of acetyl-CoA that produces CO₂ and water, with the energy thus released captured in the form of ATP.^[40] The three steps of beta-oxidation resemble the steps that occur in the production of oxaloacetate from succinate in the TCA cycle. Acyl-CoA is oxidized to trans-Enoyl-CoA while FAD is reduced to FADH₂, which is similar to the oxidation of succinate to fumarate. Following, trans-Enoyl-CoA is hydrated across the double bond to beta-hydroxyacyl-CoA, just like fumarate is hydrated to malate. Lastly, beta-hydroxyacyl-CoA is oxidized to beta-ketoacyl-CoA while NAD+ is reduced to NADH, which follows the same process as the oxidation of malate to oxaloacetate.^[41]

In the liver, the carboxylation of
epinephrine in the blood.^[40] Here the addition of oxaloacetate to the mitochondrion does not have a net anaplerotic effect, as another citric acid cycle intermediate (malate) is immediately removed from the mitochondrion to be converted into cytosolic oxaloacetate, which is ultimately converted into glucose, in a process that is almost the reverse of glycolysis.^[40]

In
ketone bodies, which too can only be burned in tissues other than the liver where they are formed, or excreted via the urine or breath.^[40] These latter amino acids are therefore termed "ketogenic" amino acids, whereas those that enter the citric acid cycle as intermediates can only be cataplerotically removed by entering the gluconeogenic pathway via malate which is transported out of the mitochondrion to be converted into cytosolic oxaloacetate and ultimately into glucose. These are the so-called "glucogenic" amino acids. De-aminated alanine, cysteine, glycine, serine, and threonine are converted to pyruvate and can consequently either enter the citric acid cycle as oxaloacetate (an anaplerotic reaction) or as acetyl-CoA to be disposed of as CO₂ and water.^[40]

In
glyceraldehyde-3-phosphate by way of gluconeogenesis. In skeletal muscle, glycerol is used in glycolysis by converting glycerol into glycerol-3-phosphate, then into dihydroxyacetone phosphate (DHAP), then into glyceraldehyde-3-phosphate.^[42]

In many tissues, especially heart and skeletal
muscle tissue, fatty acids are broken down through a process known as beta oxidation, which results in the production of mitochondrial acetyl-CoA, which can be used in the citric acid cycle. Beta oxidation of fatty acids with an odd number of methylene bridges produces propionyl-CoA, which is then converted into succinyl-CoA and fed into the citric acid cycle as an anaplerotic intermediate.^[43]

The total energy gained from the complete breakdown of one (six-carbon) molecule of glucose by glycolysis, the formation of 2 acetyl-CoA molecules, their catabolism in the citric acid cycle, and oxidative phosphorylation equals about 30 ATP molecules, in eukaryotes. The number of ATP molecules derived from the beta oxidation of a 6 carbon segment of a fatty acid chain, and the subsequent oxidation of the resulting 3 molecules of acetyl-CoA is 40.^{[citation needed]}

Citric acid cycle intermediates serve as substrates for biosynthetic processes

In this subheading, as in the previous one, the TCA intermediates are identified by italics.
Several of the citric acid cycle intermediates are used for the synthesis of important compounds, which will have significant cataplerotic effects on the cycle.^[40] Acetyl-CoA cannot be transported out of the mitochondrion. To obtain cytosolic acetyl-CoA, citrate is removed from the citric acid cycle and carried across the inner mitochondrial membrane into the cytosol. There it is cleaved by
bile salts, and vitamin D.^[39]^[40]

The carbon skeletons of many
aspartate and asparagine; and alpha-ketoglutarate which forms glutamine, proline, and arginine.^[39]^[40]

Of these amino acids, aspartate and glutamine are used, together with carbon and nitrogen atoms from other sources, to form the
purines that are used as the bases in DNA and RNA, as well as in ATP, AMP, GTP, NAD, FAD and CoA.^[40]

The
pyrimidines are partly assembled from aspartate (derived from oxaloacetate). The pyrimidines, thymine, cytosine and uracil, form the complementary bases to the purine bases in DNA and RNA, and are also components of CTP, UMP, UDP and UTP.^[40]

The majority of the carbon atoms in the porphyrins come from the citric acid cycle intermediate, succinyl-CoA. These molecules are an important component of the hemoproteins, such as hemoglobin, myoglobin and various cytochromes.^[40]
During gluconeogenesis
phosphoenolpyruvate by phosphoenolpyruvate carboxykinase, which is the rate limiting step in the conversion of nearly all the gluconeogenic precursors (such as the glucogenic amino acids and lactate) into glucose by the liver and kidney.^[39]^[40]

Because the citric acid cycle is involved in both
anabolic processes, it is known as an amphibolic
pathway. Evan M.W.Duo Click on genes, proteins and metabolites below to link to respective articles. [§ 1]

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|alt=TCACycle_WP78 edit]]

TCACycle_WP78 edit

^ The interactive pathway map can be edited at WikiPathways: "TCACycle_WP78".

Glucose feeds the TCA cycle via circulating lactate

The metabolic role of lactate is well recognized as a fuel for tissues, mitochondrial cytopathies such as DPH Cytopathy, and the scientific field of oncology (tumors). In the classical Cori cycle, muscles produce lactate which is then taken up by the liver for gluconeogenesis. New studies suggest that lactate can be used as a source of carbon for the TCA cycle.^[45]

Evolution

It is believed that components of the citric acid cycle were derived from
anaerobic bacteria, and that the TCA cycle itself may have evolved more than once.^[46] It may even predate biosis: the substrates appear to undergo most of the reactions spontaneously in the presence of persulfate radicals.^[47] Theoretically, several alternatives to the TCA cycle exist; however, the TCA cycle appears to be the most efficient. If several TCA alternatives had evolved independently, they all appear to have converged to the TCA cycle.^[48]^[49]

See also

Calvin cycle

Glyoxylate cycle

Reverse (reductive) Krebs cycle

Krebs cycle (simple English)

References

ISBN 978-0-12-181870-8
.

