The citric acid cycle

The citric acid cycle following the syllabus of Medical Biochemistry of MBBS course

1. Dr. Farhana Atia Associate Professor, Biochemistry Nilphamari Medical College Nilphamari The Citric Acid Cycle

2. The Citric Acid Cycle Other name: The Krebs cycle, tricarboxylic acid cycle It is a sequence of reactions in mitochondria that oxidizes the acetyl moiety of acetyl-CoA to CO₂ & reduces coenzymes that are reoxidized through the electron transport chain, linked to the formation of ATP

3. The Citric Acid Cycle It is the final common pathway for the oxidation of carbohydrate, lipid & protein It is the central pathway of carbohydrate, lipid, & amino acid metabolism (gluconeogenesis, lipogenesis, interconversion of amino acids) Impaired activity of citric acid cycle leading to reduced formation of ATP, occurs in Hyperammonemia (advanced liver disease) Genetic defect in citric acid cycle enzyme causes neurological damage

4. The Citric Acid Cycle Salient features: Substrate : Acetyl-CoA Product : NADH, FADH₂, 2CO₂, H₂O Site : Almost all cell containing mitochondria Compartment : Mitochondria Nature : Amphibolic The process is aerobic

5. Steps of Citric Acid Cycle Oxaloacetate is first condensed with an acetyl group of acetyl-CoA Oxaloacetate is regenerated as the cycle is completed Two carbons enter the cycle (acetyl-CoA) and two leaves (CO₂) So there is no net production or consumption of intermediates

6. Steps of Citric Acid Cycle Formation of citrate from acetyl-CoA & oxaloacetate catalyzed by citrate synthase Citrate is isomerized to isocitrate by enzyme aconitase . The poison fluoroacetate can inhibit aconitase Dehydrogenation & decarboxylation to form α-ketoglutarate by isocitrate dehydrogenase Oxidative decarboxylation to form succinyl-CoA by enzyme α-ketoglutarate dehydrogenase complex

7. Steps of Citric Acid Cycle Conversion of succinate by enzyme succinate thiokinase . Only step in TCA cycle where substrate level phosphorylation occur Dehydrogenation to fumarate by succinate dehydrogenase Addition of water to form malate by enzyme fumarase Malate is oxidized to oxaloacetate by malate dehydrogenase

8. Fluoroacetate(-) Arsenite (-) Malonate(-)

9. Final Common Metabolic Pathway Glucose, fatty acids & most amino acids are metabolized to acetyl-CoA or intermediates of TCA cycle

10. TCA Cycle is an Amphibolic Pathway It functions in both oxidative and synthetic process Catabolic role : Acetyl-CoA is oxidized to CO₂, H₂O and ATP Anabolic role : Support gluconeogenesis Synthesis of amino acid Oxaloacetate + NH₃  Aspartate α-Ketoglutarate + NH₃  Glutamate Support heme synthesis by succinyl-CoA Fatty acid synthesis by supplying acetyl-CoA

11. Role of Vitamin in TCA cycle Vitamins play key roles in the citric acid cycle Four of the B vitamins are essential in TCA cycle & energy yielding metabolism Riboflavin/B2 as FAD: Cofactor for succinate dehydrogenase Niacin/B3 as NAD⁺: Electron acceptor for isocitrate dehydrogenase Thiamine/B1 as thiamine diphosphate: Coenzyme for decarboxylation in α-ketoglutarate dehydrogenase reaction Pantothenic acid as part of coenzyme A: Esterified to carboxylic acid to form acetyl-CoA & succinyl-CoA

12. Fate of Acetyl-CoA Oxidation in TCA cycle Fatty acid synthesis Cholesterol synthesis Ketone body synthesis Supply acetyl group in different acetylation reaction as Choline + Acetyl-CoA  Acetylcholine

13. Ten ATP are formed per turn of TCA cycle In oxidations catalyzed by the dehydrogenases, three molecules of NADH & one of FADH₂ are produced for each molecule of acetyl-CoA catabolized in one turn of cycle These reducing equivalents are transferred to the respiratory chain & reoxidized One ATP (GTP) is formed by substrate level phosphorylation

14. Thank You