Inhibition of angiotensin III formation by thiol derivatives of acidic amino acids

Abstract

Angiotensin III is formed by removal of the N-terminal Asp residue of angiotensin II in a reaction catalyzed by glutamyl aminopeptidase (aminopeptidase A EC 3.4.11.7). Thiol derivatives of glutamate and aspartate in which the alpha-COOH group was replaced by -CH2SH were synthesized as inhibitors of glutamyl aminopeptidase. Glutamate thiol was a potent inhibitor of glutamyl aminopeptidase (Ki = 4 x 10(-7) M) but even more potently inhibited microsomal alanyl aminopeptidase (Ki = 2.5 x 10(-7) M). Aspartate thiol (beta-homocysteine) was a less potent but more selective inhibitor of glutamyl aminopeptidase (glutamyl aminopeptidase: Ki = 1.2 x 10(-6) M; microsomal alanyl aminopeptidase: Ki = 7.5 x 10(-6) M). Neither compound inhibited cytosolic leucyl aminopeptidase. Aspartate thiol blocked the conversion of angiotensin II to angiotensin III. These derivatives are more selective than amastatin and may be of value in studies probing the biological significance of angiotensin III.