title: A comparative QM/MM simulation study of the reaction mechanisms of human and Plasmodium falciparum HG(X)PRTases.
abstract: 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.
authors.affiliation: Laboratoire de Dynamique Moléculaire, Institut de Biologie Structurale--Jean-Pierre Ebel (CEA/CNRS/UJF), 41 rue Jules Horowitz, 38027 Grenoble Cedex 1, France. aline.thomas@ibs.fr
authors.forename: Aline
authors.initials: A
authors.lastname: Thomas
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Field
mesh_terms: D000818:Animals; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000737:chemistry*; D008958:Models, Molecular; D010963:Plasmodium falciparum / Q000201:enzymology*; D011487:Protein Conformation
chemical_list: D007041:Hypoxanthine Phosphoribosyltransferase