A stereochemical concept for the catalytic mechanism of prolylhydroxylase: Applicability to classification and design of inhibitors

Abstract

The enzyme prolylhydroxylase (E.C.1.14.11.2.) mediates the post-translational conversion of genetically coded prolyl into non-coded trans-4-hydroxyprolyl. It has a key role in the biosynthesis of interstitial collagens and the subcomponent C1q of the first complement component, and its inhibition results in a selective suppression of these proteins. This finding points to the applicability of specific prolylhydroxylase inhibitors in the causal treatment of diseases aggravated by fibrosis or immune complex formation, substances which clearly would be a major breakthrough in clinical pharmacology. The published suggestions on the reaction mechanism of prolylhydroxylase are known to be in conflict with the data on the enzyme, on model hydroxylations and on iron-dioxygen complexes and thus cannot be used as guides for the design of inhibitory structures. The Stereochemical mechanism presented here allows a detailed understanding of the kinetic findings and of the electronic rearrangements during the reaction. The exactly formulated structure-activity relationships invite pinpoint alterations of the enzyme substrates, leading to the design of structures with inhibitory potential. Competitive and enzyme-activated irreversible inhibitors are detailed. The experimental study of some of the delineated substances has begun.