title: Phosphorylation of dGMP analogs by vaccinia virus TMP kinase and human GMP kinase.
abstract: 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.
authors.affiliation: Université Pierre et Marie Curie, UR, Paris, France.
authors.forename: Constance
authors.initials: C
authors.lastname: Auvynet
authors.forename: Dimitri
authors.initials: D
authors.lastname: Topalis
authors.forename: Christophe
authors.initials: C
authors.lastname: Caillat
authors.forename: Hélène
authors.initials: H
authors.lastname: Munier-Lehmann
authors.forename: Edward
authors.initials: E
authors.lastname: Seclaman
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Luigi André
authors.initials: LA
authors.lastname: Agrofoglio
authors.forename: Pierre Alexandre
authors.initials: PA
authors.lastname: Kaminski
authors.forename: Philippe
authors.initials: P
authors.lastname: Meyer
authors.forename: Dominique
authors.initials: D
authors.lastname: Deville-Bonne
authors.forename: Chahrazade
authors.initials: C
authors.lastname: El Amri
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry; D003848:Deoxyguanine Nucleotides / Q000378:metabolism*; D015195:Drug Design; D051528:Guanylate Kinases / Q000378:metabolism*; D006801:Humans; D009703:Nucleoside-Phosphate Kinase / Q000378:metabolism*; D010766:Phosphorylation; D013379:Substrate Specificity; D014616:Vaccinia virus / Q000201:enzymology*
chemical_list: D000998:Antiviral Agents; D003848:Deoxyguanine Nucleotides; C007257:2'-deoxyguanosine 5'-phosphate; D009703:Nucleoside-Phosphate Kinase; D051528:Guanylate Kinases; C020093:dTMP kinase