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- W1990326078 abstract "2-Benzyl-3,4-epoxybutanoic acid (BEBA) which was designed rationally as an irreversible inhibitor of carboxypeptidase A on the basis of the known topology of the active site and catalytic mechanism of the enzyme indeed inactivated the enzyme very efficiently with a covalent modification at the carboxylate of Glu-270. The partition ratio of BEBA was determined to be 20.3. Of four stereoisomers of BEBA, (2S, 3R)and (2R, 3S)-BEBA show the inhibitory activity, and the other two isomers are essentially inactive. This stemspecificity of BEBA in the inhibition was explained with a proposition of a three-dimensional representation of the active site of the enzyme. All four stereoisomers were synthesized effectively and conveniently starting with optically active 2-benzyl-2-vinylacetic acid which was obtained by a kinetic resolution of racemic methyl ester of the acid using a-chymotrypsin. INTRODUCTION Carboxypeptidase A (CPA, EC 3.4.17.1) is a much studied and well characterized metalloprotease, and thus serving as a prototypic enzyme for many metalloenzymes including physiologically important proteases such as angiotensin converting enzyme and enkephalinase (ref. 1,2). The structure of the native enzyme has been determined by X-ray crystallographic method to a resolution of 1.54 A. It preferentially cleaves off the C-terminal amino acid residue that possesses an aromatic side chain from peptide substrate with L-stereospecificity (ref. 1,2). CPA has also served as a model in the development of inhibitor design strategies that can be translated to other metalloproteases of great medicinal importance (ref. 3), and accordingly a good variety of different types and potencies of inhibitors have been developed, culminating to obtaining an inhibitor of a y value in the range of ferntomolar (ref. 4). In this report, we describe the synthesis and mechanistic implication of a new type (pseudomechanism-based 72 1" @default.
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- W1990326078 date "1994-01-01" @default.
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- W1990326078 title "A new type of carboxypeptidase A inhibitor: design, synthesis, and mechanistic implication" @default.
- W1990326078 doi "https://doi.org/10.1351/pac199466040721" @default.
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