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Influence of Outer-Shell Metal Ligands on the Structural and Electronic Properties of Horse Liver Alcohol Dehydrogenase Zinc Active Site

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Dip. di Chimica, Università di Firenze, via della Lastruccia 3, I-50019 Sesto Fiorentino, Italy, European Laboratory for Non linear Spectroscopy (LENS), via Nello Carrara 1, I-50019 Sesto Fiorentino, Italy, International School for Advanced Studies (SISSA/ISAS) and INFM-DEMOCRITOS Center for Numerical Simulation, via Beirut 4, I-34014 Trieste, Italy, Dip. di Chimica, Università di Siena, via A. Moro, I-53100 Siena, Italy, CSCS-Centro Svizzero di Calcolo Scientifico, Via Cantonale, Galleria 2,CH-6928 Manno, Switzerland, and Physical Chemistry, ETH Hönggerberg HCI, CH-8093 Zurich, Switzerland
Cite this: J. Phys. Chem. B 2003, 107, 28, 6886–6892
Publication Date (Web):June 20, 2003
Copyright © 2003 American Chemical Society

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    An analysis of the high resolution 3D structures of zinc enzymes shows that the Zn−His−carboxyl(ate)−HX (X = OH or NH) H-bond motif is common. We investigate here the influence of this motif in the active site of horse liver alcohol dehydrogenase, which features the Zn−His−Asp−H2O motif. Density functional theory calculations are carried out on models of the active site complexed with the NAD+ cofactor, in which the metal ion binds either the alcohol substrate [Bahnson et al. Proc. Natl. Acad. Sci. U. S.A1997, 94, 12797−12802] 1 or a water molecule [Meijers et al. J. Biol. Chem.2001, 276, 9316−9321]. 2 Our calculations suggest that in both complexes the presence of Asp49 significantly affects the structural and electronic properties of the metal site. Furthermore, they show that inclusion of the Asp bound water molecule is required to describe the energetics correctly. Finally, they suggest that the Asp49/water pattern could play a role in the enzymatic reaction.

     Università di Firenze.

     International School for Advanced Studies (SISSA/ISAS) and INFM-DEMOCRITOS Center for Numerical Simulation.


     CSCS-Centro Svizzero di Calcolo Scientifico.

     European Laboratory for Non linear Spectroscopy (LENS).

     Università di Siena.


     To whom correspondence should be addressed. Phone:  +39-040-3787407. Fax:+39-040-3787-528. E-mail:  [email protected].


     Physical Chemistry, ETH Hönggerberg HCI.

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