Non-Viral Deoxyribonucleoside Kinases – Diversity and Practical Use

Louise Slot Christiansen; Birgitte Munch-Petersen; Wolfgang Knecht

doi:10.1016/j.jgg.2015.01.003

Volume 42 Issue 5

May 2015

Turn off MathJax

Article Contents

Article Navigation > Journal of Genetics and Genomics > 2015 > 42(5): 235-248

PDF( 734 KB)

Non-Viral Deoxyribonucleoside Kinases – Diversity and Practical Use

doi: 10.1016/j.jgg.2015.01.003

a
Department of Biology, Lund University, Lund 22362, Sweden
b
Department of Science, Systems and Models, Roskilde University, Roskilde 4000, Denmark
c
Lund Protein Production Platform, Lund University, Lund 22362, Sweden

More Information

Corresponding author: E-mail address: wolfgang.knecht@biol.lu.se (Wolfgang Knecht)
Received Date: 2014-10-31
Accepted Date: 2015-01-05
Rev Recd Date: 2015-01-04

Available Online: 2015-02-10

Publish Date: 2015-05-20

Abstract

Abstract

Deoxyribonucleoside kinases (dNKs) phosphorylate deoxyribonucleosides to their corresponding monophosphate compounds. dNks also phosphorylate deoxyribonucleoside analogues that are used in the treatment of cancer or viral infections. The study of the mammalian dNKs has therefore always been of great medical interest. However, during the last 20 years, research on dNKs has gone into non-mammalian organisms. In this review, we focus on non-viral dNKs, in particular their diversity and their practical applications. The diversity of this enzyme family in different organisms has proven to be valuable in studying the evolution of enzymes. Some of these newly discovered enzymes have been useful in numerous practical applications in medicine and biotechnology, and have contributed to our understanding of the structural basis of nucleoside and nucleoside analogue activation.
- Nucleosides,
- Nucleotides,
- Nucleoside salvage pathway,
- Evolution,
- Suicide gene therapy,
- Deoxynucleosides,
- Deoxynucleotides,
- Deoxynucleoside kinases

FullText(HTML)

References(130)

