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2oat
From Proteopedia
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==Overview== | ==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. | 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. | ||
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| + | ==Disease== | ||
| + | Known disease associated with this structure: Gyrate atrophy of choroid and retina with ornithinemia, B6 responsive or unresponsive OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=258870 258870]] | ||
==About this Structure== | ==About this Structure== | ||
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[[Category: pyridoxal phosphate]] | [[Category: pyridoxal phosphate]] | ||
| - | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov | + | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 23:08:20 2007'' |
Revision as of 21:01, 12 November 2007
|
ORNITHINE AMINOTRANSFERASE COMPLEXED WITH 5-FLUOROMETHYLORNITHINE
Contents |
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 Structure known Active Sites: FMA, FMB and FMC. 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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