Tca CycleEdit
The tricarboxylic acid cycle, tricarboxylic acid cycle (TCA cycle), also known as the citric acid cycle, is a core metabolic hub in aerobic organisms. It operates in the mitochondrion's matrix of eukaryotes and in analogous compartments in prokaryotes. The cycle oxidizes acetyl groups derived from glucose and other fuels into carbon dioxide, while capturing energy in the reduced carriers NADH and FADH2 that feed the electron transport chain and ultimately power the synthesis of ATP via oxidative phosphorylation. In addition to energy production, the cycle provides key intermediates for the biosynthesis of fatty acids, nucleotides, and several amino acids, linking energy metabolism with macromolecule production. Each turn processes one molecule of acetyl-CoA and regenerates the starting oxaloacetate to accept another acetyl unit, with two CO2 released per turn.
The TCA cycle is tightly integrated with other major pathways. The acetyl groups fed into the cycle come from the pyruvate dehydrogenase complex-mediated conversion of pyruvate to acetyl-CoA, a key link between glycolysis and aerobic respiration. The cycle’s intermediates can be siphoned off for biosynthesis, making the cycle a dynamic balance between catabolic energy production and anabolic precursor supply. Thus, the TCA cycle sits at the crossroads of metabolism, coordinating with glycolysis, glucose metabolism, and the broader network of energy-producing and biosynthetic pathways.
Core cycle and enzymes
Citrate synthase: acetyl-CoA condenses with oxaloacetate to form citrate, beginning the cycle. This step is sensitive to the cell’s energy state and substrate availability.
Aconitase: Citrate is isomerized to isocitrate via an intermediate rearrangement, enabling subsequent oxidation steps.
Isocitrate dehydrogenase: Isocitrate is oxidatively decarboxylated to produce α-ketoglutarate and NADH (or NADPH in some contexts), with release of CO2.
α-Ketoglutarate dehydrogenase complex: A second oxidative decarboxylation yields succinyl-CoA and another molecule of NADH; CO2 is released again.
Succinyl-CoA synthetase: Substrate-level phosphorylation at this step generates GTP (or ATP in some tissues) and releases CoA.
Succinate dehydrogenase: Oxidation of succinate to fumarate produces FADH2; this enzyme is part of the inner mitochondrial membrane and intersects with the electron transport chain as Complex II.
Fumarase: Hydration of fumarate yields malate.
Malate dehydrogenase: Oxidation of malate regenerates oxaloacetate with production of another NADH, completing the cycle.
Overall, per turn of the cycle for each acetyl-CoA, the process yields roughly 3 NADH, 1 FADH2, and 1 GTP (equivalently, ~10 ATP equivalents through oxidative phosphorylation), while releasing two CO2 molecules. Since glycolysis in a typical glucose-utilizing cell generates two acetyl-CoA molecules (via the pyruvate dehydrogenase complex), two turns of the cycle occur per glucose molecule, producing about six NADH, two FADH2, and two GTP, along with four CO2.
Regulation and metabolic integration
Energetic state: The TCA cycle is modulated by cellular energy charge. NADH and ATP tend to inhibit key dehydrogenases (for example, isocitrate dehydrogenase and the α-ketoglutarate dehydrogenase step), while ADP and NAD+ activate them, ensuring the cycle responds to the demand for ATP.
Substrate availability: The flux through the cycle depends on the supply of acetyl-CoA from the pyruvate dehydrogenase complex, fatty acid oxidation, and certain amino acids, as well as the availability of oxaloacetate and other intermediates.
Allosteric and hormonal signals: The cycle is influenced by cellular signals (e.g., Ca2+ in muscle) and by the broader regulatory state of metabolism, aligning energy generation with tissue-specific needs.
Pathway connectivity: Intermediates such as citrate can be exported to the cytosol for fatty acid synthesis, while aspartate and other amino acids can be formed from TCA intermediates, illustrating the cycle’s role as a producer of biosynthetic precursors in addition to energy.
Anaplerosis: When intermediates are siphoned off for biosynthesis or depleted, anaplerotic reactions (such as pyruvate carboxylase converting pyruvate to oxaloacetate) replenish the cycle to maintain continuous operation.
Biological and medical context
Evolutionary significance: The TCA cycle is an ancient and conserved pathway present across diverse life forms, reflecting a fundamental strategy for extracting energy from carbon fuels.
Disease and variation: Mutations affecting TCA cycle enzymes can influence metabolism and are studied in contexts ranging from inherited metabolic disorders to cancer metabolism. For example, mutations in certain cycle enzymes can alter metabolite levels and cellular signaling, illustrating how central metabolism can intersect with disease biology.
Integration with respiration: The NADH and FADH2 produced in the TCA cycle feed the electron transport chain and the process of oxidative phosphorylation to yield the majority of cellular ATP, highlighting the cycle’s role as the energy-generating core of aerobic metabolism.
See also