1li4

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spinqualitylabelsall models 1li4, resolution 2.01Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Human S-adenosylhomocysteine hydrolase complexed with neplanocin

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

S-Adenosylhomocysteine hydrolase (AdoHcy hydrolase) crystallizes from, solutions containing the intermediate analogue neplanocin A with the, analogue bound in its 3'-keto form at the active sites of all of its four, subunits and the four tightly bound cofactors in their reduced (NADH), state. The enzyme is in the closed conformation, which corresponds to the, structure in which the catalytic chemistry occurs. Examination of the, structure in the light of available, very detailed kinetic studies, [Porter, D. J., Boyd, F. L. (1991) J. Biol. Chem. 266, 21616-21625., Porter, D. J., Boyd, F. L. (1992) J. Biol. Chem. 267, 3205-3213. Porter, D. J. (1998) J. Biol. Chem. 268, 66-73] suggests elements of the catalytic, strategy of AdoHcy hydrolase for acceleration of the reversible conversion, of AdoHcy to adenosine (Ado) and homocysteine (Hcy). The enzyme, each, subunit of which possesses a substrate-binding domain that in the absence, of substrate is in rapid motion relative to the tetrameric core of the, enzyme, first binds substrate and ceases motion. Probably concurrently, with oxidation of the substrate to its 3'-keto form, the closed active, site is "sealed off" from the environment, as indicated by a large, (10(8)(-)(9)-fold) reduction in the rate of departure of ligands, a, feature that prevents exposure of the labile 3'-keto intermediates to the, aqueous environment. Elimination of the 5'-substituent (Hcy in the, hydrolytic direction, water in the synthetic direction) generates the, central intermediate 4',5'-didehydro-5'-deoxy-3'-ketoadenosine. Abortive, 3'-reduction of the central intermediate is prevented by a temporary, suspension of all or part of the redox catalytic power of the enzyme, during the existence of the central intermediate. The abortive reduction, is 10(4)-fold slower than the productive reductions at the ends of the, catalytic cycle and has a rate constant similar to those of nonenzymic, intramolecular model reactions. The mechanism for suspending the redox, catalytic power appears to be a conformationally induced increase in the, distance across which hydride transfer must occur between cofactor and, substrate, the responsible conformational change again being that which, "seals" the active site. The crystal structure reveals a well-defined, chain of three water molecules leading from the active site to the subunit, surface, which may serve as a relay for proton exchange between solvent, and active site in the closed form of the enzyme, permitting maintenance, of active-site functional groups in catalytically suitable protonation, states.

Disease

Known diseases associated with this structure: Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase OMIM:[180960]

About this Structure

1LI4 is a Single protein structure of sequence from Homo sapiens with NAD, NOC and IPA as ligands. Active as Adenosylhomocysteinase, with EC number 3.3.1.1 Full crystallographic information is available from OCA.

Reference

Catalytic strategy of S-adenosyl-L-homocysteine hydrolase: transition-state stabilization and the avoidance of abortive reactions., Yang X, Hu Y, Yin DH, Turner MA, Wang M, Borchardt RT, Howell PL, Kuczera K, Schowen RL, Biochemistry. 2003 Feb 25;42(7):1900-9. PMID:12590576

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