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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.
AuthorsConstance Auvynet, Dimitri Topalis, Christophe Caillat, Hélène Munier-Lehmann, Edward Seclaman, Jan Balzarini, Luigi André Agrofoglio, Pierre Alexandre Kaminski, Philippe Meyer, Dominique Deville-Bonne, Chahrazade El Amri
JournalBiochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 388 Issue 1 Pg. 6-11 (Oct 09 2009) ISSN: 1090-2104 [Electronic] United States
PMID19631609 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antiviral Agents
  • Deoxyguanine Nucleotides
  • 2'-deoxyguanosine 5'-phosphate
  • Nucleoside-Phosphate Kinase
  • Guanylate Kinases
  • dTMP kinase
Topics
  • Antiviral Agents (chemistry)
  • Deoxyguanine Nucleotides (metabolism)
  • Drug Design
  • Guanylate Kinases (metabolism)
  • Humans
  • Nucleoside-Phosphate Kinase (metabolism)
  • Phosphorylation
  • Substrate Specificity
  • Vaccinia virus (enzymology)

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