Factors Controlling Enzyme Acid/Base Catalysis or The pKa of Catalytic Residues in the Enzyme Active Site

A. Albeck, M. Shokhen, N. Khazanov

Research output: Contribution to conferencePaperpeer-review

Abstract

Acid/base catalysis plays a key role in chemical transformations of substrates and inhibitors in the active site (AS) of many enzymes. The pKa of catalytic residues is a quantitative measure, determining their principal ability to initiate enzymatic catalysis – acid or base - in the enzyme AS. We applied our original QM/SCRF(VS) approach to quantum mechanical modelling of catalytic reactions in AS of water solvated enzymes. We have derived analytical equations and formulated a simple rule rationalizing the trend of pKa shifts of catalytic residues caused by the ligand binding [1]. We rationalized the experimental observation that the pKa of the catalytic His57 NH in the tetrahedral complex (TC) of chymotrypsin with trifluoromethyl ketone inhibitors is 4–5 units higher relative to the free enzyme (FE) and why the binding of the ligand plays a triggering role that switches on catalysis in serine proteases [1,2]. We have challenged a central mechanistic paradigm of cysteine proteases that the His–Cys catalytic diad forms an ion-pair NH(+)/S(-) already in the catalytically active free enzyme. We demonstrated that the His–Cys catalytic diad in free papain is fully protonated, NH(+)/SH [3]. We studied the interaction of papain with peptidyl aldehyde transition-state (TS) analog inhibitors. The structure of the non-covalent Michaelis-like complex (MC), the TS and the TC where analyzed, and a detailed inhibition mechanism was formulated [4].
Original languageAmerican English
Number of pages1
StatePublished - 2012
Event12th Eurasia Conference on Chemical Sciences - Corfu, Greece
Duration: 16 Apr 201221 Apr 2012

Conference

Conference12th Eurasia Conference on Chemical Sciences
Country/TerritoryGreece
CityCorfu
Period16/04/1221/04/12

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