| Structural highlights
Disease
ODPA_HUMAN Defects in PDHA1 are a cause of pyruvate dehydrogenase E1-alpha deficiency (PDHAD) [MIM:312170. An enzymatic defect causing primary lactic acidosis in children. It is associated with a broad clinical spectrum ranging from fatal lactic acidosis in the newborn to chronic neurologic dysfunction with structural abnormalities in the central nervous system without systemic acidosis.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] Defects in PDHA1 are the cause of X-linked Leigh syndrome (X-LS) [MIM:308930. X-LS is an early-onset progressive neurodegenerative disorder with a characteristic neuropathology consisting of focal, bilateral lesions in one or more areas of the central nervous system, including the brainstem, thalamus, basal ganglia, cerebellum, and spinal cord. The lesions are areas of demyelination, gliosis, necrosis, spongiosis, or capillary proliferation. Clinical symptoms depend on which areas of the central nervous system are involved. The most common underlying cause is a defect in oxidative phosphorylation. LS may be a feature of a deficiency of any of the mitochondrial respiratory chain complexes.[15] [16] [17] [18] [19]
Function
ODPA_HUMAN The pyruvate dehydrogenase complex catalyzes the overall conversion of pyruvate to acetyl-CoA and CO(2), and thereby links the glycolytic pathway to the tricarboxylic cycle.[20] [21]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
At the junction of glycolysis and the Krebs cycle in cellular metabolism, the pyruvate dehydrogenase multienzyme complex (PDHc) catalyzes the oxidative decarboxylation of pyruvate to acetyl-CoA. In mammals, PDHc is tightly regulated by phosphorylation-dephosphorylation of three serine residues in the thiamin-dependent pyruvate dehydrogenase (E1) component. In vivo, inactivation of human PDHc correlates mostly with phosphorylation of serine 264, which is located at the entrance of the substrate channel leading to the active site of E1. Despite intense investigations, the molecular mechanism of this inactivation has remained enigmatic. Here, a detailed analysis of microscopic steps of catalysis in human wild-type PDHc-E1 and pseudophosphorylation variant Ser264Glu elucidates how phosphorylation of Ser264 affects catalysis. Whereas the intrinsic reactivity of the active site in catalysis of pyruvate decarboxylation remains nearly unaltered, the preceding binding of substrate to the enzyme's active site via the substrate channel and the subsequent reductive acetylation of the E2 component are severely slowed in the phosphorylation variant. The structure of pseudophosphorylation variant Ser264Glu determined by X-ray crystallography reveals no differences in the three-dimensional architecture of the phosphorylation loop or of the active site, when compared to those of the wild-type enzyme. However, the channel leading to the active site is partially obstructed by the side chain of residue 264 in the variant. By analogy, a similar obstruction of the substrate channel can be anticipated to result from a phosphorylation of Ser264. The kinetic and thermodynamic results in conjunction with the structure of Ser264Glu suggest that phosphorylation blocks access to the active site by imposing a steric and electrostatic barrier for substrate binding and active site coupling with the E2 component. As a Ser264Gln variant, which carries no charge at position 264, is also selectively deficient in pyruvate binding and reductive acetylation of E2, we conclude that mostly steric effects account for inhibition of PDHc by phosphorylation.
