1. INTRODUCTION TCA cycle (tricarboxylic acid cycle) or the Krebs cycle is a series of chemical reactions to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and proteins which oxidizes to CO2 and H2O. TCA cycle is used by organisms that respire to generate energy, either by anaerobic respiration or aerobic respiration. Site : Mitochondrial matrix 2.Reactions 1. Condensation of acetyl CoA and oxaloacetate to citric acid. 2a. Dehydration of citric acid to cis-aconitate. 2b. Hydration of cis-aconitate to isocitrate. 3. Oxidative decarboxylation of isocitrate to α-ketoglutarate. 4. Oxidative decarboxylation of α-ketoglutarate to succinyl CoA. 5. Substrate level phosphorylation of succinyl CoA to succinate. 6. Dehydrogenation of succinate to fumarate. 7. Hydration of fumarate to malate. 8. Dehydrogenation of malate to oxaloacetate. 3. Significance of TCA cycle Complete oxidation of acetyl CoA. ATP generation. Final common oxidative pathway. Integration of major metabolic pathways. Fat is burned on the wick of carbohydrates. Excess carbohydrates are converted as neutral fat No net synthesis of carbohydrates from fat. Carbon skeleton of amino acids finally enter the TCA cycle. 4. Energetics of TCA Cycle Oxidation of 3 NADH by ETC coupled with oxidative phosphorylation results in the synthesis of 9 ATP. FADH2 leads to the formation of 2ATP. One substrate level phosphorylation. Thus, a total of 12 ATP are produced from one acetyl CoA. 5. Regulation of TCA Cycle Three regulatory enzymes Citrate synthase Isocitrate dehydrogenase α-ketoglutarate dehydrogenase Citrate synthase is inhibited by ATP, NADH, acyl CoA & succinyl CoA.  Isocitrate dehydrogenase is activated by ADP & inhibited by ATP and NADH  α-ketoglutarate dehydrogenase is inhibited by succinyl CoA & NADH.  Availability of ADP is very important for TCA cycle to proceed. 6. Inhibitors of TCA Cycle Aconitase is inhibited by fluoro-acetate. This is a non-competitive inhibition. Alpha ketoglutarate is inhibited by Arsenite. This is also a non-competitive. Succinate dehydrogenase is inhibited by malonate. This is competitive inhibition. 7. Amphibolic nature of the TCA cycle TCA cycle is both catabolic & anabolic in nature, called as amphibolic. Since various compounds enter into or leave from TCA cycle, it is sometimes called as metabolic traffic circle. 8. References Textbook of Biochemistry-U Satyanarayana Textbook of Biochemistry- DM Vasudevan

1. TCA CYCLE
Presented by : Shreya Yadav

2.  TCA cycle (tricarboxylic acid cycle) or the Krebs cycle is a
series of chemical reactions to release stored energy through
the oxidation of acetyl-CoA derived from carbohydrates, fats,
and proteins which oxidizes to CO2 and H2O.
 TCA cycle is used by organisms that respire to generate
energy, either by anaerobic respiration or aerobic respiration.
 Site : Mitochondrial matrix

3. Reactions
1. Condensation of acetyl CoA and oxaloacetate to citric acid.
2a. Dehydration of citric acid to cis-aconitate.
2b. Hydration of cis-aconitate to isocitrate.
3. Oxidative decarboxylation of isocitrate to α-ketoglutarate.
4. Oxidative decarboxylation of α-ketoglutarate to succinyl CoA.

4. 5. Substrate level phosphorylation of succinyl CoA to succinate.
6. Dehydrogenation of succinate to fumarate.
7. Hydration of fumarate to malate.
8. Dehydrogenation of malate to oxaloacetate.

6. Significance of TCA cycle
 Complete oxidation of acetyl CoA.
 ATP generation.
 Final common oxidative pathway.
 Integration of major metabolic pathways.
 Fat is burned on the wick of carbohydrates.
 Excess carbohydrates are converted as neutral fat
 No net synthesis of carbohydrates from fat.
 Carbon skeleton of amino acids finally enter the TCA cycle.

7. Energetics of TCA Cycle
 Oxidation of 3 NADH by ETC coupled with oxidative
phosphorylation results in the synthesis of 9 ATP.
 FADH2 leads to the formation of 2ATP.
 One substrate level phosphorylation.
 Thus, a total of 12 ATP are produced from one acetyl CoA.

9. Regulation of TCA Cycle
Three regulatory enzymes
1. Citrate synthase
2. Isocitrate dehydrogenase
3. α-ketoglutarate dehydrogenase
Citrate synthase is inhibited by ATP, NADH, acyl CoA & succinyl
CoA. Isocitrate dehydrogenase is activated by ADP & inhibited
by ATP and NADH α-ketoglutarate dehydrogenase is inhibited
by succinyl CoA & NADH. Availability of ADP is very important
for TCA cycle to proceed.

10. Inhibitors of TCA Cycle
 Aconitase is inhibited by fluoro-acetate. This is a non-
competitive inhibition.
 Alpha ketoglutarate is inhibited by Arsenite. This is also a non-
competitive.
 Succinate dehydrogenase is inhibited by malonate. This is
competitive inhibition.

11. Amphibolic nature of the TCA cycle
 TCA cycle is both catabolic & anabolic in nature, called as
amphibolic.
 Since various compounds enter into or leave from TCA cycle,
it is sometimes called as metabolic traffic circle.

12. References
 Textbook of Biochemistry-U Satyanarayana
 Textbook of Biochemistry- DM Vasudevan