References

[1]	Alegre, M.M., Weyant, M.J., Bennett, D.T. et al. Serum detection of thymidine kinase 1 as a means of early detection of lung cancer Anticancer Res., 34 (2014),pp. 2145-2151
[2]	Ardiani, A., Johnson, A.J., Ruan, H. et al. Enzymes to die for: exploiting nucleotide metabolizing enzymes for cancer gene therapy Curr. Gene Ther., 12 (2012),pp. 77-91
[3]	Berenstein, D., Christensen, J.F., Kristensen, T. et al. Valine, not methionine, is amino acid 106 in human cytosolic thymidine kinase (TK1). Impact on oligomerization, stability, and kinetic properties J. Biol. Chem., 275 (2000),pp. 32187-32192
[4]	Birringer, M.S., Claus, M.T., Folkers, G. et al. Structure of a type II thymidine kinase with bound dTTP FEBS Lett., 579 (2005),pp. 1376-1382
[5]	Bohman, C., Eriksson, S. Deoxycytidine kinase from human leukemic spleen: preparation and characteristics of homogeneous enzyme Biochemistry, 27 (1988),pp. 4258-4265
[6]	Bondanza, A., Hambach, L., Aghai, Z. et al. Blood, 117 (2011),pp. 6469-6478
[7]	, Deininger, P.L. Human thymidine kinase gene: molecular cloning and nucleotide sequence of a cDNA expressible in mammalian cells Mol. Cell. Biol., 4 (1984),pp. 2316-2320
[8]	Carnrot, C., Wehelie, R., Eriksson, S. et al. Mol. Microbiol., 50 (2003),pp. 771-780
[9]	Carnrot, C., Vogel, S.R., Byun, Y. et al. Biol. Chem., 387 (2006),pp. 1575-1581
[10]	Chen, F., Tang, L., Xia, T. et al. Serum thymidine kinase 1 levels predict cancer-free survival following neoadjuvant, surgical and adjuvant treatment of patients with locally advanced breast cancer Mol. Clin. Oncol., 1 (2013),pp. 894-902
[11]	Chen, L.S., Wang, M., Ou, W.C. et al. Efficient gene transfer using the human JC virus-like particle that inhibits human colon adenocarcinoma growth in a nude mouse model Gene Ther., 17 (2010),pp. 1033-1041
[12]	Chen, Z., Zhou, H., Li, S. et al. Serological thymidine kinase 1 (STK1) indicates an elevated risk for the development of malignant tumours Anticancer Res., 28 (2008),pp. 3897-3907
[13]	Chen, Z.H., Huang, S.Q., Wang, Y. et al. Serological thymidine kinase 1 is a biomarker for early detection of tumours–a health screening study on 35,365 people, using a sensitive chemiluminescent dot blot assay Sensors, 11 (2011),pp. 11064-11080
[14]	Chottiner, E.G., Shewach, D.S., Datta, N.S. et al. Cloning and expression of human deoxycytidine kinase cDNA Proc. Natl. Acad. Sci. USA, 88 (1991),pp. 1531-1535
[15]	Clausen, A.R., Girandon, L., Ali, A. et al. FEBS J., 279 (2012),pp. 3889-3897
[16]	Clausen, A.R., Mutahir, Z., Munch-Petersen, B. et al. Plants salvage deoxyribonucleosides in mitochondria Nucleosides Nucleotides Nucleic Acids, 33 (2014),pp. 291-295
[17]	Egeblad-Welin, L., Sonntag, Y., Eklund, H. et al. FEBS J., 274 (2007),pp. 1542-1551
[18]	Egeblad, L., Welin, M., Flodin, S. et al. Pan-pathway based interaction profiling of FDA-approved nucleoside and nucleobase analogs with enzymes of the human nucleotide metabolism PLoS One, 7 (2012),p. e37724
[19]	Eriksson, S. Is the expression of deoxynucleoside kinases and 5′-nucleotidases in animal tissues related to the biological effects of nucleoside analogs? Curr. Med. Chem., 20 (2013),pp. 4241-4248
[20]	Eriksson, S., Munch-Petersen, B., Johansson, K. et al. Structure and function of cellular deoxyribonucleoside kinases Cell. Mol. Life Sci., 59 (2002),pp. 1327-1346
[21]	Freeman, S.M., Abboud, C.N., Whartenby, K.A. et al. The “bystander effect”: tumor regression when a fraction of the tumor mass is genetically modified Cancer Res., 53 (1993),pp. 5274-5283