ISBN 978-0-904498-22-6
.

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^ ^a ^b ^c Voet D, Voet JG (2004). Biochemistry (3rd ed.). New York: John Wiley & Sons, Inc. p. 615.

OCLC 769803483
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^ "The Nobel Prize in Physiology or Medicine 1937". The Nobel Foundation. Retrieved 2011-10-26.

^ Chandramana, Sudeep. (2014). Inclusive Growth And Youth Empowerment: A Development Model For Aspirational India. Journal of Science, Technology and Management. 7. 52–62.

PMID 16746382
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^ "The Nobel Prize in Physiology or Medicine 1953". The Nobel Foundation. Retrieved 2011-10-26.

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^
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External links

Scholia has a profile for TCA cycle (aka Krebs or citric acid cycle) (Q27436670).

An animation of the citric acid cycle at Smith College

Citric acid cycle variants at MetaCyc

Pathways connected to the citric acid cycle Archived 2008-10-26 at the Wayback Machine at Kyoto Encyclopedia of Genes and Genomes

metpath: Interactive representation of the citric acid cycle

v
t
e
Metabolism, catabolism, anabolism
General

Metabolic pathway

Metabolic network

Primary nutritional groups

Aerobic respiration

Glycolysis → Pyruvate decarboxylation → Citric acid cycle → Oxidative phosphorylation (electron transport chain + ATP synthase)

Anaerobic respiration

Electron acceptors other than oxygen

Fermentation

Glycolysis → Substrate-level phosphorylation
ABE

Ethanol

Lactic acid

Specific
paths
Protein metabolism

Protein synthesis

Catabolism (protein→peptide→amino acid)

Amino acid

Amino acid synthesis

Amino acid degradation (amino acid→pyruvate, acetyl CoA, or TCA intermediate)

Urea cycle

Nucleotide
metabolism

Purine metabolism

Nucleotide salvage

Pyrimidine metabolism

Purine nucleotide cycle

Carbohydrate metabolism
(carbohydrate catabolism
and anabolism)
Human

Glycolysis ⇄ Gluconeogenesis

Glycogenolysis ⇄ Glycogenesis

Pentose phosphate pathway

Fructolysis
Polyol pathway

Galactolysis
Leloir pathway

Glycosylation
N-linked

O-linked

Nonhuman

Photosynthesis

Anoxygenic photosynthesis

Chemosynthesis

Carbon fixation

DeLey-Doudoroff pathway

Entner-Doudoroff pathway

Xylose metabolism

Radiotrophism

Lipid metabolism
(lipolysis, lipogenesis)
Fatty acid metabolism

Fatty acid degradation (Beta oxidation)

Fatty acid synthesis

Other

Steroid metabolism

Sphingolipid metabolism

Eicosanoid metabolism

Ketosis

Reverse cholesterol transport

Other

Metal metabolism
Iron metabolism

Ethanol metabolism

Phospagen system (ATP-PCr)

Retrieved from "https://en.wikipedia.org/w/index.php?title=Citric_acid_cycle&oldid=1220687504"

[WikiPathways-45] The interactive pathway map can be edited at WikiPathways: "TCACycle_WP78".

[isbn0-12-181870-5-1] ISBN 978-0-12-181870-8
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[isbn0-904498-22-0-2] ISBN 978-0-904498-22-6
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[isbn0-393-06596-0-4] ISBN 978-0-393-06596-1
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[5] PMID 23378250
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[Voet_2004-6] Voet D, Voet JG (2004). Biochemistry (3rd ed.). New York: John Wiley & Sons, Inc. p. 615.

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[Nobel_Prize_1937-8] "The Nobel Prize in Physiology or Medicine 1937". The Nobel Foundation. Retrieved 2011-10-26.

[9] Chandramana, Sudeep. (2014). Inclusive Growth And Youth Empowerment: A Development Model For Aspirational India. Journal of Science, Technology and Management. 7. 52–62.

[10] PMID 16746382
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[Nobel_Prize_1953-11] "The Nobel Prize in Physiology or Medicine 1953". The Nobel Foundation. Retrieved 2011-10-26.

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[pmid15234968-25] PMID 15234968
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[pmid9325289-27] PMID 9325289
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[pmid19936047-28] PMID 19936047
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[pmid22174252-29] S2CID 206536295
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[30] PMID 28375741
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[31] PMID 31636445
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[32] PMID 26629338
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[33] PMID 21941621
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[34] ISBN 978-1-319-22800-2
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[35] PMID 23746507
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[pmid171557-36] S2CID 27367543
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[pmid17182618-37] PMID 17182618
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[38] PMID 12087111
.

[Voet-39] 
ISBN 978-0-471-21495-3
.

[stryer-40] 
ISBN 978-0-7167-2009-6
.

[41] OCLC 777722371
.

[42] PMID 12231658
.

[pmid2647392-43] PMID 2647392
.

[ferre-44] PMID 17344645
. this process is outlined graphically in page 73

[46] PMID 29045397
.

[pmid3332996-47] PMID 3332996
.

[48] PMID 28584880
. 83.

[pmid8703096-49] S2CID 19107073. Archived
(PDF) from the original on 2017-08-12.

[pmid11146883-50] S2CID 44260374. Archived
(PDF) from the original on 2003-05-08.

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