(±)-(1S,2R,5S)-5-amino-2-fluorocyclohex-3-enecarboxylic acid. A potent GABA aminotransferase inactivator that irreversibly inhibits via an elimination-aromatization pathway

Zhiyong Wang, Hai Yuan, Dejan Nikolic, Richard B. Van Breemen, Richard B. Silverman*

*Corresponding author for this work

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

Inhibition of γ-aminobutyric acid aminotransferase (GABA-AT) increases the concentration of GABA, an inhibitory neurotransmitter in human brain, which could have therapeutic applications for a variety of neurological diseases, including epilepsy. On the basis of studies of several previously synthesized conformationally restricted GABA-AT inhibitors, (±)-(1S,2R, 5S)-5-amino-2-fluorocyclohex-3-enecarboxylic acid (12) was designed as a mechanism-based inactivator. This compound was shown to irreversibly inhibit GABA-AT; substrate protects the enzyme from inactivation. Mechanistic experiments demonstrated the loss of one fluoride ion per active site during inactivation and the formation of N-m-carboxyphenylpyridoxamine 5′-phosphate (26), the same product generated by inactivation of GABA-AT by gabaculine (8). An elimination-aromatization mechanism is proposed to account for these results.

Original languageEnglish (US)
Pages (from-to)14513-14522
Number of pages10
JournalBiochemistry
Volume45
Issue number48
DOIs
StatePublished - Dec 5 2006

ASJC Scopus subject areas

  • Biochemistry

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