[22]	Fukuda, Y., Schuetz, J.D. ABC transporters and their role in nucleoside and nucleotide drug resistance Biochem. Pharm., 83 (2012),pp. 1073-1083
[23]	Godsey, M.H., Ort, S., Sabini, E. et al. Structural basis for the preference of UTP over ATP in human deoxycytidine kinase: illuminating the role of main-chain reorganization Biochemistry, 45 (2006),pp. 452-461
[24]	Greish, K., Frandsen, J., Scharff, S. et al. Silk-elastinlike protein polymers improve the efficacy of adenovirus thymidine kinase enzyme prodrug therapy of head and neck tumors J. Gene. Med., 12 (2010),pp. 572-579
[25]	Guittet, O., Hakansson, P., Voevodskaya, N. et al. J. Biol. Chem., 276 (2001),pp. 40647-40651
[26]	Hapke, D.M., Stegmann, A.P., Mitchell, B.S. Retroviral transfer of deoxycytidine kinase into tumor cell lines enhances nucleoside toxicity Cancer Res., 56 (1996),pp. 2343-2347
[27]	Hazra, S., Konrad, M., Lavie, A. The sugar ring of the nucleoside is required for productive substrate positioning in the active site of human deoxycytidine kinase (dCK): implications for the development of dCK-activated acyclic guanine analogues J. Med. Chem., 53 (2010),pp. 5792-5800
[28]	Hazra, S., Ort, S., Konrad, M. et al. Structural and kinetic characterization of human deoxycytidine kinase variants able to phosphorylate 5-substituted deoxycytidine and thymidine analogues Biochemistry, 49 (2010),pp. 6784-6790
[29]	Hazra, S., Sabini, E., Ort, S. et al. Extending thymidine kinase activity to the catalytic repertoire of human deoxycytidine kinase Biochemistry, 48 (2009),pp. 1256-1263
[30]	Hazra, S., Szewczak, A., Ort, S. et al. Post-translational phosphorylation of serine 74 of human deoxycytidine kinase favors the enzyme adopting the open conformation making it competent for nucleoside binding and release Biochemistry, 50 (2011),pp. 2870-2880
[31]	Hebrard, C., Cros-Perrial, E., Clausen, A.R. et al. Bacterial deoxyribonucleoside kinases are poor suicide genes in mammalian cells Nucleosides Nucleotides Nucleic Acids, 28 (2009),pp. 1068-1075
[32]	Huber, B.E., Austin, E.A., Richards, C.A. et al. Metabolism of 5-fluorocytosine to 5-fluorouracil in human colorectal tumor cells transduced with the cytosine deaminase gene: significant antitumor effects when only a small percentage of tumor cells express cytosine deaminase Proc. Natl. Acad. Sci. USA, 91 (1994),pp. 8302-8306
[33]	Ihlenfeldt, H.G.D., Munch-Petersen, B.D., Piskur, J.D., Sondergaard, L.D., 2000. Deoxynucleoside kinase from insect cells for the synthesis of nucleoside monophosphates. Patentapplication: EP0999275 A2.
[34]	Ihlenfeldt, H.G.D., Munch-Petersen, B.D., Piskur, J.D., Sondergaard, L.D., 2005. Deoxynucleoside kinase from insect cells for the synthesis of nucleoside monophosphates. Patent: EP0999275 B1.
[35]	Immonen, A., Vapalahti, M., Tyynela, K. et al. AdvHSV-tk gene therapy with intravenous ganciclovir improves survival in human malignant glioma: a randomised, controlled study Mol. Ther., 10 (2004),pp. 967-972
[36]	Jessop, T.C., Tarver, J.E., Carlsen, M. et al. Lead optimization and structure-based design of potent and bioavailable deoxycytidine kinase inhibitors Bioorganic Med. Chem. Lett., 19 (2009),pp. 6784-6787
[37]	Johansson, K., Ramaswamy, S., Ljungcrantz, C. et al. Structural basis for substrate specificities of cellular deoxyribonucleoside kinases Nat. Struc. Biol., 8 (2001),pp. 616-620
