Citric Acid Cycle

Dr. Vijaya Srinivasan,

Dept. Of Biochemistry
SRMC & RI
 THREE METABOLIC FATES OF
PYRUVATE THAT WE OBTAINED
FROM GLYCOLYSIS
 IF ANAEROBIC WHAT
HAPPENS TO PYRUVATE?
Pyruvate gets converted to
LACTATE
FATE OF PYRUVATE IN
AEROBIC CONDITIONS
PYRUVATE GETS CONVERTED
TO ACETYL CoA
REVIEW OF SYNTHESIS
OF ACETYL CoA
Pyruvate In Aerobic Conditions Gets Converted To Acetyl CoA
Cori cycle

oxaloacetate
 OBJECTIVES
 To know what happens to Acetyl CoA? What is meant by
citric acid cycle(also called TCA cycle or Krebs cycle)?
 Significance of the TCA cycle.
 Reactions of TCA cycle.
 Energetics of the TCA cycle
 Regulation of the citric acid cycle.
 Inhibitors of the enzymes of the TCA cycle.
 Amphibolic nature of citric acid cycle.
 Citric Acid Cycle

• Citric acid cycle ( Krebs cycle , TCA cycle ) is a

series of reactions that occur in mitochondria
that brings about the catabolism of acetyl
residues.
• The acetyl residues are in the form of acetyl CoA,
an ester of Coenzyme A.
• The sources of acetyl CoA are Pyruvate obtained
from glucose, fatty acids and ketogenic amino
acids.
 Significance Of The TCA Cycle

 It is the common pathway for the oxidation of

carbohydrates, protein and lipids.

 Glucose, fatty acids and amino acids are all metabolized

to acetyl CoA or intermediates of the cycle.

 It plays a major role in transamination,

gluconeogenesis,deamination and lipogenesis.

 It provides reducing equivalents that enter the respiratory

chain by which large amounts of ATP’s is generated
Citric Acid Cycle
 Reactions of Citric Acid Cycle

STEP 1 : Formation of Citrate

• The first step involves the condensation of
oxaloacetate with acetyl CoA to form citrate.
• The reaction is catalyzed by citrate synthase.
The hydrolysis of the thio ester bond of CoA
liberates free energy that drives the reaction
forward.
1. Formation of Citrate
 Step 2 : Formation of Isocitrate

• Citrate is isomerized to isocitrate by aconitase.

This conversion takes place in two steps.
• The first step involves the removal of water
molecule from citrate forming cis aconitate.
It is a transient compound.
• Immediately a molecule of water is added to
form isocitrate.
2. Formation Of Isocitrate
STEP 3: Formation of α Ketoglutarate
• A two step process both are catalyzed by the
same enzyme isocitrate dehydrogenase.
• Isocitrate is first dehydrogenated to form
oxalosuccinate, it is a unstable compound it
undergoes decarboxylation to form alpha
ketoglutarate.
• Isocitrate + NAD Oxalosuccinate 
α Ketoglutarate + CO2 + NADH + H+
3. Formation Of  Ketoglutarate
 Step 4: Formation Of Succinyl CoA
• α Ketoglutarate ( α K.G) undergoes oxidative
decarboxylation to form Succinyl CoA .

• This reaction is catalyzed by the enzyme

α ketoglutarate + NAD+ + CoA
α K.G Dehydrogenase
complex

Succinyl-CoA + CO2+ NADH + H+

4. Formation Of Succinyl CoA
 Step 4: Formation Of Succinate
Succinyl CoA + Pi + GDP

succinate thiokinase
Succinate + GTP+ CoA
This is a substrate level phosphorylation reaction
wherein a high energy phosphate is generated
from the energy trapped in thioester bond of
Succinyl CoA.
 Step 6 : Formation Of Fumarate
• Succinate is further dehydrogenated to fumarate,
this reaction is catalyzed by the enzyme succinate
dehydrogenase.
• It is the only dehydrogenation reaction that
involves direct transfer of hydrogen from the
substrate to FAD without participation of NAD.

Succinate + FAD Fumarate + FADH2

6. Formation Of Fumarate
 Step 7: Formation Of Malate

• Fumarase catalyses the addition of water to

fumarate to give Malate.

• Fumarate + H2O Malate

7. Formation Of Malate
 Step 8. Generation of Oxaloacetate
• Finally Malate is oxidized to oxaloacetate by
Malate dehydrogenase.
L- Malate + NAD Oxaloacetate +
NADH + H+
• NADH generated in this step enters the ETC ,
where 3 ATP’s are produced. The oxaloacetate
further condenses with another molecule of
Acetyl CoA and the TCA CYCLE continues.
8. Generation of Oxaloacetate
 Generation Of ATP by TCA Cycle
(From 1 molecule of Acetyl CoA)

Reaction Method of ~ p ATP

production Molecules
Isocitrate α K.G Oxidation of NADH 2.5

α K.G  succinyl CoA Oxidation of NADH 2.5

Succinyl CoA  GTP 1
Succinate
Succinate  Fumarate Oxidation of FADH2 1.5

Malate  Oxaloacetate Oxidation of NADH 2.5

TOTAL ATP 10
How Many ATP’S Are Produced
From Anaerobic Glycolysis

Ans : 2 ATP’s
 Regulation Of Citric Acid Cycle

• Acetyl CoA + Oxaloacetate Citrate

ATP
Isocitrate Dehydrogenase

• Isocitrate Oxalosucccinate
NADH

•  ketoglutarate Succinyl CoA

NADH
 Regulation Of Citric Acid Cycle

• The regulation of the cycle is also by the cellular

needs of ATP. When the energy charge of the cell is
low, the cycle operates at a faster rate.

• The citric acid cycle is the largest generator of ATP

among the metabolic pathways.

• Accumulation of NADH and FADH2 cause inhibition of

the TCA cycle.
Non Physiological Inhibitors Of The
TCA Cycle
1) Aconitase which catalyses the conversion of
citrate to aconitate is inhibited by
Flouroacetate.
2)  ketoglutarate dehydrogenase that
converts α-ketoglutarate to succinyl CoA is
inhibited by Arsenite.
3) Succinate Dehydrogenase is inhibited by
malonate.
 Amphibolic Nature Of TCA Cycle
TCA cycle has a dual role
• Catabolic role :
Acetyl CoA produced from metabolism of
carbohydrates, lipids and proteins are oxidized in this
cycle to produce CO2 and H2O.
• Anabolic or synthetic role :
Intermediates of TCA cycle are utilized for many
biosynthetic pathways.
Thank you