Also known as citric acid cycle/tricarboxylic acid cycle. It is common pathway for complete oxidation of acetyl coA into CO2 and H2O. This pathway is also called a cycle because its end product oxaloacetate is reused to start another cycle. This is a central pathway connecting all the metabolic Pathways directly or indirectly.
Highlights of citric acid cycle
- The cycle is also called tricarboxylic acid cycle (TCA cycle) as tricarboxylic acid Namely citrate, cis aconitate and isocitrate participate at the outset of the cycle
- This pathway should not be viewed as closed cycle since many compounds enter and leaves this pathway
- This pathway is both anabolic and catabolic in nature hence it is also regarded as amphibolic pathway.
- Although there is no direct participation of oxygen in the cycle but still this process takes please under aerobic conditions.This is due to the fact that NAD+ and FAD required to operate this cycle are regenerated only in the presence of oxygen.
The steps in the citric acid cycle are described below:
- In the first reaction acid acetyl CoA (2C) condenses with oxaloacetate 4C in the presence of citrate synthase to form citric acid (hence the name of the cycle)
- Citrate is isomerized to isocitrate in a two step reaction of dehydration followed by hydration. This reaction is catalyzed by Fe2+ activated enzyme aconitase and involves and intermediate cis — aconitate (not shown)
- Isocitric dehydrogenase converts isocitrate (6C) into alpha ketoglutarate (5C) by oxidative decraboxylation. Formation of NADH and Co2 occurs during this reaction.
- Alpha ketoglutarate (5C) gets converted to succinyl CoA (4C) again bu oxidative decarboxylation. In this reaction , NADH and Co2 are liberated . alpha ketoglutarate dehydrogenase catalysing this reaction requires five cofactor as in pyruvate dehydrogenase complex. These include three prothetic groups (TPP, lipoamide and FAD) and two coenzyme (CoA and NADH).
- Succinyl CoA is converted to Succinate by Succinate thiokinase. This reaction is coupled with the phosphorylation if GDP ro GTP (Substrate level Phosphorylation)
- Succinate is oxidised to fumarate by Succinate Dehydrogenase in a reaction which results in the formation of FADH2 and FAD.
- Fumarase converts fumarate to malate with addition of H2O.
- An Oxidation reaction converts malate into oxaloacetate. The reaction catalyzed by Malate dehydrogenase results in the Synthesise of NADH.
Oxaloacetate regenerated in the cycle is again available to combine with another molecule of acetyl CoA to start another cycle.
Overall reaction:
Acetyl CoA + 3NAD+ + FAD + GDP + Pi +2H2O ———> 2CO2 + 3NADH + 3H + + FADH2 + GTP + CoA
Energetics of citric acid cycle
Let us calculate how much energy ATP is extracted from glucose breakdown under aerobic condition:
- The degradation of glucose to 2 pyruvate by glycolysis yields 2 ATP and 2 NADH + 2H+
- The oxidative Decarboxylation. Of 2 pyruvate to acetyl CoA generates 2 NADH + 2H+
- Oxidation of each acetyl CoA via Citric acid cycle produce 3 NADH, 1 FADH2 and 1GTP. Therefore , two acetyl CoA will produce double the number of reducing equivalents and GTP.
- Oxidation of NADH and FADH2 by ETC is coupled to oxidative phosphorylation. Each NADH produces 2.5 ATP whereas FADH2 produces 1.5 ATP.
- The final count of ATP is : 10× 2.5+ 2×1.5 +4 = 32
The number of ATP produced varies from 30–32 , depending on the shuttle operative in a given cell.
Regulation of Citric Acid Cycle
Three enzymes namely citrate synthase, isocitrate dehydrogenase and alpha ketoglutarate dehydrogenase regulate citric acid cycle.
- Citrate synthase activity is inhibited by ATP, NADH, acetyl CoA and Succinyl CoA
- Isocitrate dehydrogenase activity is activated by ADP And inhibited by ATP and NADH.
- Alpha ketoglutarate dehydrogenase activity is inhibited by Succinyl CoA and NADH.
It is important to understand that availability of ADP is very crucial for the continuous operation of citric acid cycle.If ADP levels are low oxidation of NADH in FADH2 through electron transport chain will stop. Accumulation of NADH and FADH2 inhibited the above stated enzymes.