Abstract
Adenylate kinases are involved in the activation of antiviral drugs such as the acyclic phosphonates analogs PMEA and (R)PMPA. We examine the in vitro phosphorylation of PMEA and PMPA bearing a borano- or a H- group on the phosphorus atom. The α-borano or α-H on PMEA and PMPA were detrimental to the activity of recombinant human AMP kinases 1 and 2. Docking PMEA to the active site of AMP kinase 1 indicated that the borano group may prevent two conserved critical Arg interactions with the α-phosphate, resulting in substrate bad positioning.
Present address for B. Schneider: Laboratoire de Différenciation et Prion, CNRS-FRE 2937 Villejuif, France.
This work is dedicated to the memory of our friend and colleague Dr Simon Robert SARFATI, who died December 12, 2005.
We thank Pr. Michèle Reboud (CNRS FRE 2852 - Université Paris6) for helpful discussions. We also thank J. J. Montagne (Institut Jacques Monod, CNRS & Universités Paris 6,7) for mass spectroscopy experiments and the Service de Modélisation et Imagerie Moléculaire of the Réseau Fédératif de Recherche of Université Paris6 for calculation facilities.
The work was supported by grants from the Agence Nationale pour la Recherche contre le SIDA (France), Université Pierre-et-Marie-Curie-Paris6, French Centre National de Recherche Scientifique (FRE 2852 and ANR-05-BLAN-0368-02 for DDB and DT) and ESC-SIDACTION (for BC, KA and KB). Dr. Karine Barral was supported by a postdoctoral fellowship from Agence Nationale pour la Recherche contre le SIDA (France).