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Publication 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 JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift) ID 153873 Author(s) Storici, Paola; De Biase, Daniela; Bossa, Francesco; Bruno, Stefano; Mozzarelli, Andrea; Peneff, Caroline; Silverman, Richard B; Schirmer, Tilman Author(s) at UniBasel Schirmer, Tilman; Year 2004 Title Structures of gamma-aminobutyric acid (GABA) aminotransferase, a pyridoxal 5'-phosphate, and [2Fe2S] cluster-containing enzyme, complexed with gamma-ethynyl-GABA and with the antiepilepsy drug vigabatrin Journal Journal of Biological Chemistry Volume 279 Number 1 Pages / Article-Number 363-73 Keywords 4-Aminobutyrate Transaminase/*chemistry/*metabolism; Anticonvulsants/*chemistry; Crystallography; X-Ray; Image Processing; Computer-Assisted; Iron-Sulfur Proteins/chemistry/*metabolism; Models; Molecular; Molecular Conformation; Protein Conformation; Pyridoxal Phosphate/chemistry/*metabolism; Vigabatrin/*chemistry; gamma-Aminobutyric Acid/analogs & derivatives/*chemistry 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 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. Publisher American Society of Biological Chemists ISSN/ISBN 0021-9258 edoc-URL http://edoc.unibas.ch/dok/A5258252 Full Text on edoc No Digital Object Identifier DOI 10.1074/jbc.M305884200 PubMed ID http://www.ncbi.nlm.nih.gov/pubmed/14534310 ISI-Number WOS:000187555300044 Document type (ISI) Journal Article