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Crystal Structure of Human dihydrolipoamide dehydrogenase complexed to NADHCrystal Structure of Human dihydrolipoamide dehydrogenase complexed to NADH
Structural highlights
DiseaseDLDH_HUMAN Note=Defects in DLD are involved in the development of congenital infantile lactic acidosis. Defects in DLD are a cause of maple syrup urine disease (MSUD) [MIM:248600. MSUD is characterized by mental and physical retardation, feeding problems and a maple syrup odor to the urine. The keto acids of the branched-chain amino acids are present in the urine, resulting from a block in oxidative decarboxylation. FunctionDLDH_HUMAN Lipoamide dehydrogenase is a component of the glycine cleavage system as well as of the alpha-ketoacid dehydrogenase complexes. Involved in the hyperactivation of spermatazoa during capacitation and in the spermatazoal acrosome reaction. 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 PubMedHuman dihydrolipoamide dehydrogenase (hE3) is an enzymatic component common to the mitochondrial alpha-ketoacid dehydrogenase and glycine decarboxylase complexes. Mutations to this homodimeric flavoprotein cause the often-fatal human disease known as E3 deficiency. To catalyze the oxidation of dihydrolipoamide, hE3 uses two molecules: non-covalently bound FAD and a transiently bound substrate, NAD+. To address the catalytic mechanism of hE3 and the structural basis for E3 deficiency, the crystal structures of hE3 in the presence of NAD+ or NADH have been determined at resolutions of 2.5A and 2.1A, respectively. Although the overall fold of the enzyme is similar to that of yeast E3, these two structures differ at two loops that protrude from the proteins and at their FAD-binding sites. The structure of oxidized hE3 with NAD+ bound demonstrates that the nicotinamide moiety is not proximal to the FAD. When NADH is present, however, the nicotinamide base stacks directly on the isoalloxazine ring system of the FAD. This is the first time that this mechanistically requisite conformation of NAD+ or NADH has been observed in E3 from any species. Because E3 structures were previously available only from unicellular organisms, speculations regarding the molecular mechanisms of E3 deficiency were based on homology models. The current hE3 structures show directly that the disease-causing mutations occur at three locations in the human enzyme: the dimer interface, the active site, and the FAD and NAD(+)-binding sites. The mechanisms by which these mutations impede the function of hE3 are discussed. Crystal structure of human dihydrolipoamide dehydrogenase: NAD+/NADH binding and the structural basis of disease-causing mutations.,Brautigam CA, Chuang JL, Tomchick DR, Machius M, Chuang DT J Mol Biol. 2005 Jul 15;350(3):543-52. PMID:15946682[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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