2hdh

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spinqualitylabelsall models 2hdh, resolution 2.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

BIOCHEMICAL CHARACTERIZATION AND STRUCTURE DETERMINATION OF HUMAN HEART SHORT CHAIN L-3-HYDROXYACYL COA DEHYDROGENASE PROVIDE INSIGHT INTO CATALYTIC MECHANISM

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

Human heart short chain L-3-hydroxyacyl-CoA dehydrogenase (SCHAD), catalyzes the oxidation of the hydroxyl group of L-3-hydroxyacyl-CoA to a, keto group, concomitant with the reduction of NAD+ to NADH, as part of the, beta-oxidation pathway. The homodimeric enzyme has been overexpressed in, Escherichia coli, purified to homogeneity, and studied using biochemical, and crystallographic techniques. The dissociation constants of NAD+ and, NADH have been determined over a broad pH range and indicate that SCHAD, binds reduced cofactor preferentially. Examination of apparent catalytic, constants reveals that SCHAD displays optimal enzymatic activity near, neutral pH, with catalytic efficiency diminishing rapidly toward pH, extremes. The crystal structure of SCHAD complexed with NAD+ has been, solved using multiwavelength anomalous diffraction techniques and a, selenomethionine-substituted analogue of the enzyme. The subunit structure, is comprised of two domains. The first domain is similar to other, alpha/beta dinucleotide folds but includes an unusual helix-turn-helix, motif which extends from the central beta-sheet. The second, or, C-terminal, domain is primarily alpha-helical and mediates subunit, dimerization and, presumably, L-3-hydroxyacyl-CoA binding. Molecular, modeling studies in which L-3-hydroxybutyryl-CoA was docked into the, enzyme-NAD+ complex suggest that His 158 serves as a general base, abstracting a proton from the 3-OH group of the substrate. Furthermore, the ability of His 158 to perform such a function may be enhanced by an, electrostatic interaction with Glu 170, consistent with previous, biochemical observations. These studies provide further understanding of, the molecular basis of several inherited metabolic disease states, correlated with L-3-hydroxyacyl-CoA dehydrogenase deficiencies.

Disease

Known diseases associated with this structure: 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency OMIM:[300256], 3-hydroxyacyl-CoA dehydrogenase deficiency OMIM:[601609], Hyperinsulinemic hypoglycemia, familial, 4 OMIM:[601609]

About this Structure

2HDH is a Single protein structure of sequence from Homo sapiens with NAD as ligand. Active as 3-hydroxyacyl-CoA dehydrogenase, with EC number 1.1.1.35 Full crystallographic information is available from OCA.

Reference

Biochemical characterization and crystal structure determination of human heart short chain L-3-hydroxyacyl-CoA dehydrogenase provide insights into catalytic mechanism., Barycki JJ, O'Brien LK, Bratt JM, Zhang R, Sanishvili R, Strauss AW, Banaszak LJ, Biochemistry. 1999 May 4;38(18):5786-98. PMID:10231530

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