Phosphorylation of serine 264 impedes active site accessibility in the E1 component of the human pyruvate dehydrogenase multienzyme complex.,Seifert F, Ciszak E, Korotchkina L, Golbik R, Spinka M, Dominiak P, Sidhu S, Brauer J, Patel MS, Tittmann K Biochemistry. 2007 May 29;46(21):6277-87. Epub 2007 May 3. PMID:17474719[22]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Ito M, Huq AH, Naito E, Saijo T, Takeda E, Kuroda Y. Mutation of E1 alpha gene in a female patient with pyruvate dehydrogenase deficiency due to rapid degradation of E1 protein. J Inherit Metab Dis. 1992;15(6):848-56. PMID:1338114
- ↑ Hansen LL, Brown GK, Kirby DM, Dahl HH. Characterization of the mutations in three patients with pyruvate dehydrogenase E1 alpha deficiency. J Inherit Metab Dis. 1991;14(2):140-51. PMID:1909401
- ↑ De Meirleir L, Lissens W, Vamos E, Liebaers I. Pyruvate dehydrogenase (PDH) deficiency caused by a 21-base pair insertion mutation in the E1 alpha subunit. Hum Genet. 1992 Mar;88(6):649-52. PMID:1551669
- ↑ Dahl HH, Hansen LL, Brown RM, Danks DM, Rogers JG, Brown GK. X-linked pyruvate dehydrogenase E1 alpha subunit deficiency in heterozygous females: variable manifestation of the same mutation. J Inherit Metab Dis. 1992;15(6):835-47. PMID:1293379
- ↑ Chun K, MacKay N, Petrova-Benedict R, Robinson BH. Mutations in the X-linked E1 alpha subunit of pyruvate dehydrogenase leading to deficiency of the pyruvate dehydrogenase complex. Hum Mol Genet. 1993 Apr;2(4):449-54. PMID:8504306
- ↑ Matthews PM, Brown RM, Otero LJ, Marchington DR, LeGris M, Howes R, Meadows LS, Shevell M, Scriver CR, Brown GK. Pyruvate dehydrogenase deficiency. Clinical presentation and molecular genetic characterization of five new patients. Brain. 1994 Jun;117 ( Pt 3):435-43. PMID:8032855
- ↑ Hansen LL, Horn N, Dahl HH, Kruse TA. Pyruvate dehydrogenase deficiency caused by a 33 base pair duplication in the PDH E1 alpha subunit. Hum Mol Genet. 1994 Jun;3(6):1021-2. PMID:7545958
- ↑ Awata H, Endo F, Tanoue A, Kitano A, Matsuda I. Characterization of a point mutation in the pyruvate dehydrogenase E1 alpha gene from two boys with primary lactic acidaemia. J Inherit Metab Dis. 1994;17(2):189-95. PMID:7967473
- ↑ Chun K, MacKay N, Petrova-Benedict R, Federico A, Fois A, Cole DE, Robertson E, Robinson BH. Mutations in the X-linked E1 alpha subunit of pyruvate dehydrogenase: exon skipping, insertion of duplicate sequence, and missense mutations leading to the deficiency of the pyruvate dehydrogenase complex. Am J Hum Genet. 1995 Mar;56(3):558-69. PMID:7887409
- ↑ Takakubo F, Cartwright P, Hoogenraad N, Thorburn DR, Collins F, Lithgow T, Dahl HH. An amino acid substitution in the pyruvate dehydrogenase E1 alpha gene, affecting mitochondrial import of the precursor protein. Am J Hum Genet. 1995 Oct;57(4):772-80. PMID:7573035
- ↑ Hemalatha SG, Kerr DS, Wexler ID, Lusk MM, Kaung M, Du Y, Kolli M, Schelper RL, Patel MS. Pyruvate dehydrogenase complex deficiency due to a point mutation (P188L) within the thiamine pyrophosphate binding loop of the E1 alpha subunit. Hum Mol Genet. 1995 Feb;4(2):315-8. PMID:7757088
