pyruvate dehydrogenase (lipoamide) alpha 1
|Locus||Chr. X p22.1|
pyruvate dehydrogenase (lipoamide) alpha 2
|Locus||Chr. 4 q22-q23|
pyruvate dehydrogenase (lipoamide) beta
|Locus||Chr. 3 p21.1-14.2|
E1 performs the first two reactions within the complex. They are:
- decarboxylation of substrate 1, pyruvate.
- reductive acetylation of substrate 2, lipoic acid. Lipoic acid is covalently bound to dihydrolipoamide acetyltransferase (E2), which is second catalytic component enzyme of PDC.
This is reversed by pyruvate dehydrogenase phosphatase.
E1 is a multimeric protein:
- Mammalian E1s, including human E1, are tetrameric, composed of two α- and two β- subunits.
- Some bacterial E1s, including E1 from Escherichia coli, are composed of two similar subunits, each being as large as the sum of molecular masses of α- and β- subunits.
- The α- subunit binds magnesium ion and pyrophosphate fragment.
- The β-subunit binds pyrimidine fragment of TPP, forming together a catalytic site at the interface of subunits.
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 protien 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 188.8.131.52) 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.
- ↑ Ciszak E, Korotchkina L, Dominiak P, Sidhu S, Patel M (2003). "Structural basis for flip-flop action of thiamin pyrophosphate-dependent enzymes revealed by human pyruvate dehydrogenase". J Biol Chem 278 (23): 21240-6. PMID 12651851.
- ↑ Arjunan P, Nemeria N, Brunskill A, Chandrasekhar K, Sax M, Yan Y, Jordan F, Guest JR, Furey W. (2002). "Structure of the pyruvate dehydrogenase multienzyme complex E1 component from Escherichia coli at 1.85 A resolution". Biochemistry 41 (16): 5213-21. PMID 11955070.
- ↑ Leung PS, Rossaro L, Davis PA, et al (2007). "Antimitochondrial antibodies in acute liver failure: Implications for primary biliary cirrhosis". doi:10.1002/hep.21828. PMID 17657817.
- ↑ Recny MA, Hager LP (1982). "Reconstitution of native Escherichia coli pyruvate oxidase from apoenzyme monomers and FAD". J. Biol. Chem. 257 (21): 12878-86. PMID 6752142.
- ↑ Abdel-Hamid AM, Attwood MM, Guest JR (2001). "Pyruvate oxidase contributes to the aerobic growth efficiency of Escherichia coli". Microbiology (Reading, Engl.) 147 (Pt 6): 1483-98. PMID 11390679.
Aldehyde/oxo oxidoreductases (EC 1.2)
|1.2.1 - NAD or NADP acceptor||Aldehyde dehydrogenase - Acetaldehyde dehydrogenase (ALDH2) - Glyceraldehyde 3-phosphate dehydrogenase - Long-chain-aldehyde dehydrogenase|
|1.2.4 - disulfide acceptor||Oxoglutarate dehydrogenase - Pyruvate dehydrogenase - Branched-chain alpha-keto acid dehydrogenase complex|
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