Activities per year
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 . We rationalized the experimental observation that the pKa of the catalytic His57 NH 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 . 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 .
|Original language||American English|
|Number of pages||1|
|State||Published - 2012|
|Event||12th Eurasia Conference on Chemical Sciences - Corfu, Greece|
Duration: 16 Apr 2012 → 21 Apr 2012
|Conference||12th Eurasia Conference on Chemical Sciences|
|Period||16/04/12 → 21/04/12|
FingerprintDive into the research topics of 'Factors Controlling Enzyme Acid/Base Catalysis or The pKa of Catalytic Residues in the Enzyme Active Site'. Together they form a unique fingerprint.
- 1 Invited talk
Amnon Albeck (Invited speaker)16 Apr 2012 → 21 Apr 2012
Activity: Talk or presentation › Invited talk