1. Tricarboxylic acid cycle (TCA Cycle) [Kreb’s cycle] [Citric acid cycle] Is the final common oxidative pathway for carbohydrates, fats and amino acids Along with energy, cycle supplies many intermediates required for the synthesis of amino acids, glucose, heme etc  Site: mitochondrial matrix  Oxidation of acetyl CoA  Co 2 + H 2 O  Occurs in a cyclic manner, generate ATP   carbon, acetyl CoA + 4 carbon, Oxaloacetate = 6 carbon tricarboxylic acid, citrate

3. Cis-aconitate is a transient one with very short half-life. Immediate H 2 O added to it and forms Isocitrate CO 2  Isocitrate  oxalosuccinate   -ketoglutatrate. It is an oxidative decarboxylation Oxalosuccinate is unstable so it undergoes spontaneous decarboxylation to from  -KG TCA is both catabolic and anabolic  amphibolic

4. Energetics of TCA Cycle Steps 4, 6, 10  3 NADH 1 NADH = 3 ATP] 3 ATP x 3 = 9 ATP Step 8  1 FADH 2 1 FADH 2 = 2 ATP]2 ATP x 1 = 2 ATP Step 7  1 GTP 1 GTP = 1 ATP1 ATP x 1 = 1 ATP Therefore 1 acetyl CoA gives 12 ATP Two acetyl CoA in citric acid cycle produces 24 ATP Energetics of complete oxidation of glucose Aerobic glycolysis  8 ATP Oxidation of 2 pyruvate = 6 ATP Oxidation of 2 Acetyl CoA by TCA cycle  24 ATP Net Gain = 38 ATP

5. Amphibolic nature of TCA cycle Non essential aa Aspartate Acetyl CoA Purines, Transamination Pyrimidines. Oxaloacetate Citrate Acetyl CoA Fatty acids, steroids Pyruvate Malate  -KG Transanimation Succinyl COA Glutamate Heme Non-essential a a, purines

6. Anaplerosis The reactions concerned to replenish the intermediates of TCA cycle are called anaplerotic reactions or anaplerosis Pyruvate +CO 2 + ATP carboxylase oxaloacetate + ADP + Pi Pyruvate +CO 2 + NADPH + H + Malic enzyme Malate Inhibitors that inhibit the enzymes of TCA cycle are: Aconitase fluoroacetate  - Ketoglutarate DHArsenite Non-competitive Succinate DH Malonate }- competitive

7. Regulation of TCA cycle 1.Citrate synthase: inhibited by ATP, NADH, acyl CoA and succinyl CoA 2. Isocitrate dehydrogenase: Inhibited by ATP and NADH and activated by ADP 3.  -KG dehydrogenase inhibited by NADH & succinyl CoA The availability of ADP: Important for proceeding the TCA cycle if not oxidation of NADH and FADH 2 through election transport chain stops. Accumulation of NADH and FADH 2, inhibit the enzymes of TCA cycle. Ref: Essentials of Biochemistry/Handbook of Biochemistry