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Pyruvate dehydrogenase (E1) is the first component enzyme of pyruvate dehydrogenase complex (PDC). It thus contributes to transforming pyruvate into acetyl-CoA by a process called pyruvate decarboxylation. Acetyl-CoA may then be used in the citric acid cycle to carry out cellular respiration, so pyruvate dehydrogenase contributes to linking the glycolysis metabolic pathway to the citric acid cycle. EC 188.8.131.52.
Additional recommended knowledge
E1 performs the first two reactions within the complex. They are:
Phosphorylation of E1 by pyruvate dehydrogenase kinase (PDK) inactivates E1 and subsequently the entire PDC.
This is reversed by pyruvate dehydrogenase phosphatase.
E1 is a multimeric protein:
E1 has two catalytic sites, each providing thiamine pyrophosphate (TPP) and magnesium ion as cofactors.
Conformation and reactions
Biochemical and structural data for E1s revealed a mechanism of activation of TPP cofactor by forming the conserved hydrogen bond with glutamate residue (Glu59 in human E1) and by imposing a V-conformation that brings the N4’ atom of the aminopyrimidine to the distance required for the intramolecular hydrogen bonding with the thiazolium C2 atom.
This unique combination of contacts and conformation of TPP leads eventually to formation of the reactive C2-carbanion.
After the cofactor TPP reacts with pyruvate, which undergoes decarboxylation, the acetyl portion becomes a hydroxyethyl derivative covalently attached to TPP.
In the second reaction, E1 transfers two electrons and the acetyl group to the second substrate, lipoic acid. This reduces the oxidized lipoic acid and transfers the acetyl group to the lipollyl group to form an acetyl thioester.
Stimulation and inhibition
Pyruvate dehydrogenase is an autoantigen recognized in primary biliary cirrhosis, a form of acute liver failure. These antibodies appear to recognize oxidized protein that has resulted from inflamatory immune responses. Some of these inflamatory responses are explained by gluten sensitivity. Other mitochondrial autoantigens include oxoglutarate dehydrogenase and branched-chain alpha-keto acid dehydrogenase complex, which are antigens recognized by anti-mitochondrial antibodies.
In bacteria, a form of pyruvate dehydrogenase (also called pyruvate oxidase, EC 184.108.40.206) exists that links the oxidation of pyruvate into acetate and carbon dioxide to the reduction of ferrocytochrome. In E. coli this enzyme is encoded by the pox B gene and the protein has a flavin cofactor. This enzyme increases the efficiency of growth of E. coli under aerobic conditions.
|This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Pyruvate_dehydrogenase". A list of authors is available in Wikipedia.|