Citric acid cycle

The citric acid cycle—called the Krebs cycle, Szent–Györgyi–Krebs cycle, or TCA cycle—is a sequence of biochemical steps that frees energy from nutrients by oxidizing acetyl-CoA. That energy becomes available as ATP. Organisms that rely on respiration, whether anaerobic or aerobic, use this cycle; fermenting organisms follow different routes. The cycle also supplies building blocks for certain amino acids and the reducing agent NADH, which other reactions require. Because it plays such a central role in many biochemical processes, it is thought to be one of the earliest metabolic systems to evolve. Although it is called a "cycle," metabolites do not have to follow a single path; at least three alternative versions of the citric acid cycle are known.

The name comes from citric acid (a tricarboxylic acid, mostly present as citrate at biological pH), which is used up and then remade by the cycle’s reactions. The cycle takes in acetate (as acetyl-CoA) and water, reduces NAD⁺ to NADH, and gives off carbon dioxide. The NADH produced then enters the oxidative phosphorylation (electron transport) pathway. Together, these two linked processes oxidize nutrients to create usable chemical energy in the form of ATP.

In eukaryotic cells, the cycle runs in the mitochondrial matrix. In prokaryotes like bacteria, which lack mitochondria, the reactions happen in the cytosol, and the proton gradient for ATP production forms across the cell’s plasma membrane instead of the inner mitochondrial membrane.

For each pyruvate molecule coming from glycolysis, the cycle yields three NADH, one FADH₂, and one GTP (or ATP).

**Discovery** In the 1930s, Albert Szent-Györgyi identified several parts and reactions of the cycle, earning the 1937 Nobel Prize in Physiology or Medicine for his work on fumaric acid, a cycle component. He studied pigeon breast muscle because this tissue keeps its oxidative ability even after being ground in a Latapie mincer and released into aqueous solutions, making it ideal for studying oxidation. The full cycle was identified in 1937 by Hans Adolf Krebs and William Arthur Johnson at the University of Sheffield; Krebs received the 1953 Nobel Prize for this work, and the cycle is sometimes named after him. That same year, German biochemists Carl Martius and Franz Knoop independently described the cycle.

**Overview** The citric acid cycle links the metabolism of carbohydrates, fats, and proteins. Eight enzymes carry out the reactions, fully oxidizing acetate (a two-carbon molecule from acetyl-CoA) into two carbon dioxide molecules. Sugars, fats, and proteins are broken down to produce acetyl-CoA, which enters the cycle. During the cycle, three molecules of NAD⁺ are reduced to NADH, one FAD is reduced to FADH₂, and one GDP plus one inorganic phosphate (Pi) are converted into one GTP. The NADH and FADH₂ then feed into oxidative phosphorylation to generate ATP.

A major source of acetyl-CoA is glycolysis, which breaks down sugars into pyruvate. Pyruvate is then decarboxylated by the pyruvate dehydrogenase complex to form acetyl-CoA. This acetyl-CoA is the cycle’s starting point. Acetyl-CoA can also come from fatty acid oxidation.

The cycle begins when a two-carbon acetyl group from acetyl-CoA is transferred to the four-carbon compound oxaloacetate, producing the six-carbon citrate. Citrate then undergoes a series of chemical changes, losing two carboxyl groups as CO₂. The carbon atoms lost as CO₂ originally came from oxaloacetate, not directly from acetyl-CoA. The carbons donated by acetyl-CoA become part of the oxaloacetate backbone after the first turn of the cycle, and losing those donated carbons as CO₂ takes several turns. However, because the cycle also supplies precursors for building other molecules, those carbons may not be lost at all.

Most electrons from the cycle’s oxidation steps are transferred to NAD⁺, forming NADH. For each acetyl group that enters, three NADH are produced. The cycle also involves redox reactions in mitochondria. Electrons from the oxidation of succinate are first transferred to the FAD cofactor of succinate dehydrogenase, reducing it to FADH₂, then to ubiquinone (Q) in the mitochondrial membrane, producing ubiquinol (QH₂), which feeds into the electron transport chain at Complex III. In oxidative phosphorylation, each NADH yields about 2.5 ATP, and each FADH₂ yields about 1.5 ATP. At the end of each cycle, the four-carbon oxaloacetate is regenerated.