citric acid cycle

The TCA cycle begins with condensation of acetyl-CoA (2 carbons) with oxaloacetate (4 carbons) to form citrate (6 carbons), catalyzed by citrate synthase. Through 8 enzymatic steps, citrate is oxidized, releasing 2 CO2 molecules and regenerating oxaloacetate to continue the cycle. Key enzymes include isocitrate dehydrogenase (rate-limiting, produces NADH, inhibited by ATP/NADH) and alpha-ketoglutarate dehydrogenase (requires thiamine, lipoic acid, FAD, NAD+, CoA - same cofactors as pyruvate dehydrogenase; inhibited in thiamine deficiency and arsenic poisoning). Succinate dehydrogenase is unique as it's embedded in the inner mitochondrial membrane and directly feeds electrons to Complex II of the ETC.

Per turn of the cycle (1 acetyl-CoA), products include: 3 NADH, 1 FADH2, 1 GTP (or ATP), and 2 CO2. These electron carriers feed into oxidative phosphorylation, generating approximately 25 ATP per glucose molecule from this stage.

Clinical relevance: Isocitrate dehydrogenase mutations (IDH1/IDH2) are found in certain gliomas and AML, producing oncometabolite 2-hydroxyglutarate. Fumarase deficiency causes hereditary leiomyomatosis and renal cell cancer (HLRCC). The cycle also provides biosynthetic intermediates - citrate for fatty acid synthesis, alpha-ketoglutarate for amino acid synthesis, succinyl-CoA for heme synthesis, and oxaloacetate for gluconeogenesis, making it both catabolic and anaplerotic.

Inhibitors like arsenite (inhibits alpha-KG dehydrogenase) and fluoroacetate (inhibits aconitase after conversion to fluorocitrate) cause cycle disruption and are classic pharmacology/toxicology topics.