[38]	Johansson, M., Karlsson, A. Cloning and expression of human deoxyguanosine kinase cDNA Proc. Natl. Acad. Sci. USA, 93 (1996),pp. 7258-7262
[39]	Johansson, M., Karlsson, A. Cloning of the cDNA and chromosome localization of the gene for human thymidine kinase 2 J. Biol. Chem., 272 (1997),pp. 8454-8458
[40]	Jordan, A., Reichard, P. Ribonucleotide reductases Ann. Rev. Biochem., 67 (1998),pp. 71-98
[41]	Jordheim, L.P., Dumontet, C. Review of recent studies on resistance to cytotoxic deoxynucleoside analogues Biochim. Biophys. Acta, 1776 (2007),pp. 138-159
[42]	Jordheim, L.P., Galmarini, C.M., Dumontet, C. Gemcitabine resistance due to deoxycytidine kinase deficiency can be reverted by fruitfly deoxynucleoside kinase, DmdNK, in human uterine sarcoma cells Cancer Chemother. Pharm., 58 (2006),pp. 547-554
[43]	Kakinoki, K., Nakamoto, Y., Kagaya, T. et al. Prevention of intrahepatic metastasis of liver cancer by suicide gene therapy and chemokine ligand 2/monocyte chemoattractant protein-1 delivery in mice J. Gene Med., 12 (2010),pp. 1002-1013
[44]	Kappock, T.J., Ealick, S.E., Stubbe, J. Modular evolution of the purine biosynthetic pathway Curr. Opin. Chem. Biol., 4 (2000),pp. 567-572
[45]	Ke, P.Y., Chang, Z.F. Mitotic degradation of human thymidine kinase 1 is dependent on the anaphase-promoting complex/cyclosome-CDH1-mediated pathway Mol. Cell. Biol., 24 (2004),pp. 514-526
[46]	Khan, Z., Knecht, W., Willer, M. et al. Plant thymidine kinase 1: a novel efficient suicide gene for malignant glioma therapy Neuro Oncol., 12 (2010),pp. 549-558
[47]	Knecht, W., Mikkelsen, N.E., Clausen, A.R. et al. Biochem. Biophys. Res. Com., 382 (2009),pp. 430-433
[48]	Knecht, W., Munch-Petersen, B., Piskur, J. J. Mol. Biol., 301 (2000),pp. 827-837
[49]	Knecht, W., Petersen, G.E., Munch-Petersen, B. et al. Deoxyribonucleoside kinases belonging to the thymidine kinase 2 (TK2)-like group vary significantly in substrate specificity, kinetics and feed-back regulation J. Mol. Biol., 315 (2002),pp. 529-540
[50]	Knecht, W., Petersen, G.E., Sandrini, M.P. et al. Mosquito has a single multisubstrate deoxyribonucleoside kinase characterized by unique substrate specificity Nucl. Acids Res., 31 (2003),pp. 1665-1672
[51]	Knecht, W., Rozpedowska, E., Le Breton, C. et al. Gene Ther., 14 (2007),pp. 1278-1286
[52]	Knecht, W., Sandrini, M.P., Johansson, K. et al. A few amino acid substitutions can convert deoxyribonucleoside kinase specificity from pyrimidines to purines EMBO J., 21 (2002),pp. 1873-1880
[53]	Konrad, A., Lai, J., Mutahir, Z. et al. The phylogenetic distribution and evolution of enzymes within the thymidine kinase 2-like gene family in metazoa J. Mol. Evol., 78 (2014),pp. 202-216
[54]	Kosinska, U., Carnrot, C., Eriksson, S. et al. FEBS J., 272 (2005),pp. 6365-6372
[55]	Kosinska, U., Carnrot, C., Sandrini, M.P. et al. FEBS J., 274 (2007),pp. 727-737
[56]	Larsen, N.B., Munch-Petersen, B., Piskur, J. Tomato thymidine kinase is subject to inefficient TTP feedback regulation Nucleosides Nucleotides Nucleic Acids, 33 (2014),pp. 287-290
[57]	Lau, Y.F., Kan, Y.W. Direct isolation of the functional human thymidine kinase gene with a cosmid shuttle vector Proc. Natl. Acad. Sci. USA, 81 (1984),pp. 414-418
[58]	Legent, K., Mas, M., Dutriaux, A. et al. Cell Cycle, 5 (2006),pp. 740-749
[59]	Li, C.L., Lu, C.Y., Ke, P.Y. et al. Perturbation of ATP-induced tetramerization of human cytosolic thymidine kinase by substitution of serine-13 with aspartic acid at the mitotic phosphorylation site Biochem. Biophys. Res. Com., 313 (2004),pp. 587-593
