Premium
Electronic roles of active site residues in the catalysis and inhibition of carbonic anhydrase
Author(s) -
Cook Charles M.,
Lee Richard H.,
Allen Leland C.
Publication year - 2009
Publication title -
international journal of quantum chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.484
H-Index - 105
eISSN - 1097-461X
pISSN - 0020-7608
DOI - 10.1002/qua.560240726
Subject(s) - chemistry , pseudopotential , carbonic anhydrase , active site , reaction coordinate , zinc , carbonic anhydrase ii , ab initio , computational chemistry , electronic structure , transition state , molecule , crystallography , catalysis , atomic physics , enzyme , organic chemistry , physics
Ab initio electronic structure calculations were carried out to achieve a qualitative description of the charge redistribution that takes place in the enzymatic conversion of CO 2 to HCO 3 ‐ . The electronic effect produced by each of the active site species which act on CO 2 (a zinc ion ( + 2) bound into the enzyme by three His residues, two water molecules, His 64, Glu 106, and Thr 199) has been assigned. Zinc is found to be five‐coordinate, and force optimization leads to a six‐membered ring transition state, one side of which is a hydrogen bond to an oxygen of CO 2 . The proposed reaction mechanism is compatible with all contemporary experimental measurements. The well‐known sulfonamide inhibitors of carbonic anhydrase are shown to partially mimic the geometry of the transition state. A schematic for a superior transition state analog is presented; the development of such inhibitors may be useful in the improved treatment of glaucoma. (His) 3 Zn is replaced by (H 3 N) 3 Zn, and zinc is represented by a d ‐orbital containing 12‐electron pseudopotential. For calculations on the transition state, (H 3 N) 3 Zn is further replaced by an eight‐electron model: two electrons for each ligand's donor pair plus the two outer zinc electrons. This model is calibrated by matching proton affinities and the zinc‐water separation in the (H 3 N) 3 ZnOH 2 2+ pseudopotential representation.