Download citric acid cycle - usmle step 1 and 2 for android

CITRIC ACID CYCLE










About 65-70% of the ATP is generated in Kreb’s cycle
It essentially involves the oxidation of acetyl CoA to CO2 and H2O
This cycle utilizes about 2/3rd of total oxygen consume dby body
It is final common oxidative pathway for carbohydrates, fats and aminoacids
It synthesizes energy and also provides many intermediates required fro synthesis of
aminoacids, glucose, heme
It was proposed by Adolf Krebs in 1937
It was awarded the Nobel prize for physiology and medicine 1953
The enzymes of TCA cycle are located in mitochondrial matrix, in close proximity to the electron
transport chain
This cycle basically involves the combination of 2 carbon acetyl CoA with a 4 carbon
oxaloacetate to produce 6 carbon tricarboxylic acid citrate
Oxaloacetate plays a catalytic role in citric acid cycle
REACTIONS OF CITRIC ACID CYCLE
1. Formation of citrate
 Kreb’s cycle starts with condensation of acetyl CoA and oxaloacteate catalysed by
enzyme citrate synthase
 This is an aldol condensation reaction leading to formation of an intermediate cityrl CoA
which on hydrolysis yields citrate
 Citrate is freely permeable across the mitochondrial membrane
 It serves as a good source of cytosolic acetyl CoA which is used for synthesis of fatty
acids
 Citrate inhibits phosphofructokinase and activates acetyl CoA carboxylase
2 & 3. Citrate is isomerized to isocitrate by enzyme aconitase
This is achieved by 2 stage reaction of dehydration followed by hydration through formation
of an intermediate cis-aconitate
4 and 5. Formation of ketoglutarate
 Enzyme isocitrate dehydrogenase catalyses the conversion of isocitrate to oxalosuccinate and
then to α-ketoglutarate
 The formation of NADH and liberation of CO2 occurs at this stage
 Three types of ICD are known,
- NAD+ specific located only in mitochondria
- NADP+ specific present in mitochondria
- And in cytosol
 The mitochondrial NAD+ dependent ICD is responsible for the conversion of isocitrate to αketoglutarate
6. Conversion of α-ketoglutatrate to succinyl CoA
 It occurs through oxidative decarboxylation catalysed by α-ketoglutarate dehydrogenase
complex
 This enzyme is dependent on 5 factors
- TPP
- Lipoamide
- NAD+
- FAD
- CoA
 Second NADH is produced and the second CO2 is liberated
7. Formation of succinate
 Succinyl CoA is converted to succinate by succinate thiokinase
 This reaction is coupled with the phosphorylation of GDP to GTP
 GTP is converted into ATP by enzyme phopshokinase
8. Conversion of succinate to fumarate
 Succinate is oxidized by succinate dehydrogenase to fumarate
 This reaction results in production of FADH2 and not NADH
9. Formation of malate
 The enzyme fumarase catalyses the conversion of fumarate to malate with addition of H2O
10. Conversion of malate to oxaloacetate
 Malate is then oxidized to oxaloacetate by malate dehydrogenase
 Third and final synthesis of NADH occurs at this stage
 The oxaloacetate is regenerated which can combine with another molecule of acetyl CoA and
continue the cycle
SUMMARY OF TCA CYCLE
Acetyl CoA + 3 NAD+ + FAD + GDP + Pi + 2H2O → 2CO2 + 3NADH2 + 3H+ + FADH2 + GTP + CoA
REQUIREMENT OF O2 BY TCA CYCLE
 There is no direct participation of oxygen in krebs cycle
 Cycle operates only under aerobic conditions
 NAD+ and FAD required for operation of the cycle can be regenerated in the respiratory chain
only in presence of O2
Energy reaction
ATP synthesized
3NADH → 3NAD+
9
FADH2 →FAD
2
Substrate phosphorylation
1
Total ATP for 1 Acetyl CoA
12
INHIBITORS OF KREBS CYCLE
ENZYME
Aconitase
Αlpha-Ketoglutartae
Succinate dehydrogenase
INHIBITOR
Fluoroacetate (non-competitive)
Arsenite (non-competitive)
Malonate (competitive)
REGULATION OF CITRIC ACID CYCLE
1.
2.
3.
4.
Citrate synthase – it is inhibited by ATP, NADH, acyl CoA and succinyl CoA
Isocitrate dehydrogenase is activated by ADP and inhibited by ATP and NADH
Alpha-Ketoglutarate dehydrogenase is inhibited by succinyl CoA and NADH
Availability of ADP
AMPHIBOLIC NATURE OF CITRIC ACID CYCLE
Citric acid cycle is both catabolic and anabolic in nature so regarded amphibolic
Anabolic reactions are
1. Oxaloacetate and ketoglutarate serve as precursors for the synthesis of aspartate and glutamate
which in turn are required for the synthesis of other non essential amino acids purines and
pyrimidines
2. Succinyl CoA is used for synthesis of porphyrins and heme
3. Mitochondrial citrate is transported to the cytosol where it is cleaved to provide acetyl CoA for
the biosynthesis of fatty acids, sterols
ANAPLEROSIS OR ANAPLEROTIC REACTIONS


The reactions required to replenish or fill up to intermediates of citric acid cycle are called
anaplerotic reaction or anaplerosis
The salient features of important anapleurotic reactions are described
1. Pyruvate carboxylase catalyses the conversion of pyruvate to oxaloacetate. This is an ATP
dependent carboxylation reaction
Pyruvate + CO2 + ATP → Oxaloacetate + ADP + Pi
2. Pyruvate is converted to malate by NADP+ dependent malate dehydrogenase
Pyruvate + CO2 + NADPH + H+ ↔ Malate + NADP+ + H2O
3. Transamination is a process wherein an aminoacid transfers its amino group to a keto acid
and itself gets converted into keto acid
4. Alpha – Ketoglutarate can be synthesized from glutamate by glutamate dehydrogenase
reaction
Glutamate + NAD(P+) + H2O ↔ α-ketoglutarate + NAD(P)H + H+ + NH4+
ENERGETICS OF GLUCOSE OXIDATION


When a molecule of glucose (6 carbon) undergoes glycolysis , 2 molecules of pyruvate or lactate
(3 carbon) are produced
Pyruvate is oxidatively decarboxylated to acetyl CoA which enters citric acid cycle and gets
completely oxidized to CO2 and H2O
C6H12O6 + 6CO2 + 38ADP + 38Pi → 6CO2 + 6H2O + 38ATP