Citation

Neumann U, Gütschow M. J. Biol. Chem. 1994; 269(34): 21561-21567.

Copyright

(Copyright © 1994, American Society for Biochemistry and Molecular Biology)

DOI

unavailable

PMID

8063794

Abstract

A series of 2-(sulfonyloxy) and 2-(acyloxy)-1H-isoindole-1,3(2H)-diones and analogous 1H-benz[de]isoquinoline-1,3(2H)-diones was prepared, and their potential to inactivate chymotrypsin was investigated. The N-(sulfonyloxy) and N-(acyloxy)phthalimides were found to be potent inactivators of chymotrypsin and related serine proteinases. For the most active compounds, N-(dansyloxy)phthalimide and N-(tosyloxy)phthalimide, the second-order rate constant of chymotrypsin inactivation was in the range of 250,000 m-1 s-1. N-(Mesyloxy)-phthalimide was the most active compound for inactivation of leukocyte elastase. It was shown that these compounds act as true suicide substrates. Enzyme-catalyzed opening of the heterocyclic ring results in the formation of an acyl-enzyme with attached O-acyl or O-sulfonylhydroxamic acid moiety. Subsequent Lossen rearrangement leads to the formation of a highly reactive isocyanate, which irreversibly modifies the target protease.

Language: en

Keywords

Acylation; Amino Acid Sequence; Chymotrypsin; Elastin; Enzyme Reactivators; Leukocytes; Models, Chemical; Molecular Sequence Data; Phthalimides; Serine Proteinase Inhibitors; Spectrometry, Fluorescence