- ↑ Lissens W, De Meirleir L, Seneca S, Benelli C, Marsac C, Poll-The BT, Briones P, Ruitenbeek W, van Diggelen O, Chaigne D, Ramaekers V, Liebaers I. Mutation analysis of the pyruvate dehydrogenase E1 alpha gene in eight patients with a pyruvate dehydrogenase complex deficiency. Hum Mutat. 1996;7(1):46-51. PMID:8664900 doi:<46::AID-HUMU6>3.0.CO;2-N 10.1002/(SICI)1098-1004(1996)7:1<46::AID-HUMU6>3.0.CO;2-N
- ↑ Tripatara A, Kerr DS, Lusk MM, Kolli M, Tan J, Patel MS. Three new mutations of the pyruvate dehydrogenase alpha subunit: a point mutation (M181V), 3 bp deletion (-R282), and 16 bp insertion/frameshift (K358SVS-->TVDQS). Hum Mutat. 1996;8(2):180-2. PMID:8844217 doi:<180::AID-HUMU11>3.0.CO;2-Z 10.1002/(SICI)1098-1004(1996)8:2<180::AID-HUMU11>3.0.CO;2-Z
- ↑ Otero LJ, Brown RM, Brown GK. Arginine 302 mutations in the pyruvate dehydrogenase E1alpha subunit gene: identification of further patients and in vitro demonstration of pathogenicity. Hum Mutat. 1998;12(2):114-21. PMID:9671272 doi:<114::AID-HUMU6>3.0.CO;2-# 10.1002/(SICI)1098-1004(1998)12:2<114::AID-HUMU6>3.0.CO;2-#
- ↑ Hansen LL, Brown GK, Kirby DM, Dahl HH. Characterization of the mutations in three patients with pyruvate dehydrogenase E1 alpha deficiency. J Inherit Metab Dis. 1991;14(2):140-51. PMID:1909401
- ↑ Chun K, MacKay N, Petrova-Benedict R, Federico A, Fois A, Cole DE, Robertson E, Robinson BH. Mutations in the X-linked E1 alpha subunit of pyruvate dehydrogenase: exon skipping, insertion of duplicate sequence, and missense mutations leading to the deficiency of the pyruvate dehydrogenase complex. Am J Hum Genet. 1995 Mar;56(3):558-69. PMID:7887409
- ↑ Matthews PM, Marchington DR, Squier M, Land J, Brown RM, Brown GK. Molecular genetic characterization of an X-linked form of Leigh's syndrome. Ann Neurol. 1993 Jun;33(6):652-5. PMID:8498846 doi:http://dx.doi.org/10.1002/ana.410330616
- ↑ Dahl HH, Brown GK. Pyruvate dehydrogenase deficiency in a male caused by a point mutation (F205L) in the E1 alpha subunit. Hum Mutat. 1994;3(2):152-5. PMID:8199595 doi:http://dx.doi.org/10.1002/humu.1380030210
- ↑ Naito E, Ito M, Yokota I, Saijo T, Matsuda J, Osaka H, Kimura S, Kuroda Y. Biochemical and molecular analysis of an X-linked case of Leigh syndrome associated with thiamin-responsive pyruvate dehydrogenase deficiency. J Inherit Metab Dis. 1997 Aug;20(4):539-48. PMID:9266390
- ↑ Korotchkina LG, Patel MS. Mutagenesis studies of the phosphorylation sites of recombinant human pyruvate dehydrogenase. Site-specific regulation. J Biol Chem. 1995 Jun 16;270(24):14297-304. PMID:7782287
- ↑ Kato M, Wynn RM, Chuang JL, Tso SC, Machius M, Li J, Chuang DT. Structural basis for inactivation of the human pyruvate dehydrogenase complex by phosphorylation: role of disordered phosphorylation loops. Structure. 2008 Dec 10;16(12):1849-59. PMID:19081061 doi:10.1016/j.str.2008.10.010
- ↑ Seifert F, Ciszak E, Korotchkina L, Golbik R, Spinka M, Dominiak P, Sidhu S, Brauer J, Patel MS, Tittmann K. Phosphorylation of serine 264 impedes active site accessibility in the E1 component of the human pyruvate dehydrogenase multienzyme complex. Biochemistry. 2007 May 29;46(21):6277-87. Epub 2007 May 3. PMID:17474719 doi:http://dx.doi.org/10.1021/bi700083z
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