The citric acid cycle, also known as the tricarboxylic acid (TCA) cycle or Krebs cycle, is a cyclic series of enzymatic reactions converting acetyl-CoA into carbon dioxide and chemical energy in the form of NADH, FADH2, and GTP. This cycle occurs in the mitochondrial matrix and is central to aerobic metabolism.
Overview of the Cycle
- Starts and ends with oxaloacetate, ensuring its regeneration.
- One acetyl-CoA molecule enters the cycle at a time.
- Generates reducing equivalents (NADH, FADH2) used in the electron transport chain for ATP synthesis.
- Produces one molecule of GTP per cycle via substrate-level phosphorylation.
- Eight enzymatic steps that sequentially oxidize acetyl-CoA.
Detailed Steps and Enzymes
- Citrate Synthase: Condenses two-carbon acetyl-CoA with four-carbon oxaloacetate to form six-carbon citrate. Coenzyme A is released. This irreversible and rate-limiting step consumes one water molecule.
- Aconitase: Isomerizes citrate (a tertiary alcohol) to isocitrate (a secondary alcohol) via cis-aconitate intermediate. Reaction is reversible and uses iron-sulfur clusters.
- Isocitrate Dehydrogenase: Catalyzes oxidative decarboxylation of isocitrate to α-ketoglutarate, releasing the first CO2 and producing NADH. Irreversible, Mg2+ or Mn2+ required.
- α-Ketoglutarate Dehydrogenase: Converts α-ketoglutarate to succinyl-CoA, releasing second CO2 and generating another NADH. Requires cofactors TPP, lipoic acid, FAD, CoASH, and NAD+. Irreversible.
- Succinyl-CoA Synthetase: Converts succinyl-CoA to succinate with the formation of GTP from GDP via substrate-level phosphorylation. Mg2+ and Pi are cofactors.
- Succinate Dehydrogenase: Oxidizes succinate to fumarate, reducing FAD to FADH2. Only enzyme bound to the inner mitochondrial membrane. Reaction reversible.
- Fumarase: Hydrates fumarate to malate. Reversible reaction.
- Malate Dehydrogenase: Oxidizes malate to oxaloacetate, producing the third NADH of the cycle, completing the regeneration of oxaloacetate.
Energy Yield
Each turn of the citric acid cycle produces 3 NADH, 1 FADH2, and 1 GTP. Oxidative phosphorylation converts NADH to 3 ATP and FADH2 to 2 ATP. Hence, net yield per acetyl-CoA is 12 ATP. Since each glucose molecule produces two acetyl-CoA molecules, total ATP produced via this cycle during glucose oxidation is 24 ATP.
Medical and Metabolic Importance
- Final oxidative pathway for carbohydrates, fats, and proteins.
- Provides biosynthetic precursors for fatty acids, cholesterol, amino acids, porphyrins, and glucose.
- Defects impair energy metabolism and lead to metabolic diseases.
- Altered cycle function in liver diseases (hepatitis, cirrhosis) impacts metabolism.
Regulation
Key enzymes citrate synthase, isocitrate dehydrogenase, and α-ketoglutarate dehydrogenase are allosterically controlled. ATP and NADH inhibit these enzymes, whereas ADP and Ca2+ activate them. This regulation matches cycle velocity with cellular energy demands.
Inhibitors of the Cycle
- Fluoroacetate is converted in vivo to fluorocitrate which inhibits aconitase, a lethal synthesis.
- Arsenic inhibits α-ketoglutarate dehydrogenase.
- Malonate competitively inhibits succinate dehydrogenase.
Aerobic Glucose Oxidation
Glucose oxidation encompasses glycolysis, pyruvate dehydrogenase-mediated conversion to acetyl-CoA, and the citric acid cycle. Total ATP yield from glucose oxidation is approximately 38 ATP, depending on shuttle systems used for electron transport into mitochondria. The process is about 70% efficient, with heat generated maintaining body temperature.
Understanding citric acid cycle intricacies is pivotal for grasping cellular metabolism, bioenergetics, and pharmacological targeting in medical biochemistry.
Detailed Notes:
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