2oat

From Proteopedia

Revision as of 18:03, 18 December 2007

ORNITHINE AMINOTRANSFERASE COMPLEXED WITH 5-FLUOROMETHYLORNITHINE

Overview

Ornithine aminotransferase (l-ornithine:2-oxoacid delta-aminotransferase;, EC 2.6.1.13), a pyridoxal-5'-phosphate-dependent mitochondrial enzyme, controls the l-ornithine level in tissues by catalyzing the transfer of, the delta-amino group of l-ornithine to 2-oxoglutarate, producing, l-glutamate- gamma-semialdehyde and l-glutamate. (2S, 5S)-5-Fluoromethylornithine is the only inhibitor exclusively specific for, ornithine aminotransferase known to date. Both in vitro and in vivo, it, blocks the enzyme by a suicide reaction leading to a covalent adduct with, the cofactor. The crystal structure of the enzyme-inhibitor complex was, solved at a resolution of 1.95 A. No significant conformational changes, compared with the native enzyme structure were observed. The structure, reveals the atomic details of the cofactor-inhibitor adduct and its, interactions with the active site of the enzyme. The main residues, responsible for specific binding of the inhibitor are Arg180, which forms, a strong salt bridge with the alpha-carboxylate and Tyr55, which is, involved in a short hydrogen bond with the alpha-amino group. The, experimental observation that in the racemic mixture, (2S, 5S)-5-fluoromethylornithine is exclusively responsible for the enzyme, inhibition can be explained on the basis of the active site topology., Model building studies strongly suggest that the natural substrate, l-ornithine, in its external aldimine adduct with the enzyme, makes use of, the same recognition site as the inhibitor. It is proposed that the, neutralization of the active site Arg413 by a salt bridge with Glu235 also, plays an important role in productive binding of both, 5-fluoromethylornithine and l-ornithine. Arg180 and Arg413 are believed to, be instrumental in recognition of l-glutamate, by binding its gamma and, alpha-carboxylate groups, respectively. This requires a different, side-chain conformation of Glu235. Lys292 is the only obvious candidate, for catalyzing the rate-limiting proton transfer steps in the, transamination reaction.

Disease

Known disease associated with this structure: Gyrate atrophy of choroid and retina with ornithinemia, B6 responsive or unresponsive OMIM:[258870]

About this Structure

2OAT is a Single protein structure of sequence from Homo sapiens with PFM as ligand. Active as Ornithine aminotransferase, with EC number 2.6.1.13 Known structural/functional Sites: , and . Full crystallographic information is available from OCA.

Reference

Crystal structure of human ornithine aminotransferase complexed with the highly specific and potent inhibitor 5-fluoromethylornithine., Storici P, Capitani G, Muller R, Schirmer T, Jansonius JN, J Mol Biol. 1999 Jan 8;285(1):297-309. PMID:9878407

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