A Comparative QM/MM Simulation Study of the Reaction Mechanisms of Human and Plasmodium falciparum HG(X)PRTases

Aline Thomas* and Martin J. Field
Contribution from the Laboratoire de Dynamique Molculaire, Institut de Biologie Structurale - Jean-Pierre Ebel (CEA/CNRS/UJF), 41 rue Jules Horowitz, 38027 Grenoble Cedex 1, France
J. Am. Chem. Soc., 2006, 128 (31), pp 10096–10102
DOI: 10.1021/ja060823+
Publication Date (Web): July 15, 2006
Copyright © 2006 American Chemical Society
*

In papers with more than one author, the asterisk indicates the name of the author to whom inquiries about the paper should be addressed.

, aline.thomas@ibs.fr

Abstract

Abstract Image

QM/MM hybrid potential free-energy simulations are performed to compare the reaction mechanisms of human hypoxanthine guanine phosphoribosyl transferase (HGPRTase) and the corresponding enyzme from Plasmodium falciparum (Pf), hypoxanthine guanine xanthine phosphoribosyl transferase (HGXPRTase). These enzymes share 44% of sequence identity but display very different affinities for xanthine. The calculations show that in both enzymes phosphoribosyl transfer proceeds via a dissociative mechanism from an anionic form of the substrate. Nevertheless, there are significant differences in the geometries of critical structures along the reaction paths which it may be possible to exploit for the design of specific inhibitors against the Pf enzyme.

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History

  • Published In Issue August 09, 2006
  • Received February 3, 2006

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