TY - JOUR
T1 - 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
AU - Storici, Paola
AU - Qiu, Jian
AU - Schirmer, Tilman
AU - Silverman, Richard B.
PY - 2004/11/9
Y1 - 2004/11/9
N2 - (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.
AB - (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.
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U2 - 10.1021/bi0487185
DO - 10.1021/bi0487185
M3 - Article
C2 - 15518554
AN - SCOPUS:8344248823
SN - 0006-2960
VL - 43
SP - 14057
EP - 14063
JO - Biochemistry
JF - Biochemistry
IS - 44
ER -