The Citric Acid Cycle: Overview

The citric acid cycle, also called the tricarboxylic acid (TCA) or Krebs cycle, is the second phase of cellular respiration that oxidizes biomolecules to produce energy. In eukaryotes, it occurs in the mitochondrial matrix, while in prokaryotes it takes place within the cytosol. This cycle is central to aerobic energy production.

Pyruvate, the end product of glycolysis, combines with coenzyme A to generate acetyl-CoA. The enzyme citrate synthase then initiates the cycle by condensing acetyl-CoA with oxaloacetate, a four-carbon molecule, to form citric acid, the first six-carbon product of the cycle.

The cycle involves eight major enzymatic steps: citrate synthase forms citric acid, aconitase rearranges it to isocitrate, isocitrate dehydrogenase oxidizes isocitrate to α-ketoglutarate, α-ketoglutarate dehydrogenase forms succinyl-CoA, succinyl-CoA synthetase produces succinate, succinate dehydrogenase creates fumarate, fumarase yields malate, and malate dehydrogenase regenerates oxaloacetate.

During each cycle, two carbon atoms from citric acid are removed and released as two molecules of carbon dioxide. This oxidation process also releases four electrons that are captured by coenzyme carriers. At the cycle's end, oxaloacetate is regenerated to accept another acetyl group.

The majority of citric acid cycle intermediates are components of other biochemical pathways that produce metabolites such as porphyrins, fatty acids, and amino acids. If these intermediates are diverted away from the cycle, the cycle's integrity is compromised and the cycle halts, disrupting energy production.

The citric acid cycle oxidizes molecules derived from carbohydrates, proteins, and fats into carbon dioxide while releasing electrons. These electrons are captured and transferred to the electron transport chain, where they drive the production of ATP through oxidative phosphorylation and energy capture.

Oxaloacetate is a four-carbon molecule that combines with acetyl groups to initiate each cycle turn. At the cycle's end, malate dehydrogenase regenerates oxaloacetate, enabling the cycle to continue. This regeneration is essential for sustained energy production and metabolic function in aerobic organisms.