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

• Published in: Biochemical and biophysical research communications Vol. 388; no. 1; pp. 6 - 11
• Main Authors: Auvynet, Constance, Topalis, Dimitri, Caillat, Christophe, Munier-Lehmann, Hélène, Seclaman, Edward, Balzarini, Jan, Agrofoglio, Luigi André, Kaminski, Pierre Alexandre, Meyer, Philippe, Deville-Bonne, Dominique, El Amri, Chahrazade
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09.10.2009; Elsevier
• Subjects: 8-oxo-dGMP; 9-deaza-dGMP; Alkylated dGMP; Antiviral Agents - chemistry; Biochemistry; Biochemistry, Molecular Biology; Deoxyguanine Nucleotides - metabolism; Drug Design; Glyoxal-dGMP; GMP kinase; Guanylate Kinases - metabolism; Humans; Life Sciences; Nucleoside-Phosphate Kinase - metabolism; O 6-Me-dGMP; Phosphorylation; Substrate Specificity; TMP kinase; Vaccinia virus; Vaccinia virus - enzymology; dThd; Phosphorylation; TMP kinase; HSV; 9-deaza-dGMP; Glyoxal-dGMP; Alkylated dGMP; dT (M, D, T); Vaccinia virus; hGMPK; VZV; GMP kinase; O 6-Me-dGMP; TK; BVdU; 8-oxo-dGMP; hTMPK; Vacc-TMPK
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2009.07.089

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.