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Citric Acid cycle or Tricarboxylic Acid cycle or Krebs Cycle Dr. Humaira Aman
At the end of the lecture, students would be able to:
Define krebs cycle. Describe briefly the reactions
of cycle. Explain the total energy
produced by the TCA cycle.
Overview
Final pathway for the oxidative metabolism of amino acids, carbohydrates and fatty acids.
Krebs in mitochondrial matrix
In Mitochondria
In Cytosol
Overall goal
Makes ATP Makes
NADH Makes
FADH2
REACTIONS OF TCA CYCLE
“The wheel is turnin’ and the sugar’s a burnin’”
A.OXIDATIVE DECARBOXYLATION OF PYRUVATE
Reaction of pyruvate dehydrogenase complex (PDC)
2 per glucose (all of Krebs)
Oxidative decarboxylation
Makes NADH
Pyruvate dehydrogenase Complex (PDC)It is a multi-enzyme complex containing three enzymes :
E-1 : Pyruvate dehydrogenase , uses Thiamine pyrophosphate as cofactor bound to E1
E-2 : Dihydrolipoyl transacetylase, Lipoic acid bound, CoA as substrate
E-3 : Dihydrolipoyl Dehydrogenase FAD bound, NAD+ as substrate
REGULATION OF PYRUVATE DEHYDROGENASE COMPLEX
B. SYNTHESIS OF CITRATE
Citrate synthase1. Binding of Oxaloacetate to the enzyme results in conformational change
which facilitates the binding of the next substrate, the acetyl Coenzyme A. There is a further conformational change which leads to formation of products.
Aconitase: This enzyme catalyses the isomerization reaction by removing and then adding back the water ( H and OH ) to cis-aconitate in at different positions. Isocitrate is consumed rapidly by the next step thus deriving the reaction in forward direction.
C. ISOMERIZATION OF CITRATE
D. OXIDATION & DECARBOXYLATION OF ISOCITRATE
Isocitrate dehydrogenase: Oxidative decarboxylation Rate limiting step. Enzyme activated by ADP and Ca++ and inhibited by
ATP and NADH
E. OXIDATION & DECARBOXYLATION OF α-KETOGLUTARATE
- Ketoglutarate dehydrogenase complex: This is a complex of different enzymatic activities similar to the pyruvate dehydrogenase complex. It has the same mechanism of reaction with E1, E2 and E3 enzyme units. NAD+ is an electron acceptor.
F. CLEAVAGE OF SUCCINYL CoA
Succinyl CoA synthatse:
G. OXIDATION OF SUCCINATE
Succinate Dehydrogenase: Oxidation of succinate to fumarate. This is the only citric acid cycle enzyme that is tightly bound to the inner mitochondrial membrane. It is an FAD dependent enzyme.
H . HYDRATION OF FUMARATE catalyzed by Fumarase: Hydration of Fumarate to malate.
I. OXIDATION OF MALATE
Malate dehydrogenase: Oxidation of malate to oxaloacetate: It is an NAD+dependent enzyme. Reaction is pulled in forward direction by the next reaction (citrate synthase reaction) as the oxaloacetate is depleted at a very fast rate.