Transcript Citric Acid Cycle

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Glycolysis
1. From glucose to pyruvate;
2. 10-step reactions;
3. Three inreverseable reactions
hexokinase
phosphofructokinase-1
pyruvate kinase
4. Rate limiting enzyme:
phosphofructokinase-1
5. Production:
2 ATP (net)
2 NADH + H
6. Function:
Supply energy in anaerobic
condition.
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Glycolysis in red blood cells
1. Relies exclusively on glycolysis as
fuel to produce ATP;
2. End product is lactate;
3. Produce 2,3-BPG enhancing the
ability of RBCs to release oxygen.
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The Citric Acid Cycle
Kreb’s Cycle
Tricarboxylic acid cycle (TAC)
“The wheel is turnin’ and the sugar’s a
burnin’”
More than 95% of the energy for the human being is
generated through this pathway (in conjunction with the
oxidative phosphorylation process)
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What happened for 2 pyruvates?
Basically three options depending on the environmental conditions
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From pyruvate to acetyl-CoA
Pyruvate + CoA + NAD+
Acetyl-CoA + CO2 + NADH + H+
Pyruvate produced from glycolysis must be decarboxylated to acetyl
CoA before it enters TCA cycle.
Key irreversible step in the metabolism of glucose.
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Reaction irreversible
Catalytic
cofactors
Pyruvate is first transported into mitochondria via a
specific transporter on the inner membrane and then
oxidized to acetyl-CoA by the catalysis of pyruvate
dehydrogenase complex.
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Pyurvate dehydrogenase complex
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Acetyl-CoA: fuel for the Citric Acid Cycle
Coenzyme A was first discovered by Lipmann
in 1945.
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Lipoate
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FAD
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Nicotinamide Adenine Dinucleotide (NAD)
Reduction
Oxidation
Used primarily in the cell as an electron carrier to
mediate numerous reactions
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Oxidization of acetyl-CoA
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Control of the Pyruvate Dehydrogenase Complex
• Regulation by its products
NADH & Acetyl-CoA: inhibit
NAD+ & CoA: stimulate
• Regulation by energy charge
ATP : inhibit
AMP: stimulate
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The citric acid cycle
consists of eight successive reactions
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Step 1: citrate formation
Enzyme: Citrate synthase
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Step 2: Citrate isomerized to isocitrate
Dehydration
Hydration
Enzyme: aconitase
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Step 3: Isocitrate to -ketoglutarate
1st NADH produced
1st CO2 removed
Enzyme: isocitrate dehydrogenase
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Step 4: Succinyl-CoA formation
2nd NADH produced, 2nd CO2 removed
Enzyme: -ketoglutarate dehydrogenase
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Step 5: Succinate formation
Enzyme: succinyl-CoA synthetase
A GTP (ATP) produced
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Steps 6: Fumarate formation
Enzyme: Succinate dehydrogenase
A FADH2 produced
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Steps 7: Malate formation
Enzyme: fumarase
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Step 8: Malate to Oxaloacetate
3rd NADH produced
Enzyme: malate dehydrogenase
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Citric Acid Cycle:
Overview
Input: 2-carbon units
Output: 2 CO2
1 GTP
3 NADH: 2.5X3=7.5 ATP
1 FADH2: 1.5X1=1.5 ATP
Total: 10 ATP
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Biosynthetic roles of the citric acid cycle
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Summary
• Pyruvate is converted to acetyl-CoA by the action of
pyruvate dehydrogenase complex, a huge enzyme
complex.
• Acetyl-CoA is converted to 2 CO2 via the eight-step
citric acid cycle, generating three NADH, one FADH2,
and one ATP (by substrate-level phophorylation).
• Intermediates of citric acid cycle are also used as
biosynthetic precursors for many other biomolecules,
including fatty acids, steroids, amino acids, heme,
pyrimidines, and glucose.
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Why is citric acid cycle so important?
Citric acid cycle is of central importance in all living cells that use
oxygen as part of cellular respiration.
In aerobic organisms, the citric acid cycle is part of a metabolic
pathway involved in the chemical conversion of carbohydrates, fats
and proteins into carbon dioxide and water to generate energy.
In addition, it provides precursors for synthesis of many
compounds including some amino acids.
In carbohydrate metabolism:
1. Glycolysis to produce pyruvate;
2. Pyruvate is oxidized to acetyl-CoA;
3. Acetyl-CoA enters the citric acid cycle.
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In protein catabolism:
1. Proteins are broken down by proteases into their
constituent amino acids.
2. The carbon backbone of these amino acids are converted
to acetyl-CoA and entering into the citric acid cycle.
In fat catabolism:
1. Triglycerides are hydrolyzed to into fatty acids and
glycerol.
2. In the liver the glycerol can be converted into pyruvate.
3. Fatty acids are broken down through a process known as
beta oxidation which results in acetyl-coA which can be used
in the citric acid cycle.
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Regulation of Citric Acid Cycle
• 3 control sites
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Control of citric acid cycle
Control points:
1. Citrate synthase
2. Isocitrate dehydrogenase
3. - ketoglutarate dehydrogenase
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Regulation of Citric Acid Cycle
Site 1
Acetyl CoA + Oxaloacetate
Citrate
Enzyme: citrate synthase
Inhibited by ATP
Stimulated by ADP
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Regulation of Citric Acid Cycle
Site 2
Isocitrate
-Ketoglutarate
• Enzyme: isocitrate dehydrogenase
• Inhibited by ATP, NADH,
succinyl-CoA
• Stimulated by ADP & NAD+
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Regulation of Citric Acid Cycle
Site 3
- ketoglutarate
succinyl-CoA
Enzyme:
-ketoglutarate dehydrogenase
Inhibited by ATP, NADH,
succinyl-CoA
Stimulated by ADP & NAD+
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Aerobic oxidation of glucose
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Aerobic oxidation of glucose – How many ATP we can get?
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Total Energy per glucose through aerobic
oxidation
• Cytosol
– 2 ATP
– 2 NADH
• NADH in cytosol can’t get into mitochondrion
• In eukaryotes two pathways to transfer NADH into MC
– transferred to FADH2
» get 1.5 ATP/ FADH2
» 2 X 1.5 ATP = 3 ATP
– Or transferred to NADH
» Get 2.5 ATP/ NADH
» 2 NADH X 2.5 ATP= 5 ATP
Total 3+ 2 or 5 + 2 so either 5 or 7 ATP
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• In mitochondrion:
– Each NADH makes 2.5 ATP
– Each FADH2 makes 1.5 ATP
– GTP = ATP
• So…
– From pyruvate in mitochondrion
• 8 NADH X 2.5 ATP = 20 ATP
• 2 FADH2 X 1.5 ATP= 3 ATP
• 2 GTP = 2 ATP
• TOTAL in mitochondrion 25 ATP
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