Mechanism of inactivation of γ-aminobutyric acid aminotransferase by (S)-4-amino-4,5-dihydro-2-thiophenecarboxylic acid

Mengmeng Fu, Dejan Nikolic, Richard B. Van Breemen, Richard B. Silverman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


(S)-4-Amino-4,5-dihydro-2-thiophenecarboxylic acid ((S)-6) was previously synthesized (Adams, J. L.; Chen, T. M.; Metcalf, B. W. J. Org. Chem. 1985, 50, 2730-2736.) as a heterocyclic mimic of the natural product gabaculine (5-amino-1,3-cyclohexadienylcarboxylic acid), a mechanism-based inactivator of γ-aminobutyric acid aminotransferase (GABA-AT) (Rando, R. R. Biochemistry 1977, 16, 4604). Inactivation of GABA-AT by (S)-6 is time- dependent and protected by substrate. Two methods were utilized to demonstrate that, in addition to inactivation, about 0.7 equiv per inactivation event undergoes transamination. Inactivation results from the reaction of (S)-6 with the pyridoxal 5'-phosphate (PLP) cofactor. The adduct was isolated and characterized by ultraviolet-visible spectroscopy, electrospray mass spectrometry, and tandem mass spectrometry. All of the results support a structure (11) that derives from the predicted aromatization inactivation mechanism (Scheme 2) originally proposed by Metcalf and co-workers for this compound. This is only the third example, besides gabaculine and L-cycloserine, of an inactivator of a PLP-dependent enzyme that acts via an aromatization mechanism.

Original languageEnglish (US)
Pages (from-to)7751-7759
Number of pages9
JournalJournal of the American Chemical Society
Issue number34
StatePublished - Sep 1 1999

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry


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