Citric Acid Cycle (Krebs Cycle)

The citric acid cycle, also called the Krebs cycle or tricarboxylic acid cycle, is the central mitochondrial hub of oxidative metabolism. It accepts the two-carbon acetyl group of acetyl-CoA, oxidises it completely to carbon dioxide, and in doing so reduces the coenzymes NAD+ and FAD that feed electrons into the respiratory chain.

Definition

The citric acid cycle is the cyclic, eight-reaction mitochondrial pathway in which the acetyl group of acetyl-CoA is condensed with oxaloacetate and oxidised to two molecules of CO2, regenerating oxaloacetate while producing reduced coenzymes (NADH and FADH2) and one high-energy phosphate per turn.

Scope

The entry covers the eight-step cyclic sequence from citrate synthesis to oxaloacetate regeneration, its products (reduced coenzymes, GTP/ATP, and CO2), its dual role in both energy production and biosynthesis, and its regulation. It treats the cycle as a metabolic topic in biochemistry, not as clinical guidance.

Core questions

• How is the acetyl group of acetyl-CoA oxidised to carbon dioxide?
• What are the energy-yielding products of one turn of the cycle?
• How does the cycle connect to the electron transport chain?
• How does the cycle serve both catabolic and biosynthetic roles?

Key concepts

• Acetyl-CoA as the entry molecule
• Condensation with oxaloacetate to form citrate
• Two decarboxylation steps releasing CO2
• Production of NADH, FADH2, and GTP/ATP per turn
• Regeneration of oxaloacetate (cyclic nature)
• Amphibolic function in catabolism and biosynthesis
• Anaplerotic reactions replenishing intermediates

Mechanisms

Each turn begins as the two-carbon acetyl group of acetyl-CoA condenses with the four-carbon oxaloacetate to form citrate. A series of isomerisation, oxidation, and decarboxylation reactions then releases two molecules of CO2, reduces three NAD+ to NADH and one FAD to FADH2, and produces one molecule of GTP or ATP by substrate-level phosphorylation, while regenerating oxaloacetate so the cycle can continue. The reduced coenzymes carry their electrons to the electron transport chain, where most of the ATP is ultimately made. Beyond oxidation, several cycle intermediates are withdrawn for biosynthesis; anaplerotic reactions replenish these intermediates so the cycle keeps turning, giving it an amphibolic character.

Clinical relevance

Because the cycle sits at the crossroads of carbohydrate, fat, and amino-acid metabolism, disturbances in its enzymes or in the supply of its intermediates can have broad metabolic consequences, and mutations in certain cycle enzymes are associated with disease. This entry explains the biochemistry and is not a basis for individual diagnosis or treatment.

History

Hans Krebs, building on earlier observations about the oxidation of organic acids in tissue and on Albert Szent-Györgyi's work on respiratory catalysts, formulated the cyclic pathway in 1937, demonstrating that the oxidation of acetyl units proceeds through a self-regenerating sequence of tricarboxylic and dicarboxylic acids. The discovery of coenzyme A by Fritz Lipmann later clarified how acetyl groups enter the cycle, and the pathway became a cornerstone of metabolic biochemistry.

Key figures

• Hans Krebs
• Albert Szent-Györgyi
• Fritz Lipmann

Seminal works

• krebs-1937

Frequently asked questions

Why is the citric acid cycle called a cycle?

Because its final reaction regenerates oxaloacetate, the molecule that begins the sequence; the pathway returns to its starting point with each turn, so a small pool of intermediates can process many acetyl groups.

Does the citric acid cycle directly make most of the cell's ATP?

No. Each turn makes only one molecule of GTP or ATP directly; the cycle's main energetic contribution is the reduced coenzymes NADH and FADH2, which drive the bulk of ATP production at the electron transport chain.