Electronic aspects of LADH catalytic mechanism

Abstract

AbstractElectronic aspects of the catalytic mechanism of liver alcohol dehydrogenase (LADH) are studied with the help of ab initio analytical gradient SCF MO methods. Three points are considered: (i) role of the catalytic zinc; (ii) geometry and electronic structure of the transition state for the hydride transfer reactions; and (iii) factors affecting the energy gap for the hydride transfer step, namely, substrate binding to zinc, reaction field, and serine 48 effects on the potential energy profile. The coordination sphere of the catalytic zinc has been modeled with an ammonia molecule and two SH− groups; complexes with CH3O−, CH3OH, and CH2O have been studied; a (6, 2, 2, 2, 1/6, 2, 1/3, 2) basis set has been used for Zn++; a (5, 2, 1, 1/3, 2) was used for oxygen, carbon, and sulfur; and a (3, 1) was used for hydrogen atoms. The hydride step was studied with two model systems: pyridinium cation/1,4‐dihydropyridine coupled to the CH3O−/CH2O reaction, and cyclopropenyl cation/cyclopropene coupled to the CH3O−/CH2O system. For the latter, the role of Ser48 has been studied at the supermolecule level. The calculation on the hydride transfer step has been done at a 4–31G basis set level. The results obtained shed new light on the sources of catalytic activity of liver alcohol dehydrogenases.