The citric acid cycle, also known as the Krebs cycle or tricarboxylic acid (TCA) cycle, is a series of enzymatic reactions that occurs in the mitochondrial matrix of eukaryotic cells and in the cytosol of prokaryotic cells. The cycle is a central metabolic pathway that is involved in the breakdown of nutrients such as glucose, fatty acids, and amino acids to generate energy in the form of ATP.
The citric acid cycle begins with the condensation of acetyl-CoA and oxaloacetate, forming citrate. Citrate is then isomerized to isocitrate, which is oxidized by the enzyme isocitrate dehydrogenase to produce alpha-ketoglutarate, carbon dioxide, and NADH. Alpha-ketoglutarate is then oxidized by the enzyme alpha-ketoglutarate dehydrogenase, producing carbon dioxide, NADH, and succinyl-CoA. Succinyl-CoA is then converted to succinate by the enzyme succinyl-CoA synthetase, generating ATP via substrate-level phosphorylation. Succinate is then oxidized to fumarate by the enzyme succinate dehydrogenase, producing FADH2. Fumarate is then converted to malate by the enzyme fumarase, and malate is subsequently oxidized to oxaloacetate by the enzyme malate dehydrogenase, generating NADH and completing the cycle.
The citric acid cycle is regulated at multiple steps, including the reactions catalyzed by pyruvate dehydrogenase, citrate synthase, isocitrate dehydrogenase, and alpha-ketoglutarate dehydrogenase. These enzymes are subject to regulation by allosteric effectors, covalent modification, and gene expression.
The citric acid cycle plays a central role in metabolism by generating ATP and providing precursors for biosynthetic pathways. The cycle also plays a critical role in the regulation of energy metabolism, particularly in response to changes in nutrient availability and energy demand. Dysfunction of the citric acid cycle is associated with a variety of metabolic diseases, including diabetes, cancer, and neurodegenerative disorders.