Citric Acid Cycle

• Assoc. Prof. Dr. Atif Amin Baig ,

• Faculty of Medical Sciences,
• University Sultan Zainal Abidin.
• atifamin@unisza.edu.my
 Recalls
• What is Hexose Pentose Phosphate Pathway?
• Demand for Hexose Pentose Phosphate Pathway?
• Site for Hexose Pentose Phosphate Pathway?
• Summary of Hexose Pentose Phosphate Pathway?
• What is guconeogenesis?
• Sites and need?
• Precursors of gluconeogenesis?
• Glycolysis Vs glyconeogenesis?
• Cori Cycle and its importance?
 Learning Outcomes
1. Explain the citric acid cycle as a common final metabolic pathway
2. What is coenzyme A and acetyl Co-A?
3. List the sources of acetyl CoA
4. Describe the conversion of pyruvate to acetyl CoA
5. Explain the citric acid cycle pathway including its location, intermediates, enzymes
and coenzymes
6. Discuss the energetics of tricarboxylic acid cycle (TCA) cycle
7. Discuss the importance of citric acid cycle
8. Explain the amphibolic nature of TCA cycle
9. Define the anaplerotic reactions with examples
10. Describe the regulation of TCA cycle
CENTRAL METABOLIC INTEGRATION
 Co-Enzyme A
Coenzyme A (CoA, CoASH, or HSCoA) is a coenzyme, notable for its role in
the synthesis and oxidation of fatty acids, and the oxidation of pyruvate in
the citric acid cycle. All genomes sequenced to date encode enzymes that use
coenzyme A as a substrate, and around 4% of cellular enzymes use it (or
a thioester, such as acetyl-CoA) as a substrate. In humans, CoA biosynthesis
requires cysteine, pantothenate, and adenosine triphosphate
 ACETYL CO-A
Coenzyme A is a nucleotide with a complex structure. It serves to activate residues of carboxylic
acids (acyl residues). Bonding of the carboxy group of the carboxylic acid with the thiol group of the
coenzyme creates a thioester bond (-S-CO-R) in which the acyl residue has a high chemical
potential. It can therefore be transferred to other molecules in exergonic reactions. This fact plays an
important role in lipid metabolism in particular, as well as in two reactions of the tricarboxylic acid
cycle.
 Group Transfer Potential of Acetyl Co-A

Acetyl CoA + H2O 􏰃  acetate + CoA

Delta G = -32 KJ-1  ATP

 Citric Acid Cycle

The tricarboxylic acid cycle (TCA cycle, also

known as the citric acid cycle or Krebs cycle) is a
cyclic metabolic pathway in the mitochondrial
matrix.
 Steps of TCA
• Comprises of total eight steps.

• In eight steps, it oxidizes acetyl residues (CH3-

CO-) to carbon dioxide (CO2).

• The reducing equivalents obtained in this

process are transferred to NAD+ or
ubiquinone, and from there to the respiratory
chain.
 Respiration: Stage 1
Generates some: ATP, NADH, FADH2
 Respiration: Stage 2

Generates more
NADH, FADH2 and
one GTP
 The Citrate Synthase Reaction
(Step #1)
• The only cycle reaction with C-C bond formation
• Essentially irreversible process
Isomerization of Citrate by
Aconitase (Step #2)
 The Isocitrate Dehydrogenase
Reaction (Step #3)
Oxidation of the alcohol to ketone involves the
transfer of a hydride from the C-H of the alcohol to
the nicotinamide cofactor – 3 step mechanism
Oxidation of -ketoglutarate
(Step #4)
Substrate-Level Phosphorylation
(Step #5)
Succinate Dehydrogenase
(Step #6)
 Hydration
of Fumarate
to Malate
(Step #7)
Oxidation of Malate to
Oxaloacetate (Step #8)
Products from One Turn of the
Cycle

Therefore, the total

numbers of molecules
generated in the
oxidation of pyruvate
and the Krebs Cycle is:
9 NADH
2 FADH2
6 CO2
 Net Effect of the Citric Acid Cycle

Acetyl-CoA + 3NAD+ + FAD + GDP + Pi + 2 H2O

2CO2 +3NADH + FADH2 + GTP + CoA + 3H+

• Carbons of acetyl groups in acetyl-CoA are

oxidized to CO2
• Electrons from this process reduce NAD+ and FAD
• One GTP is formed per cycle, this can be
converted to ATP
• Intermediates in the cycle are not depleted
Role of the Citric Acid Cycle in Anabolism
 Functions of Citric Acid Cycle
1. Oxidized Acetyl CoA to ATP
( 1 mol Acetyl CoA to 12 mol ATP )

2. The citric acid cycle is AMPHIBOLIC :

- it can oxidized to yield ATP
- it is important in the provision of carbon
skeletons for gluconeogenesis, fatty acid
synthesis and interconversion of amino acid
 Anaplerotic Reactions
• Plerosis of intermediates of a metabolism
• Can be anaplerotic
• Can be cataplerotic

• Examples:
1. Pyruvate  Oxaloacetate
2. Aspartate  Oxaloacetate
3. Glutamate  α-ketoglutarate
4. β-Oxidation of fatty acids  Succinyl Co-A
 Regulation of Citric Acid Cycle
• The citric acid cycle in contrast is regulated by
three simple mechanisms.

1. Substrate availability
2. Product inhibition
3. Competitive feedback inhibition.
Thank you