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.