Krebs Cycle (Citric Acid)

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### Krebs Cycle Overview The Krebs cycle, also known as the Citric Acid Cycle or Tricarboxylic Acid (TCA) Cycle, is a central metabolic pathway in aerobic organisms. It plays a crucial role in converting Acetyl-CoA into energy (ATP, NADH, FADH2) and precursor molecules for biosynthesis. It occurs in the mitochondrial matrix. - **Input:** Acetyl-CoA (from pyruvate oxidation, fatty acid oxidation, amino acid breakdown) - **Products per Acetyl-CoA:** - 3 NADH - 1 FADH2 - 1 GTP (or ATP) - 2 CO2 - **Function:** Energy production and provision of biosynthetic precursors. ### Steps of the Krebs Cycle The cycle consists of eight steps, each catalyzed by specific enzymes: 1. **Citrate Synthase:** - Acetyl-CoA (2C) + Oxaloacetate (4C) $\rightarrow$ Citrate (6C) - **Enzyme:** Citrate Synthase - **Type:** Condensation - **Inhibitor:** ATP, NADH, Succinyl-CoA, Citrate 2. **Aconitase:** - Citrate (6C) $\rightleftharpoons$ Isocitrate (6C) - **Enzyme:** Aconitase - **Type:** Rearrangement (dehydration followed by hydration) 3. **Isocitrate Dehydrogenase:** - Isocitrate (6C) $\rightarrow$ $\alpha$-Ketoglutarate (5C) + CO2 + NADH - **Enzyme:** Isocitrate Dehydrogenase - **Type:** Oxidative Decarboxylation - **Regulation:** Rate-limiting step. Activated by ADP, Ca2+. Inhibited by ATP, NADH. 4. **$\alpha$-Ketoglutarate Dehydrogenase Complex:** - $\alpha$-Ketoglutarate (5C) $\rightarrow$ Succinyl-CoA (4C) + CO2 + NADH - **Enzyme:** $\alpha$-Ketoglutarate Dehydrogenase Complex - **Type:** Oxidative Decarboxylation - **Regulation:** Activated by Ca2+. Inhibited by Succinyl-CoA, NADH. 5. **Succinyl-CoA Synthetase (Succinate Thiokinase):** - Succinyl-CoA (4C) + GDP + Pi $\rightleftharpoons$ Succinate (4C) + GTP + CoA-SH - **Enzyme:** Succinyl-CoA Synthetase - **Type:** Substrate-level phosphorylation (GTP can be converted to ATP) 6. **Succinate Dehydrogenase:** - Succinate (4C) + FAD $\rightarrow$ Fumarate (4C) + FADH2 - **Enzyme:** Succinate Dehydrogenase (part of Complex II of the electron transport chain) - **Type:** Oxidation 7. **Fumarase (Fumarate Hydratase):** - Fumarate (4C) + H2O $\rightleftharpoons$ Malate (4C) - **Enzyme:** Fumarase - **Type:** Hydration 8. **Malate Dehydrogenase:** - Malate (4C) + NAD+ $\rightleftharpoons$ Oxaloacetate (4C) + NADH + H+ - **Enzyme:** Malate Dehydrogenase - **Type:** Oxidation - **Note:** Oxaloacetate is regenerated to continue the cycle. ### Energy Yield per Glucose Molecule Since one glucose molecule produces two pyruvate molecules through glycolysis, and each pyruvate is oxidized to one Acetyl-CoA, the Krebs cycle runs twice per glucose molecule. - **Per Acetyl-CoA:** - 3 NADH - 1 FADH2 - 1 GTP (equivalent to 1 ATP) - **Per Glucose (2 Acetyl-CoA):** - 6 NADH - 2 FADH2 - 2 GTP (equivalent to 2 ATP) **Conversion to ATP (approximate):** - 1 NADH $\approx$ 2.5 ATP - 1 FADH2 $\approx$ 1.5 ATP **Total ATP equivalent from Krebs Cycle (per glucose):** - 6 NADH $\times$ 2.5 ATP/NADH = 15 ATP - 2 FADH2 $\times$ 1.5 ATP/FADH2 = 3 ATP - 2 GTP = 2 ATP - **Total ATP equivalent = 20 ATP** (from the cycle only, excluding glycolysis and pyruvate oxidation) ### Regulation of the Krebs Cycle The cycle is tightly regulated at several points to meet the cell's energy demands. - **Citrate Synthase:** - Inhibited by: ATP, NADH, Succinyl-CoA, Citrate - Activated by: ADP - **Isocitrate Dehydrogenase:** - Inhibited by: ATP, NADH - Activated by: ADP, Ca2+ - **$\alpha$-Ketoglutarate Dehydrogenase Complex:** - Inhibited by: Succinyl-CoA, NADH - Activated by: Ca2+ - **Substrate Availability:** Concentrations of Acetyl-CoA and Oxaloacetate affect the cycle rate. - **Anaplerotic Reactions:** Reactions that replenish cycle intermediates, e.g., pyruvate carboxylase converting pyruvate to oxaloacetate. ### Biological Significance - **Energy Production:** Primary source of ATP through oxidative phosphorylation. - **Biosynthetic Precursors:** - Citrate: For fatty acid synthesis - $\alpha$-Ketoglutarate: For amino acid synthesis (glutamate) and purines - Succinyl-CoA: For porphyrin synthesis (heme) - Oxaloacetate: For amino acid synthesis (aspartate) and gluconeogenesis - **Connection to Other Metabolic Pathways:** Closely linked to glycolysis, fatty acid oxidation, amino acid metabolism, and the electron transport chain.