Mechanistic crystallography, mechanism of inactivation of γ-aminobutyric acid aminotransferase by (1R,3S,4S)-3-amino-4- fluorocyclopentane-1-carboxylic acid as elucidated by crystallography

Paola Storici, Jian Qiu, Tilman Schirmer*, Richard B. Silverman

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

(1R,3S,4S)-3-Amino-4-fluorocyclopentane-1-carboxylic acid (7) was previously shown to be a mechanism-based inactivator of γ-aminobutyric acid aminotransferase (GABA-AT) [Qiu, J. and Silverman, R. B. (2000) J. Med. Chem. 43, 706-720]. Two mechanisms were considered as reasonable possibilities, a Michael addition mechanism and an enamine mechanism. On the basis of a variety of chemical studies, including tedious radiolabeling experiments, it was concluded that inactivation by 7 proceeds by a Michael addition mechanism. Here, a crystal structure of 7 bound to pig liver GABA-AT is reported, which clearly demonstrates that the adduct formed is derived from an enamine mechanism. This represents another example of how crystallography is an important tool for elucidation of inactivation mechanisms.

Original languageEnglish (US)
Pages (from-to)14057-14063
Number of pages7
JournalBiochemistry
Volume43
Issue number44
DOIs
StatePublished - Nov 9 2004

ASJC Scopus subject areas

  • Biochemistry

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