Title

Catalytic Mechanism of Serine Proteinases

Document Type

Article

Journal/Book Title

Proceedings of the National Academy of Sciences

Publication Date

2-1976

Publisher

National Academy of Sciences

Volume

73

Issue

2

First Page

432

Last Page

436

Abstract

The catalytic activity of the serine proteinases is studied using molecular orbital methods on a model of the enzyme-substrate complex. A mechanism is employed in which Ser-195, upon donating a proton to the His-57-Asp-102 dyad, attacks the substrate to form the tetrahedral intermediate. As His-57 then donates a proton to the leaving group, the intermediate decomposes to the acyl enzyme. An analogous process takes place during deacylation, as a water molecule takes the place of Ser-195 as the nucleophile. The motility of the histidine is found to be an important factor in both steps. An attempt is made to include the effects of those atoms not explicitly included in the calculations and to compare the reaction rate of the proposed mechanism with that of the uncatalyzed hydrolysis. This mechanism is found to be in good agreement with structural and kinetic data.