6h55
core of the human pyruvate dehydrogenase (E2)
Structural highlights
Disease[ODP2_HUMAN] Note=Primary biliary cirrhosis is a chronic, progressive cholestatic liver disease characterized by the presence of antimitochondrial autoantibodies in patients' serum. It manifests with inflammatory obliteration of intra-hepatic bile duct, leading to liver cell damage and cirrhosis. Patients with primary biliary cirrhosis show autoantibodies against the E2 component of pyruvate dehydrogenase complex. Defects in DLAT are the cause of pyruvate dehydrogenase E2 deficiency (PDHE2 deficiency) [MIM:245348]; also known as lactic acidemia due to defect of E2 lipoyl transacetylase of the pyruvate dehydrogenase complex. Pyruvate dehydrogenase (PDH) deficiency is a major cause of primary lactic acidosis and neurological dysfunction in infancy and early childhood. In this form of PDH deficiency episodic dystonia is the major neurological manifestation, with other more common features of pyruvate dehydrogenase deficiency, such as hypotonia and ataxia, being less prominent. Function[ODP2_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. Publication Abstract from PubMedThe pseudo-atomic structural model of human pyruvate dehydrogenase complex (PDHc) core composed of full-length E2 and E3BP components, calculated from our cryoelectron microscopy-derived density maps at 6-A resolution, is similar to those of prokaryotic E2 structures. The spatial organization of human PDHc components as evidenced by negative-staining electron microscopy and native mass spectrometry is not homogeneous, and entails the unanticipated formation of local clusters of E1:E2 and E3BP:E3 complexes. Such uneven, clustered organization translates into specific duties for E1-E2 clusters (oxidative decarboxylation and acetyl transfer) and E3BP-E3 clusters (regeneration of reduced lipoamide) corresponding to half-reactions of the PDHc catalytic cycle. The addition of substrate coenzyme A modulates the conformational landscape of PDHc, in particular of the lipoyl domains, extending the postulated multiple random coupling mechanism. The conformational and associated chemical landscapes of PDHc are thus not determined entirely stochastically, but are restrained and channeled through an asymmetric architecture and further modulated by substrate binding. Structural and Functional Analyses of the Human PDH Complex Suggest a "Division-of-Labor" Mechanism by Local E1 and E3 Clusters.,Prajapati S, Haselbach D, Wittig S, Patel MS, Chari A, Schmidt C, Stark H, Tittmann K Structure. 2019 Apr 26. pii: S0969-2126(19)30131-5. doi:, 10.1016/j.str.2019.04.009. PMID:31130485[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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