1ohy
From Proteopedia
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==Overview== | ==Overview== | ||
| - | Gamma-aminobutyric acid aminotransferase (GABA-AT) is a pyridoxal, 5'-phosphate-dependent enzyme responsible for the degradation of the, inhibitory neurotransmitter GABA. GABA-AT is a validated target for, antiepilepsy drugs because its selective inhibition raises GABA, concentrations in brain. The antiepilepsy drug, gamma-vinyl-GABA, (vigabatrin) has been investigated in the past by various biochemical, methods and resulted in several proposals for its mechanisms of, inactivation. In this study we solved and compared the crystal structures, of pig liver GABA-AT in its native form (to 2.3-A resolution) and in, complex with vigabatrin as well as with the close analogue, gamma-ethynyl-GABA (to 2.3 and 2.8 A, respectively). Both inactivators, form a covalent ternary adduct with the active ... [ | + | Gamma-aminobutyric acid aminotransferase (GABA-AT) is a pyridoxal, 5'-phosphate-dependent enzyme responsible for the degradation of the, inhibitory neurotransmitter GABA. GABA-AT is a validated target for, antiepilepsy drugs because its selective inhibition raises GABA, concentrations in brain. The antiepilepsy drug, gamma-vinyl-GABA, (vigabatrin) has been investigated in the past by various biochemical, methods and resulted in several proposals for its mechanisms of, inactivation. In this study we solved and compared the crystal structures, of pig liver GABA-AT in its native form (to 2.3-A resolution) and in, complex with vigabatrin as well as with the close analogue, gamma-ethynyl-GABA (to 2.3 and 2.8 A, respectively). Both inactivators, form a covalent ternary adduct with the active site Lys-329 and the, pyridoxal 5'-phosphate (PLP) cofactor. The crystal structures provide, direct support for specific inactivation mechanisms proposed earlier on, the basis of radio-labeling experiments. The reactivity of GABA-AT, crystals with the two GABA analogues was also investigated by polarized, absorption microspectrophotometry. The spectral data are discussed in, relation to the proposed mechanism. Intriguingly, all three structures, revealed a [2Fe-2S] cluster of yet unknown function at the center of the, dimeric molecule in the vicinity of the PLP cofactors. |
==About this Structure== | ==About this Structure== | ||
| - | 1OHY is a | + | 1OHY is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Sus_scrofa Sus scrofa] with FE, PLP and S as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/4-aminobutyrate_transaminase 4-aminobutyrate transaminase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.6.1.19 2.6.1.19] Structure known Active Site: AC1. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1OHY OCA]. |
==Reference== | ==Reference== | ||
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[[Category: vigabatrin pyridoxal phosphate]] | [[Category: vigabatrin pyridoxal phosphate]] | ||
| - | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 5 15:14:41 2007'' |
Revision as of 13:09, 5 November 2007
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4-AMINOBUTYRATE-AMINOTRANSFERASE INACTIVATED BY GAMMA-ETHYNYL GABA
Overview
Gamma-aminobutyric acid aminotransferase (GABA-AT) is a pyridoxal, 5'-phosphate-dependent enzyme responsible for the degradation of the, inhibitory neurotransmitter GABA. GABA-AT is a validated target for, antiepilepsy drugs because its selective inhibition raises GABA, concentrations in brain. The antiepilepsy drug, gamma-vinyl-GABA, (vigabatrin) has been investigated in the past by various biochemical, methods and resulted in several proposals for its mechanisms of, inactivation. In this study we solved and compared the crystal structures, of pig liver GABA-AT in its native form (to 2.3-A resolution) and in, complex with vigabatrin as well as with the close analogue, gamma-ethynyl-GABA (to 2.3 and 2.8 A, respectively). Both inactivators, form a covalent ternary adduct with the active site Lys-329 and the, pyridoxal 5'-phosphate (PLP) cofactor. The crystal structures provide, direct support for specific inactivation mechanisms proposed earlier on, the basis of radio-labeling experiments. The reactivity of GABA-AT, crystals with the two GABA analogues was also investigated by polarized, absorption microspectrophotometry. The spectral data are discussed in, relation to the proposed mechanism. Intriguingly, all three structures, revealed a [2Fe-2S] cluster of yet unknown function at the center of the, dimeric molecule in the vicinity of the PLP cofactors.
About this Structure
1OHY is a Single protein structure of sequence from Sus scrofa with FE, PLP and S as ligands. Active as 4-aminobutyrate transaminase, with EC number 2.6.1.19 Structure known Active Site: AC1. Full crystallographic information is available from OCA.
Reference
Structures of gamma-aminobutyric acid (GABA) aminotransferase, a pyridoxal 5'-phosphate, and [2Fe-2S] cluster-containing enzyme, complexed with gamma-ethynyl-GABA and with the antiepilepsy drug vigabatrin., Storici P, De Biase D, Bossa F, Bruno S, Mozzarelli A, Peneff C, Silverman RB, Schirmer T, J Biol Chem. 2004 Jan 2;279(1):363-73. Epub 2003 Oct 8. PMID:14534310
Page seeded by OCA on Mon Nov 5 15:14:41 2007
Categories: 4-aminobutyrate transaminase | Single protein | Sus scrofa | Schirmer, T. | Storici, P. | FE | PLP | S | 4-aminobutyric acid | Aminotransferase | Antiepileptic drug target | Mitochondrion | Neurotransmitter degradation | Plp-dependent enzyme | Transferase | Transit peptide | Vigabatrin pyridoxal phosphate
