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PYRUVATE DEHYDROGENASE/
BIOC DR. TISCHLER LECTURE 27 PYRUVATE DEHYDROGENASE/ CITRIC ACID CYCLE
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OBJECTIVES PDH reaction
Pathways in mitochondrial matrix; role of inner membrane & cristae PDH reaction a) reactants & products for E1, E2, E3 components cofactors: associated with each; prosthetic group or a co-substrate; vitamin source; function nutritional deficiencies severely impair regulation of the PDH complex (allostery; covalent modification) 3. Reactions of citric acid cycle where NADH, FADH2, GTP form 4. Compounds that regulate the citric acid cycle, enzymes they regulate, their effect
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Figure 1. The Mitochondrion
outer membrane inner membrane Impermeable to all charged molecules and neutral > 100 MW matrix cristae intermembrane space PDH; citric acid cycle; fatty acid -oxidation; ketone metabolism; gluconeogenesis & urea cycle (part) Increase surface area; contains electron transport; membrane transporters
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Figure 2. The pyruvate dehydrogenase complex
Acetyl CoA CH 3 - C S O CH 3 - C OH CH 3 - C COOH O CH 3 - C OH CoASH CH 3 - C OH CoASH CoASH Pyruvate CO2 TPP FAD CO2 E1 E3 CO2 E2 CO2 Lipoate HS SH NAD+ Lipoate TPP = thiamine pyrophosphate S S substrates products prosthetic group coenzymes Figure 2. The pyruvate dehydrogenase complex
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Acetyl CoA CO2 NAD+ substrates products coenzymes CH - C S CoA O TPP
3 - C S CoA O TPP E1 E3 E2 FADH2 CO2 Lipoate S NAD+ TPP = thiamine pyrophosphate substrates products prosthetic group coenzymes
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Acetyl CoA NADH CO2 NAD+ substrates products coenzymes CH - C S CoA O
3 - C S CoA O TPP FAD E1 E3 E2 NADH CO2 Lipoate S NAD+ TPP = thiamine pyrophosphate substrates products prosthetic group coenzymes
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Pyruvate NAD+ CoASH CO2 Acetyl CoA NADH Lipoate S E1 TPP E2 E3 FAD CH
- C COOH O CO2 Acetyl CoA CoA NADH
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Table 1. Cofactors for each component of the PDH
complex with the cofactor category and vitamin source Subunit Cofactor Type Vitamin Source E1 Thiamine pyrophosphate Prosthetic Thiamine E2 Coenzyme A Lipoamide (lipoic acid + lys residue) Co-substrate Pantothenic acid none-dietary E3 FAD NAD+ Riboflavin Niacin
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Pyruvate NAD + E 1 2 CoASH 3 CO2 NADH Acetyl CoA feedback inhibits E 2 feedback inhibits E 3 Figure 3. Allosteric feedback inhibition of E2 by acetyl CoA and E3 by NADH
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Figure 4. Regulation of E1 by covalent modification through phosphorylation
NAD+ CoASH ACTIVE ENZYME Pyruvate E3 E2 E1 NADH CO2 Acetyl CoA PDH Phosphatase Pi OH ATP ADP activate PDH kinase PDH Kinase inhibit PDH kinase E1 OPO 4 E2 E3 INACTIVE ENZYME Pyruvate CoASH NAD+
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Figure 5. Reactions of the citric acid cycle.
Glucose Figure 5. Reactions of the citric acid cycle. fatty acids, ketone bodies glycolysis PDH Acetyl CoA CoA Citrate [1] Pyruvate Oxaloacetate cis - Aconitate Isocitrate Malate NAD+ NADH [ 6] -Ketoglutarate NAD+ NADH, CO2 [2] CoA, NAD+ [3] Succinyl CoA NADH, CO2 Fumarate FAD FADH2 [5] Succinate GDP [4] GTP ADP ATP
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Citrate Synthase: oxaloacetate + acetyl CoA citrate O=C-OH C=O CH2 CoA-S CH3 HO-C-COOH + CoA-SH Isocitrate Dehydrogenase: isocitrate + NAD+ -ketoglutarate + NADH + CO2 O=C-OH HC-COOH CH2 HC-OH
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-Ketoglutarate Dehydrogenase:
-Ketoglutarate + CoA + NAD+ Succinyl CoA + NADH + CO2 O=C-OH CH2 HC-OH CoA-S C=O Succinyl CoA Synthetase: Succinyl CoA + GDP Succinate + GTP CoA-S C=O CH2 O=C-OH
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Succinate Dehydrogenase:
Succinate + FAD Fumarate + FADH2 CH2 O=C-OH CH Malate Dehydrogenase: Malate + NAD+ Oxaloacetate + NADH HC-OH CH2 O=C-OH C=O
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Table 2. Allosteric regulation of the citric acid cycle.
Enzyme regulated Regulatory substance Effect Isocitrate dehydrogenase ADP NADH, ATP activation inhibition -Ketoglutarate dehydrogenase NADH, succinyl CoA, GTP
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