The Tricarboxylic Acid (TCA) Cycle

The tricarboxylic acid (TCA) cycle -- also called the Krebs cycle, after the biochemist Hans Krebs who first worked out its sequence of reactions, or sometimes the citric acid cycle, after its first, and most abundant, intermediate -- is the second stage of aerobic respiration and takes place within the mitochondrial matrix. It is a cyclical, rather than a straight-line, pathway: each turn of the cycle both consumes one molecule of acetyl CoA and regenerates the four-carbon compound with which the cycle began, so that the same set of intermediates can be used over and over again, turn after turn, for as long as acetyl CoA continues to be supplied.

Each turn of the cycle begins when the two-carbon acetyl group carried by acetyl CoA is combined with a four-carbon compound already present in the mitochondrial matrix, oxaloacetic acid (OAA), in a reaction catalysed by the enzyme citrate synthase, forming the six-carbon compound citric acid (citrate) -- the tricarboxylic (three-carboxyl-group) acid that gives the cycle its name -- and releasing coenzyme A to be reused in a further link reaction.

Citric acid is then rearranged to isocitric acid, which undergoes the first of two oxidative decarboxylation steps in the cycle: it is oxidised (reducing one NAD+ to NADH) and simultaneously decarboxylated, releasing one molecule of carbon dioxide and forming the five-carbon compound alpha-ketoglutaric acid. This compound then undergoes a second, closely analogous oxidative decarboxylation, again releasing one molecule of carbon dioxide and reducing a second NAD+ to NADH, and forming, via a short-lived intermediate bound to coenzyme A, the four-carbon compound succinyl CoA.

The energy released as succinyl CoA is subsequently converted to succinic acid is directly captured as one molecule of GTP (a close chemical relative of ATP, readily interconvertible with it, and often simply counted as one ATP), through substrate-level phosphorylation -- the only step in the entire TCA cycle at which ATP-equivalent energy is captured directly, rather than being stored in a reduced coenzyme for later use in the electron transport system.

Succinic acid is then oxidised to fumaric acid, but by an enzyme, succinate dehydrogenase, that (unusually, for the cycle) uses FAD rather than NAD+ as its coenzyme, so this step reduces FAD to FADH2 rather than producing another NADH. Fumaric acid is then hydrated to malic acid, which is finally oxidised -- reducing a fourth and final NAD+ to NADH in this turn of the cycle -- back to oxaloacetic acid, completing the cycle and regenerating the very compound with which the turn began, ready to combine with a fresh molecule of acetyl CoA and begin again. …