Download The Citric acid cycle

Glycolysis occurs in
the cytosol of cells.
Pyruvate enters the
mitochondrion to be
metabolized further.
Mitochondrial
Compartments:
matrix
cristae
inner
membrane
intermembrane
space
mitochondrion
outer
membrane
The matrix contains Pyruvate Dehydrogenase, 
enzymes of Krebs Cycle, and other pathways,
e.g., fatty acid oxidation & amino acid metabolism.
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CH 5. Citric acid cycle
CH 5. Citric acid cycle
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 CoA 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
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the mitochondrial matrix
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CH 5. Citric acid cycle
Citric acid cycle is also an important source of
precursors for biosynthetic reactions
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CH 5. Citric acid cycle
Citric acid cycle
intermediates are
always in flux
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CH 5. Citric acid cycle
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+
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CH 5. Citric acid cycle
The citric acid cycle oxidizes two carbon
units. These enter the cycle as Acetyl-CoA
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CH 5. Citric acid cycle
Oxidative Decarboxylation of Pyruvate
- Pyruvate Dehydrogenase complex is a large multi-subunit complex located in
the mitochondria
- Irreversible reaction; Acetyl CoA cannot 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.
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CH 5. Citric acid cycle
CH 5. Citric acid cycle
Pyruvate
Dehydrogenase: a large
complex containing many
copies of each of 3
enzymes, E1, E2, & E3.
Pyruvate Dehydrogenase Subunits
Enzyme
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Abbreviated
Prosthetic Group
Pyruvate
Dehydrogenase
E1
Thiamine
pyrophosphate (TPP)
Dihydrolipoyl
Transacetylase
E2
Lipoamide
Dihydrolipoyl
Dehydrogenase
E3
FAD
Cofactors for the
Pyruvate
Dehydrogenase include
CoA-SH, NAD+, TPP,
FAD, Lipolate
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CH 5. Citric acid cycle
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CH 5. Citric acid cycle
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 form
-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
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CH 5. Citric acid cycle
CH 5. Citric acid cycle
Regulation Pyruvate Dehydrogenase (PDH) complex
Pyruvate Dehydrogenase is regulated both allosterically and by reversible
phosphorylation
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CH 5. Citric acid cycle
Regulation of Pyruvate Dehydrogenase
Pyruvate Dehydrogenase is regulated both allosterically and by reversible
phosphorylation
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CH 5. Citric acid cycle
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CH 5. Citric acid cycle
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CH 5. Citric acid cycle
4C
6C
6C
5C
4C
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CH 5. Citric acid cycle
The Citric acid cycle
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CH 5. Citric acid cycle
The Citric acid cycle
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CH 5. Citric acid cycle
The Citric acid cycle
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CH 5. Citric acid cycle
The Citric acid cycle
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CH 5. Citric acid cycle
Control Points in the Citric Acid Cycle
Citric acid cycle is controlled at two
points
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CH 5. Citric acid cycle
Control Points in the Citric Acid Cycle
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CH 5. Citric acid cycle
Single molecule of glucose can potentially yield ~38
molecules of ATP
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CH 5. Citric acid cycle