Citric acid cycle (TCA cycle)

Stable Identifier
Homo sapiens
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In the citric acid or tricarboxylic acid (TCA) cycle, the acetyl group of acetyl CoA (derived primarily from oxidative decarboxylation of pyruvate, beta-oxidation of long-chain fatty acids, and catabolism of ketone bodies and several amino acids) can be completely oxidized to CO2 in reactions that also yield one high-energy phosphate bond (as GTP or ATP) and four reducing equivalents (three NADH + H+, and one FADH2). Then, the electron transport chain oxidizes NADH and FADH2 to yield nine more high-energy phosphate bonds (as ATP). All reactions of the citric acid cycle take place in the mitochondrion.

Eight canonical reactions mediate the synthesis of citrate from acetyl-CoA and oxaloacetate and the metabolism of citrate to re-form oxaloacetate. Three reactions are reversible: the interconversions of citrate and isocitrate, of fumarate and malate, and of malate and oxaloacetate. The reverse reactions are irrelevant under normal physiological conditions but appear to have a role in glucose- and glutamine-stimulated insulin secretion (Zhang et al., 2020) and cancer metabolism (e.g., Jiang et al., 2016). Succinate synthesis from succinyl-CoA can be coupled to the phosphorylation of either GDP (the canonical reaction) or ADP; we annotate both reactions. Two mitochondrial isocitrate dehydrogenase isozymes catalyze the oxidative decarboxylation of isocitrate to form alpha-ketoglutarate (2-oxoglutarate): IDH3 catalyzes the canonical reaction coupled to the reduction of NAD+, while IDH2 catalyzes the same reaction coupled to the reduction of NADP+, a reaction whose normal physiological function is unclear. Both reactions are annotated.

The cyclical nature of the reactions responsible for the oxidation of acetate was first suggested by Hans Krebs from biochemical studies of pigeon breast muscle (Krebs et al., 1938; Krebs and Eggleston, 1940). Ochoa and colleagues studied many molecular details of individual reactions, mainly by studying enzymes purified from pig hearts (Ochoa, 1980). While the human homologs of these enzymes have all been identified, their biochemical characterization has, in general, been limited, and many molecular details of the human reactions are inferred from those worked out in studies of the model systems. Studies examining the impact of elevated citric acid cycle intermediates such as succinate and fumarate led to the recognition of the role of metabolites in driving cancer progression ('oncometabolites') (Pollard et al., 2005; reviewed in Hayashi et al., 2018). The role of TCA enzymes in disease was reviewed by Kang et al., 2021.

Literature References
PubMed ID Title Journal Year
16746585 The formation of citric and alpha-ketoglutaric acids in the mammalian body

Krebs, HA, Johnson, WA, Salvin, E

Biochem J 1938
34884868 Emerging Role of TCA Cycle-Related Enzymes in Human Diseases

Saito, T, Miyado, K, Suzuki, M, Kang, W

Int J Mol Sci 2021
16747180 The oxidation of pyruvate in pigeon breast muscle

Eggleston, LV, Krebs, HA

Biochem J 1940
33321098 Reductive TCA cycle metabolism fuels glutamine- and glucose-stimulated insulin secretion

Gray, SM, Lu, D, Wang, Y, Jensen, MV, Zhang, GF, El, K, Newgard, CB, Campbell, JE, Becker, TC

Cell Metab 2021
15987702 Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations

Wortham, NC, Griffiths, JR, Moat, SJ, Pollard, PJ, Barclay, E, Barwell, J, Mitchell, M, Tomlinson, IP, Alam, NA, Hargreaves, IP, Poulsom, R, Dalgleish, A, Heales, SJ, Hodgson, SV, Hunt, T, Gleeson, MJ, McGrath, JA, Brière, JJ, Rustin, P, Chung, YL, Olpin, S

Hum Mol Genet 2005
27049945 Reductive carboxylation supports redox homeostasis during anchorage-independent growth

Metallo, CM, Yang, C, Jiang, L, Shestov, AA, Swain, P, Terada, LS, Wang, QA, Schmidt, S, DeBerardinis, RJ, Schwartz, B, Parker, SJ, Adams, ND, Dranka, BP, Pietrak, B, McCabe, MT

Nature 2016
30844107 Hypoxia/pseudohypoxia-mediated activation of hypoxia-inducible factor-1α in cancer

Harada, H, Yokota, A, Hayashi, Y, Huang, G

Cancer Sci 2019
6773467 The pursuit of a hobby

Ochoa, S

Annu Rev Biochem 1980
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