Phosphorylation of dGMP analogs by vaccinia virus TMP kinase and human GMP kinase.

Constance Auvynet (1) , Dimitri Topalis (2) , Christophe Caillat (3) , Hélène Munier-Lehmann (4) , Edward Seclaman (4) , Jan Balzarini (5) , Luigi André Agrofoglio (6) , Pierre-Alexandre Kaminski (7) , Philippe Meyer (8) , Dominique Deville-Bonne (2) , Chahrazade El Amri (9)

1 FRE 2852 - Peptidome de la Peau des Amphibiens
2 Laboratoire d'Enzymologie Moléculaire
3 LEBS - Laboratoire d'Enzymologie et Biochimie Structurales
4 Chimie Organique
5 Rega Institute for Medical Research [Leuven, België]
6 ICOA - Institut de Chimie Organique et Analytique
7 Department of Molecular and Optical Physics
8 IRFU - Institut de Recherches sur les lois Fondamentales de l'Univers
9 UPMC - Université Pierre et Marie Curie - Paris 6

Vaccinia virus thymidylate kinase, although similar in sequence to human TMP kinase, has broader substrate specificity and phosphorylates (E)-5-(2-bromovinyl)-dUMP and dGMP. Modified guanines such as glyoxal-dG, 8-oxo-dG, O(6)-methyl-dG, N(2)-ethyl-dG and N(7)-methyl-dG were found present in cancer cell DNA. Alkylated and oxidized dGMP analogs were examined as potential substrates for vaccinia TMP kinase and also for human TMP and GMP kinases. Molecular models obtained from structure-based docking rationalized the enzymatic data. All tested nucleotides are found surprisingly substrates of vaccinia TMP kinase and also of human GMP kinase. Interestingly, O(6)-methyl-dGMP is the only analog specific for the vaccinia enzyme. Thus, O(6)-Me-dGMP could be useful for designing new compounds of medical interest either in antipoxvirus therapy or in experimental combined gene/chemotherapy of cancer. These results also provide new insights regarding dGMP analog reaction with human GMP kinase and their slow recycling by salvage pathway nucleotide kinases.

Domains: Biochemistry [q-bio.BM]

Constance Auvynet, Dimitri Topalis, Christophe Caillat, Hélène Munier-Lehmann, Edward Seclaman, et al.. Phosphorylation of dGMP analogs by vaccinia virus TMP kinase and human GMP kinase.. Biochemical and Biophysical Research Communications, 2009, 388 (1), pp.6-11. ⟨10.1016/j.bbrc.2009.07.089⟩. ⟨pasteur-00417244⟩