( 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.
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Fu et al. (1999) studied this question.