The citric acid cycle is a cyclic sequence of enzyme-catalyzed reactions central to metabolism and cellular respiration. It receives two-carbon acetyl groups carried by acetyl-CoA, releases carbon dioxide, and conserves part of the available chemical energy in reduced electron carriers and a phosphorylated nucleotide. Also called the Krebs cycle or tricarboxylic acid cycle, it links nutrient breakdown with the production of compounds needed for biosynthesis. Its defining feature is the regeneration of oxaloacetate, the four-carbon acceptor that begins each turn. (reactome.org)
Cellular location and metabolic inputs
In eukaryotes, the canonical cycle operates in the mitochondrion. Most participating enzymes are located in the mitochondrial matrix; succinate dehydrogenase is embedded in the inner mitochondrial membrane and also functions as complex II of the electron transport chain. The cycle itself does not directly consume oxygen, but its sustained operation during aerobic respiration depends on the reoxidation of its reduced electron carriers through oxygen-dependent electron transport. (openstax.org)
Acetyl-CoA can originate from several nutrients. Glycolysis converts glucose into pyruvate, which the pyruvate dehydrogenase complex converts into acetyl-CoA while releasing carbon dioxide and producing NADH. This preparatory reaction is distinct from the cycle proper. Fatty-acid breakdown through beta-oxidation also supplies acetyl-CoA, while the degradation of some amino acids supplies either acetyl-CoA or intermediates entering at other points. The pathway therefore integrates carbohydrate, fat, and amino-acid metabolism. (openstax.org)
Reaction sequence
The canonical oxidative cycle comprises eight reactions:
- Citrate formation. Citrate synthase combines acetyl-CoA with oxaloacetate to form six-carbon citrate. Hydrolysis of the acetyl-CoA thioester helps drive the reaction, and free coenzyme A is released. (reactome.org)
- Isomerization. Aconitase rearranges citrate into isocitrate through the intermediate cis-aconitate. This repositions the hydroxyl group for subsequent oxidation. (openstax.org)
- First oxidative decarboxylation. NAD-dependent isocitrate dehydrogenase converts isocitrate into five-carbon α-ketoglutarate, producing carbon dioxide and NADH. (reactome.org)
- Second oxidative decarboxylation. The α-ketoglutarate dehydrogenase complex forms four-carbon succinyl-CoA, releasing another carbon dioxide and generating another NADH. (reactome.org)
- Nucleotide phosphorylation. Succinyl-CoA synthetase converts succinyl-CoA into succinate. The reaction supports substrate-level phosphorylation, producing GTP or ATP, depending on the enzyme isoform. (reactome.org)
- Succinate oxidation. Succinate dehydrogenase converts succinate into fumarate. Its enzyme-bound FAD accepts electrons, which are subsequently transferred to ubiquinone in the respiratory chain. (reactome.org)
- Hydration. Fumarase adds water to fumarate, forming L-malate. (reactome.org)
- Oxaloacetate regeneration. Malate dehydrogenase oxidizes malate into oxaloacetate and produces a third NADH, restoring the acceptor for another turn. (reactome.org)
Energy conservation
For each acetyl-CoA entering the canonical cycle, the conventional balance is two carbon dioxide molecules, three NADH, one FADH₂ equivalent, and one GTP or ATP. Oxaloacetate is regenerated rather than consumed in the net reaction. The FADH₂ notation is an accounting convention: the flavin at succinate dehydrogenase remains enzyme-bound rather than being released as a freely diffusible carrier. (reactome.org)
Most ATP associated with the cycle is produced indirectly through oxidative phosphorylation, not by its single substrate-level phosphorylation step. Electrons from NADH and succinate oxidation enter the respiratory chain, which supports the membrane gradient used to synthesize ATP. Using conventional estimates of approximately 2.5 ATP per mitochondrial NADH and 1.5 ATP per succinate-derived electron pair, one turn corresponds to roughly 10 ATP equivalents, including its directly formed nucleotide. This is an approximate energetic yield, not a fixed output under every cellular condition. (reactome.org)
Regulation and biosynthetic functions
Cycle activity responds to substrate supply, product accumulation, and cellular energy demand. Important control points include citrate synthase, isocitrate dehydrogenase, and α-ketoglutarate dehydrogenase. High ATP and NADH availability generally restrains oxidative flux, whereas ADP favors activity at appropriate regulatory steps. Regulation also involves enzyme maturation and modifications of enzyme activity, allowing the pathway to coordinate with other mitochondrial processes. (openstax.org)
The cycle is amphibolic: it contributes both to nutrient degradation and to biosynthesis. α-Ketoglutarate and oxaloacetate provide carbon skeletons for amino-acid production, while succinyl-CoA can contribute to heme synthesis. Intermediates thus serve as metabolic resources rather than merely successive stages in fuel oxidation. Their withdrawal must be balanced by reactions that restore the intermediate pool. (reactome.org)
These replenishing processes are called anaplerotic reactions. One important example is the conversion of pyruvate and bicarbonate into oxaloacetate by pyruvate carboxylase, with ATP consumption. Acetyl-CoA activates this enzyme, linking acetyl-group availability to the supply of its four-carbon acceptor. The same reaction also participates in gluconeogenesis. (reactome.org)
Discovery
Hans Adolf Krebs established the cyclic interpretation of these reactions in 1937, building on earlier investigations of tissue respiration and organic-acid metabolism. Studies of pigeon breast muscle helped reveal how a regenerated intermediate could support continuing oxidation. In 1953, Krebs received half of the Nobel Prize in Physiology or Medicine for discovering the cycle; Fritz Lipmann received the other half for discovering coenzyme A and its importance in intermediary metabolism. (leopoldina.org)