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PDH (Pyruvate Dehydrogenase Multienzyme Complex), Precursor, Enzyme,…
PDH (Pyruvate Dehydrogenase Multienzyme Complex)
Substrates
Pyruvate
NAD+
CoASH
Products
Acetyl CoA
NADH + H
CO2
Coenzymes
Oxidized lipoamide
Common to PDH & a-ketoglutarate; affected by arsenate poisoning
Mercuric ions
: inhibits PDH --> binds to thiol group
CoASH
Vit. B5 (pantothenic acid)
Accepts acetyl from acetyl lipoamide
Thiamine pyrophosphate (TPP)
Chronic alcholism: decreases thiamine absorption = inhibits PDH
FAD
NAD
Vit. B3 (Niacin)
Regenerates enzyme complex by transfer of protons
Accepts H+ from FADH2
Mitochondria
Mitochondrial Pyruvate Carrier (MPC)
1 mol glucose = 2 mol pyruvate
1 NADH = 2.5 ATP (2 pyruvate from glycolysis means 2 NADH)
2.5 x 2 = 5 ATP (Net yield)
Dihydrolipoyl dehydrogenase (DLDH)
Reduced NAD to NADH
Overall reaction: Pyruvate + NAD + CoA --> Acetyl CoA + NADH + H + CO2
Cofactors
Lipoamide
E2: Dihydrolipoyl transacetylase
Acetyl lipoamide
: carrier of 2 carbon unit from HETPP, forms Acetyl CoA
Accepts acetyl group from TPP
FAD
Vit. B2 (riboflavin)
E3: Dihydrolipoyl dehydrogenase
Produces dihydrolipoamide, not ATP
Accepts H+ from lipoamide
TPP
Vit. B1 (thiamine)
E1: Pyruvate dehydrogenase
Removal of CO2 in synthesis of Acetyl CoA
Binds & decarboxylates pyruvate
Metabolic Fates of Pyruvate
Alanine
Transamination via
Alanine Aminotransferase
Oxaloacetate
Carboxylation via
Pyruvate Carboxylase
Acetyl CoA
Oxidative Decarboxylation via
Pyruvate Dehydrogenase
Ethanol
Decarboxylation via
Pyruvate Decarboxylase
Lactate
Reduction via
Lactate Dehydrogenase
PDH Multienzyme Complex Reactions
E1 - Decarboxylation
of Pyruvate to HETPP and CO2 via Pyruvate dehydrogenase
Substrate: Pyruvate
Enzyme: PDH / E1
Coenzyme: Thiamine pyrophosphate
Product: Hydroxyethylthiamine pyrophosphate (HETPP) & CO2
E2: Transfer of acetyl group
from acetyl lipoamide to CoASH via Dihydrolipoyl transacetylase
HETPP
Redox reation
Enzyme: DLTA / E2
Coenzyme: oxidized lipoamide
Product: Acetyl lipoamide / dihydrolipoamide
Acetyl lipoamide / Acetyl dihydrolipoamide
Acetyl in acetyl-lipoamide transferred to CoASH = forms acetyl CoA
Enzyme: DLTA / E2
Coenzyme: CoASH
Product: Acetyl CoA
Acetyl lipoamide: becomes reduced lipoamide
Highly exergonic
Irreversible
E3: Reoxidation
of reduced lipoamide via dihydrolipoyl dehydrogenase
Substrate: Reduced lipoamide
Enzyme: DLDH / E3
Coenzyme: FAD & NAD
Product: Oxidized lipoamide, FADH2, NADH, H+
Regulation of PDH Complex
Negative Feedback
Inc. Acetyl CoA = Dec. conversion of pyruvate to Acetyl CoA
Inc. NADH = Dec. reduction of NAD to NADH
Covalent Modification
PDH Inactive
Phosphorylation by kinase
Activators
NADH
Acetyl CoA
ATP
Inhibitors
Pyruvate
NAD
ADP
CoASH
PDH Active
Dephosphorylation by phosphatase
Activators: Mg, Ca, Insulin, Epinephrine
Precursor
Enzyme
Prosthetic group
= tightly bound