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B6db references: 14534310

type Journal Article
authors Storici, P.; De Biase, D.; Bossa, F.; Bruno, S.; Mozzarelli, A.; Peneff, C.; Silverman, R.B.; Schirmer, T.

title Structures of GABA aminotransferase, a pyridoxal 5'-phosphate and [2Fe-2S] cluster containing enzyme, complexed with -EthynylGABA and with the antiepilepsy drug vigabatrin.
journal J Biol Chem
ui 14534310
year (2003)
volume 279
number 1
pages 363-73
abstract 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, -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 resolution) and in complex with vigabatrin as well as with the close analogue -ethynyl-GABA (to 2.3 and 2.8, respectively). Both inactivators form a covalent ternary adduct with the active site Lys329 and the pyridoxal 5-phosphate (PLP) cofactor. The crystal structures provide direct support for specific inactivation mechanisms proposed earlier on the basis of radiolabeling 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.
last changed 2018/11/27 09:03

B6db references