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| | {{STRUCTURE_2oat| PDB=2oat | SCENE= }} | | {{STRUCTURE_2oat| PDB=2oat | SCENE= }} |
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| - | '''ORNITHINE AMINOTRANSFERASE COMPLEXED WITH 5-FLUOROMETHYLORNITHINE'''
| + | ===ORNITHINE AMINOTRANSFERASE COMPLEXED WITH 5-FLUOROMETHYLORNITHINE=== |
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| - | ==Overview==
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| - | 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.
| + | The line below this paragraph, {{ABSTRACT_PUBMED_9878407}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 9878407 is the PubMed ID number. |
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| | + | {{ABSTRACT_PUBMED_9878407}} |
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| | ==Disease== | | ==Disease== |
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| | [[Category: Plp-dependent enzyme]] | | [[Category: Plp-dependent enzyme]] |
| | [[Category: Pyridoxal phosphate]] | | [[Category: Pyridoxal phosphate]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 10:31:59 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 03:05:22 2008'' |
Revision as of 00:05, 28 July 2008
Template:STRUCTURE 2oat
ORNITHINE AMINOTRANSFERASE COMPLEXED WITH 5-FLUOROMETHYLORNITHINE
Template:ABSTRACT PUBMED 9878407
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. 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
Page seeded by OCA on Mon Jul 28 03:05:22 2008
