| Structural highlights
Disease
ODPB_HUMAN Defects in PDHB are the cause of pyruvate dehydrogenase E1-beta deficiency (PDHBD) [MIM:614111. 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]
Function
ODPB_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.[2] [3]
Publication Abstract from PubMed
The pyruvate dehydrogenase multienzyme complex (PDHc) connects glycolysis to the tricarboxylic acid cycle by producing acetyl-CoA via the decarboxylation of pyruvate. Because of its pivotal role in glucose metabolism, this complex is closely regulated in mammals by reversible phosphorylation, the modulation of which is of interest in treating cancer, diabetes, and obesity. Mutations such as that leading to the alphaV138M variant in pyruvate dehydrogenase, the pyruvate-decarboxylating PDHc E1 component, can result in PDHc deficiency, an inborn error of metabolism that results in an array of symptoms such as lactic acidosis, progressive cognitive and neuromuscular deficits, and even death in infancy or childhood. Here we present an analysis of two X-ray crystal structures at 2.7 A resolution, the first of the disease-associated human alphaV138M E1 variant and the second of human wild-type (WT) E1 with a bound adduct of its coenzyme thiamin diphosphate (ThDP) and the substrate analogue acetylphosphinate (AcPhi). The structures provide support for the role of regulatory loop disorder in E1 inactivation, and the alphaV138M variant structure also reveals that altered coenzyme binding can result in such disorder even in the absence of phosphorylation. Specifically, both E1 phosphorylation at alphaSer264 and the alphaV138M substitution result in disordered loops that are not optimally oriented or available to efficiently bind the lipoyl domain of PDHc E2. Combined with an analysis of alphaV138M activity, these results underscore the general connection between regulatory loop disorder and loss of E1 catalytic efficiency.
Pyruvate dehydrogenase complex deficiency is linked to regulatory loop disorder in the alphaV138M variant of human pyruvate dehydrogenase.,Whitley MJ, Arjunan P, Nemeria NS, Korotchkina LG, Park YH, Patel M, Jordan F, Furey WF J Biol Chem. 2018 Jul 3. pii: RA118.003996. doi: 10.1074/jbc.RA118.003996. PMID:29970614[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Brown RM, Head RA, Boubriak II, Leonard JV, Thomas NH, Brown GK. Mutations in the gene for the E1beta subunit: a novel cause of pyruvate dehydrogenase deficiency. Hum Genet. 2004 Jul;115(2):123-7. Epub 2004 May 11. PMID:15138885 doi:10.1007/s00439-004-1124-8
- ↑ 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
- ↑ 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
- ↑ Whitley MJ, Arjunan P, Nemeria NS, Korotchkina LG, Park YH, Patel M, Jordan F, Furey WF. Pyruvate dehydrogenase complex deficiency is linked to regulatory loop disorder in the alphaV138M variant of human pyruvate dehydrogenase. J Biol Chem. 2018 Jul 3. pii: RA118.003996. doi: 10.1074/jbc.RA118.003996. PMID:29970614 doi:http://dx.doi.org/10.1074/jbc.RA118.003996
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