Citric Acid Cycle or Kreb’s cycle

Citric acid cycle or Krebs cycle

Content

• Citric acid cycle

• Energetics

Objective

At the end of this lecture, student will be able to

• Explain the conversion of Pyruvate to Acetyl CoA

• Explain the reaction of Krebs cycle

• Describe the energetics of TCA

• Explain the regulation of TCA

CONVERSION
OF PYRUVATE TO ACETYL CoA

• Pyruvate is converted to acetyl CoA by oxidative
decarboxylation

• It is a irreversible reaction, catalysed by PDH complex,
which is found only in mitochondria

• High activity of PDH are found in heart & kidney

• PDH complex requires five coenzymes; TPP, lipoamide, FAD,
CoA & NAD+

• The overall reaction is

• Pyruvate is decarboxylated to give hydroxyethyl TPP
catalysed by PDH

• Dihydrolipoyl transacetylase brings about the formation of
acetyl lipoamide and then catalyses the transfer of acetyl group to coenzyme A
to produce acetyl CoA

• The cycle is complete when reduced lipoamide is converted
to oxidized lipoamide by dihydro lipoyl dehydrogenase, where transfer of
reducing equivalents to FAD

• FADH2  in turn,
transfers the reducing equivalents to NAD+ 
to give NADH + H+, which can enters ETC to give 3 ATP (6 ATP from 2
moles of pyruvate formed from glucose)

Kreb’s
cycle

• Also known as citric acid cycle/tricarboxylic acid (TCA)
cycle

• Most imp metabolic pathway for the energy supply to the
body

• About 65-70% of the ATP is synthesized

• Involves oxidation of acetyl CoA to CO2 & H2O

• About 2/3 of total O2 consumed by body is utilizd for TCA

• It is the final pathway for carbohydrates, fats &
amino acids

• Provides many intermediates required for the synthesis of
amino acids, glucose, heme etc

• Proposed by Hans Adolf Krebs in 1937

• The enzymes of TCA cycle are located in mitochondrial
matrix

• Krebs cycle basically involves combination of a 2C acetyl
CoA with a 4C xaloacetate to producea 6C citrate

• In the reactions, 2C are oxidized to CO2 &
oxaloacetate is regenerated and recycled

• Oxaloacetate plays a catalytic role in citric acid cycle

Reactions of Kreb’s
cycle:

• Oxidative decarboxylation of pyruvate to acetyl CoA by PDH
complex is a connecting link between glycolysis & TCA cycle

The reactions of citric acid cycle are as follows:

1. Acetyl-CoA to Citrate

2. Citrate to Isocitrate

3. Isocitrate to ά-ketocitrate

4. Oxalosuccinate to ά-ketoglurate

5. ά-ketoglurate to Succinyl-CoA

6. Succinyl-CoA to Succinate

7. Succinate to Fumarate

8. Fumarate to Malate

9. Malate to Oxaloacetate

1. Formation of
citrate:
acetyl CoA condenses with oxaloacetate by the citrate synthase to
form citrate

Citrate is isomerized to isocitrate by aconitase with the
formation of an intermediate cis-aconitate

2. Formation of
a-ketoglutarate:
Enzyme isocitrate dehydrogenase catalyses the conversion
of isocitrate to oxalosuccinate and then to α- ketoglutarate. Formation of NADH
& liberation of CO2 occur

3. Conversion of
α-ketoglutarate to succinyl CoA:

• This step is carried out through oxidative
decarboxylation, catalyzed by α-ketoglutarate dehydrogenase complex

• This enzyme is dependent on five cofactors-TPP, lipoamide,
NAD+, FAD & CoA

4. Formation of
succinate:

• Succinyl CoA is converted to succinate by succinate
thiokinase

• In this reaction, GDP is phosphorylated to CTP (substrate
level phosphorylation)                

GTP + ADP ↔ATP + GDP

• GTP is converted to ATP by nucleoside diphosphate kinase

5. Conversion of
succinate to fumarate:

• Succinate is oxidized by succinate dehydrogenase to
fumarate

• In this reaction production of FADH2 occurs

9. Formation of
malate:

• Fumarase catalyses the conversion of fumarate to malate
with the addition of H2O

10. Conversion of
malate to oxaloacetate:

• Malate is then oxidized to oxaloacetate by malate
dehydrogenase

• Here synthesis of NADH occurs

• The oxaloacetate is regenerated which can combine with
another molecule of acetyl CoA and continue the cycle

Summary of TCA cycle

Acetyl CoA + 3NAD+ + FAD + CDP + Pi +2H2O
→ 2CO2 + 3NADH + 3H+ + FADH2 + GTP + CoA

Inhibitors of Krebs
cycle

Energetics of TCA
cycle:

• During TCA cycle, 4 reducinge quivalents (3 as NADH and
one as FADH2) are produced

• Oxidation of 3 NADH by ETC synthesized 9 ATP

• Oxidation of 1FADH2 by ETC synthesized 2 ATP

• 1 GTP is converted to ATP

• Thus, 12 ATP are produced from one acetyl CoA

Regulation of citric
acid cycle:
regulation is either by enzymes or Availability of ADP level

• Citrate synthase → Inhibited by ATP, NADH, acetyl CoA
& succinyl CoA

• lsocitrate dehydrogenase →Inhibited by ATP and NADH

• α-Ketoglutarate dehydrogenase → Inhibited by succinyl CoA
& NADH

• P → Unless sufficient levels of ADP are available, oxidation
of NADH and FADH2 through ETC stops

• Aaccumulation of NADH & FADH2 will lead to inhibition
of the enzymes and also limits the supply of NAD+ and FAD which are essential
for TCA cycle to proceed

Amphibolic
nature of TCA cycle

• TCA cycle provides various intermediates for the synthesis
of many compounds needed by the body

• TCA cycle is both cataholic and anaholic in nature, hence
regarded as amphibolic

• TCA cycle is actively involved in gluconeogenesis,
transamination and deamination

• The most important anabolic reactions are

1. Oxaloacetate & α-ketoglutarate:

• Serve  as  precursors 
for  the  synthesis 
of  aspartate  and 
glutamate which, in turn, are required for the synthesis of other
non-essential acids, purines and pyrimidines

2. Succinyl CoA is used for the synthesis of porphyrins and
heme

3. Mitochondrial c itrate is transported to cytosol, where
it is cleaved to provide acetyl CoA for the biosynthesis of fatty acids,
sterols etc

Anaplerosis or
anaplerotic reactions

• The reactions concerned to fill up the intermediates of
citric acid cycle are called as anaplerotic reactions or anaplerosis

1. Pyruvate carboxylase catalyses the conversion of pyruvate
to oxaloacetate and 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 + NADPH++H2O

3. Transamination is transfers of amino group to keto group
and itself gets converted to a keto acid

The formation of α-ketoglutarate and oxaloacetate occurs by
this mechanism

4. α-Ketoglutarate can also be synthesized from glutamate by
glutamate dehydrogenase action

Glutamate + NADP+
+ HO → α-Ketoglutarate + NADPH + H+ + NH4+

Summary

• Pyruvate is converted to acetyl CoA by PDH and is a
irreversible reaction

• PDH complex requires five coenzymes; TPP, lipoamide, FAD,
CoA & NAD+

• Also known as citric acid cycle/tricarboxylic acid (TCA)
cycle

• 12 ATP are produced from one acetyl CoA

• Citrate synthase, lsocitrate dehydrogenase &
α-Ketoglutarate dehydrogenase are regulators of TCA cycle

• TCA cycle is both cataholic and anaholic in nature, hence
regarded as amphibolic

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