isocitrate

Isocitrate is a tricarboxylic acid that functions as an intermediate in the citric acid cycle (Krebs cycle). It is formed from citrate by the enzyme aconitase through a reversible dehydration–rehydration rearrangement and is then oxidatively decarboxylated to α-ketoglutarate, releasing carbon dioxide and reducing NAD+ or NADP+ to NADH or NADPH.

The oxidative step is catalyzed by isocitrate dehydrogenase, of several forms in different organisms. In mammals, the main catalytic routes are the mitochondrial NAD+-dependent IDH3 and the cytosolic/mitochondrial NADP+-dependent IDH1/IDH2. Both pathways convert isocitrate to α-ketoglutarate and CO2, but IDH3 generates NADH while IDH1/IDH2 generate NADPH, linking isocitrate metabolism to energy production and reductive biosynthesis.

Isocitrate can also be redirected by organisms possessing the glyoxylate cycle. In plants, bacteria, and fungi, isocitrate lyase cleaves isocitrate into succinate and glyoxylate, enabling net conversion of acetyl-CoA into four-carbon compounds for gluconeogenesis. Mammals lack a complete glyoxylate cycle, so this pathway is not present in humans.

Regulation of isocitrate metabolism reflects cellular energy and redox status. Isocitrate dehydrogenase activity is influenced by ADP (activator) and NADH (inhibitor), among other factors, and thus isocitrate levels correlate with flux through the citric acid cycle. α-Ketoglutarate, the product of the isocitrate dehydrogenase reaction, is a key intermediate in amino acid and nucleotide biosynthesis, linking energy metabolism to anabolism.

Clinical notes include the relevance of mutations in IDH enzymes in certain cancers, where altered enzyme activity affects metabolite balance and cellular signaling, including the production of oncometabolites from α-ketoglutarate.