Citric Acid Cycle

Citric acid cycle
 The tricarboxylic acid cycle (TCA cycle) also called the citric
acid cycle or the Krebs cycle, plays several roles in
metabolism.
 It is the final pathway where the oxidative catabolism of

carbohydrates, amino acids and fatty acids converge, their
carbon skeletons being converted to CO2.
 This oxidation provides energy for the production of the

majority of adenosine triphosphate (ATP) in most animals,
including humans.
Stages of Catabolism
Citric acid cycle
Citric acid cycle
 The TCA cycle occurs totally in the mitochondria and is,

therefore, in close proximity to there actions of electron
transport, which oxidize the reduced coenzymes (NADH
and FADH2) produced by the cycle.
 The TCA cycle is an aerobic pathway, because O2 is

required as the final electron acceptor.
 Anaplerotic (“filling up”):

Reactions such as the catabolism of some amino acids
generate intermediates of the cycle and are called anaplerotic
(“filling up”) reactions.
Citric acid cycle
The TCA cycle also supplies intermediates for a number of

important synthetic reactions. For example,
 The cycle functions in the formation of glucose from the

carbon skeletons of some amino acids.
 It provides building blocks for the synthesis of some amino

acids and heme.
 Therefore, this cycle should not be viewed as a closed circle

but, instead, as a traffic circle with compounds entering
and leaving as required.
Citric acid cycle
Citric acid cycle
Reactions of Citric acid cycle
 In the TCA cycle, oxaloacetate is first condensed with an

acetyl group from acetyl coenzyme A (CoA) and then is
regenerated as the cycle is completed.
 Therefore, the entry of one acetyl CoA into one round of

the TCA cycle does not lead to the net production or
consumption of intermediates.
 Two carbons entering the cycle as acetyl CoA are balanced

by two CO2 exiting.
Citric acid Cycle
Oxidative decarboxylation of pyruvate:

 The major source of acetyl CoA, the two-carbon substrate
for the TCA cycle, is the oxidative decarboxylation of
pyruvate.
 Pyruvate, the end product of aerobic glycolysis, must be

transported from the cytosol into the mitochondrion.
 This is accomplished by a specific transporter that

facilitates movement of pyruvate across the inner
mitochondrial membrane.
Oxidative decarboxylation of pyruvate:

 Once in the mitochondrial matrix, pyruvate is converted to
acetyl CoA by the pyruvate dehydrogenase complex (PDH
complex), which is a multienzyme complex.
 The pyruvate dehydrogenase complex (PDH complex) is

not part of the TCA cycle, but it supplies substrate for the
cycle.
PDH complex component enzymes:

 The PDH complex is a protein aggregate of multiple copies
of three enzymes:
 Pyruvate decarboxylase (E1, sometimes called pyruvate

dehydrogenase)
 Dihydrolipoyl transacetylase (E2)
 Dihydrolipoyl dehydrogenase (E3)
Each catalyzes a part of the overall reaction.

PDH complex coenzymes:

The PDH complex contains five coenzymes that act as carriers
or oxidants for the intermediates of the reactions.
 E1 requires thiamine pyrophosphate (TPP)

 E2 requires lipoic acid and CoA
 E3 requires flavin adenine dinucleotide (FAD) and
nicotinamide adenine dinucleotide (NAD+)
Citric acid Cycle
Step-1: Synthesis of citrate from acetyl coenzyme A and oxaloacetate
Step-2: Isomerization of citrate
Step-3: Oxidative decarboxylation of isocitrate
Step-4: Oxidative decarboxylation of α-ketoglutarate
Step-5: Cleavage of succinyl coenzyme A
Nucleoside
diphosphate
kinase
Step-6: Oxidation of succinate
Step-7: Hydration of fumarate
Step-8: Oxidation of malate
Energy produced by Citric acid cycle
Regulation of Citric acid cycle
TCA cycle is controlled by the regulation of several

enzymes:
 Citrate synthase
 Isocitrate dehydrogenase
 α-ketoglutarate dehydrogenase complex

Regulation of Citric acid cycle
Energy produced by Metabolism of
Carbohydrates
If NADH= 3 ATP If NADH= 2.5 ATP
If FADH2= 2 ATP If FADH2= 1.5 ATP
1 Glycolysis
8 ATP 7ATP
2 PDH complex 6 ATP 5 ATP
3 Citric acid cycle 24 ATP 20 ATP
4 Total 38 ATP 32 ATP

Citric Acid Cycle

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Citric acid cycle

 It is the final pathway where the oxidative catabolism of

 This oxidation provides energy for the production of the

 The TCA cycle occurs totally in the mitochondria and is,

 The TCA cycle is an aerobic pathway, because O2 is

 Anaplerotic (“filling up”):

The TCA cycle also supplies intermediates for a number of

 The cycle functions in the formation of glucose from the

 It provides building blocks for the synthesis of some amino

 Therefore, this cycle should not be viewed as a closed circle

 In the TCA cycle, oxaloacetate is first condensed with an

 Therefore, the entry of one acetyl CoA into one round of

 Two carbons entering the cycle as acetyl CoA are balanced

Oxidative decarboxylation of pyruvate:

 Pyruvate, the end product of aerobic glycolysis, must be

 This is accomplished by a specific transporter that

Oxidative decarboxylation of pyruvate:

 The pyruvate dehydrogenase complex (PDH complex) is

PDH complex component enzymes:

 Pyruvate decarboxylase (E1, sometimes called pyruvate

Each catalyzes a part of the overall reaction.

PDH complex coenzymes:

 E1 requires thiamine pyrophosphate (TPP)

TCA cycle is controlled by the regulation of several

 α-ketoglutarate dehydrogenase complex

2 PDH complex 6 ATP 5 ATP

3 Citric acid cycle 24 ATP 20 ATP

4 Total 38 ATP 32 ATP

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