Oxidative Decarboxylation of Pyruvate
- Pyruvate Dehydrogenase complex is a large multi-subunit complex located in
the mitochondria
- Irreversible reaction; Acetyl CoA cannot be converted into pyruvate
- Pyruvate dehydrogenase is not a part of citric acid cycle but it a major
source of fuel for citric acid cycle which is Acetyl CoA
- Pyruvate Dehydrogenase complex is aggregate of three enzymes:
1- Pyruvate dehydrogenase component called (pyruvate
decarboxylase)
2- Dihydrolipoyl transacetylase
3- Dihydrolipoyl dehydrogenase
Each subunit of this large complex catalyzes a part of the overall reactions.
The citric acid cycle oxidizes two carbon
units. These enter the cycle as Acetyl-CoA
Regulation Pyruvate Dehydrogenase complex
-Product inhibition
-The enzyme complex is inhibited by Acetyl CoA when it is
accumulated; the production rate is higher than the cell
capacity of oxidation with citric acid cycle
- High NADH/NAD+ ratio inhibits this enzyme complex
Covalent modification
-Two forms of the enzyme complex;
- Active non- phosphorylated form
- Inactive phosphorylated
-The two forms can be interconverted by the action of two enzymes
phosphatase and kinase
- The kinase is activated by an increase in the ratio of acetyl CoA/
CoA ratio or NADH/ NAD+.
- elevated ADP\ATP ratio  demand for energy  inhibits the
kinase and activate the phosphatase to produce more of the active
non-phosphorylated enzymes
Regulation Pyruvate Dehydrogenase complex
Pyruvate Dehydrogenase is regulated both allosterically and by reversible
phosphorylation
The Citric acid cycle
- Citric acid cycle contains a series of oxidation-reduction
reactions
- Carbon entering the cycle, leaves fully oxidized as CO2.
- “High energy” electrons leave the cycle with high energy
electron carriers as NADH and FADH2.
- Very little ATP is made directly in the cycle.
- No oxygen is used in the cycle.
Overall reaction
3NAD+ + FAD + GDP + Pi + 2H2O + acetyl-CoA
3NADH + FADH2 + GTP + CoA + 2CO2 + 3H+
Citric acid cycle
Krebs cycle, tricarboxylic acid cycle TCA
The central function is the oxidation of acetyl CoA to CO2
- It is the final common pathway for oxidation of fuel
molecules
- Acetyl Co is derived from the metabolism of fuel
molecules as amino acids, fatty acids, and carbohydrates.
- Citric acid cycle is also an important source of precursors
•Some intermediates are precursors of amino acid
• One of the intermediates is used in the synthesis of
porphorins
• Another is used in the synthesis of fatty acids and
sterols.
- Citric Acid Cycle located in the mitochondrial matrix
Citric acid cycle is also an important source of
precursors for biosynthetic reactions
Citric acid cycle
intermediates are
always in flux
4C
6C
6C
5C
4C
The Citric acid cycle
The Citric acid cycle
The Citric acid cycle
The Citric acid cycle
Control Points in the Citric Acid Cycle
IDH catalyzes the rate-limiting
step
Regulation of the TCA cycle
occurs at both the level of entry
of substrates into the cycle as
well as at the key reactions of
the cycle.
Fuel enters the TCA cycle
primarily as acetyl-CoA.
The generation of acetyl-CoA
from carbohydrates is,
therefore, a major control point
of the cycle.
This is the reaction catalyzed by
the PDH complex.
Control Points in the Citric Acid Cycle
Single molecule of glucose can potentially yield ~38
molecules of ATP
• The end
Regulation of Pyruvate Dehydrogenase
Pyruvate Dehydrogenase is regulated both allosterically and by reversible
phosphorylation
Cofactors for the
Pyruvate
Dehydrogenase include
CoA-SH, NAD+, TPP,
FAD, Lipolate
Oxidative Decarboxylation of Pyruvate
occurs in multi-step reactions
E1: Pyruvate dehydrogenase
E2: Dihydrolipoyl transacetylase
E3: Dihydrolipoyl dehydrogenase