Mechanistically significant diastereoselection in the sulfoximine inhibition of carboxypeptidase A.
The diastereomers of L-alpha-[ [S-(2-phenylethyl)sulfonimidoyl]methyl]benzenepropanoic acid bind differentially to carboxypeptidase A. These putative transition state-analogue inhibitors show unique and interpretationally significant pH dependences for Ki, as well as for the visible absorption spectra of their E.I complexes in the case of the cobalt-substituted enzyme. From the geometry of the enzymically preferred isomer, it may be concluded that the mechanism of peptide scission by the enzyme entails addition of a nucleophile to the si face of the bound-substrate prochiral carboxamide linkage. New interpretational constraints on the mode of action of the enzyme are thereby imposed.
Mock
W L
WL
Department of Chemistry, University of Illinois, Chicago 60680-4348.
Zhang
J Z
JZ
D001665:Binding Sites; D002268:Carboxypeptidases / Q000037:antagonists & inhibitors*; D043422:Carboxypeptidases A; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007097:Imines / Q000494:pharmacology*; D007700:Kinetics; D013057:Spectrum Analysis; D013237:Stereoisomerism
D007097:Imines; C068042:S,S-dimethyl sulfoximine; D002268:Carboxypeptidases; D043422:Carboxypeptidases A