| Abstract
| - (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 thenatural product gabaculine (5-amino-1,3-cyclohexadienylcarboxylic acid), a mechanism-based inactivator ofγ-aminobutyric acid aminotransferase (GABA-AT) (Rando, R. R. Biochemistry1977, 16, 4604). Inactivationof GABA-AT by (S)-6 is time-dependent and protected by substrate. Two methods were utilized to demonstratethat, in addition to inactivation, about 0.7 equiv per inactivation event undergoes transamination. Inactivationresults from the reaction of (S)-6 with the pyridoxal 5‘-phosphate (PLP) cofactor. The adduct was isolated andcharacterized by ultraviolet−visible spectroscopy, electrospray mass spectrometry, and tandem massspectrometry. All of the results support a structure (11) that derives from the predicted aromatization inactivationmechanism (Scheme ) originally proposed by Metcalf and co-workers for this compound. This is only thethird example, besides gabaculine and l-cycloserine, of an inactivator of a PLP-dependent enzyme that actsvia an aromatization mechanism.
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