[60]	Loffler, M., Fairbanks, L.D., Zameitat, E. et al. Pyrimidine pathways in health and disease Trends Mol. Med., 11 (2005),pp. 430-437
[61]	Löffler, M., Zameitat, E.
[62]	Ma, S., Qu, W., Mao, L. et al. Oncology Rep., 27 (2012),pp. 1443-1450
[63]	Ma, S., Zhao, L., Zhu, Z. et al. J. Gene Med., 13 (2011),pp. 305-311
[64]	Mazzon, C., Rampazzo, C., Scaini, M.C. et al. Cytosolic and mitochondrial deoxyribonucleotidases: activity with substrate analogs, inhibitors and implications for therapy Biochem. Pharm., 66 (2003),pp. 471-479
[65]	Mikkelsen, N.E., Johansson, K., Karlsson, A. et al. Biochemistry, 42 (2003),pp. 5706-5712
[66]	Mikkelsen, N.E., Munch-Petersen, B., Eklund, H. FEBS J., 275 (2008),pp. 2151-2160
[67]	Moolten, F.L. Tumor chemosensitivity conferred by inserted herpes thymidine kinase genes: paradigm for a prospective cancer control strategy Cancer Res., 46 (1986),pp. 5276-5281
[68]	Moolten, F.L., Wells, J.M. Curability of tumors bearing herpes thymidine kinase genes transferred by retroviral vectors J. Natl. Cancer Inst., 82 (1990),pp. 297-300
[69]	Munch-Petersen, B. Reversible tetramerization of human TK1 to the high catalytic efficient form is induced by pyrophosphate, in addition to tripolyphosphates, or high enzyme concentration FEBS J., 276 (2009),pp. 571-580
[70]	Munch-Petersen, B. Enzymatic regulation of cytosolic thymidine kinase 1 and mitochondrial thymidine kinase 2: a mini review Nucleosides Nucleotides Nucleic Acids, 29 (2010),pp. 363-369
[71]	Munch-Petersen, B., Cloos, L., Tyrsted, G. et al. Diverging substrate specificity of pure human thymidine kinases 1 and 2 against antiviral dideoxynucleosides J. Biol. Chem., 266 (1991),pp. 9032-9038
[72]	Munch-Petersen, B., Knecht, W., Lenz, C. et al. J. Biol. Chem., 275 (2000),pp. 6673-6679
[73]	Munch-Petersen, B., Piskur, J., Sondergaard, L. J. Biol. Chem., 273 (1998),pp. 3926-3931
[74]	Munch-Petersen, B., Piskur, J., Sondergaard, L. Adv. Exp. Med. Biol., 431 (1998),pp. 465-469
[75]	Munch-Petersen, B., Tyrsted, G., Cloos, L. Reversible ATP-dependent transition between two forms of human cytosolic thymidine kinase with different enzymatic properties J. Biol. Chem., 268 (1993),pp. 15621-15625
[76]	Murphy, J.M., Armijo, A.L., Nomme, J. et al. J. Med. Chem., 56 (2013),pp. 6696-6708
[77]	Mutahir, Z.
[78]	Mutahir, Z., Clausen, A.R., Andersson, K.M. et al. Thymidine kinase 1 regulatory fine-tuning through tetramer formation FEBS J., 280 (2013),pp. 1531-1541
[79]	Nasr, F., Bertauche, N., Dufour, M.E. et al. Mol. Gen. Genetics, 244 (1994),pp. 23-32
[80]	Nasu, Y., Saika, T., Ebara, S. et al. Mol. Ther., 15 (2007),pp. 834-840
[81]	Nathanson, D.A., Armijo, A.L., Tom, M. et al. Co-targeting of convergent nucleotide biosynthetic pathways for leukemia eradication J. Exp. Med., 211 (2014),pp. 473-486
[82]	Neschadim, A., Wang, J.C., Lavie, A. et al. Cancer Gene Ther., 19 (2012),pp. 320-327
[83]	Neschadim, A., Wang, J.C., Sato, T. et al. Cell fate control gene therapy based on engineered variants of human deoxycytidine kinase Mol. Ther., 20 (2012),pp. 1002-1013
[84]	Nomme, J., Murphy, J.M., Su, Y. et al. Structural characterization of new deoxycytidine kinase inhibitors rationalizes the affinity-determining moieties of the molecules Acta Crystallogr. D Biol. Crystallogr., 70 (2014),pp. 68-78
[85]	Okazaki, R., Kornberg, A. J. Biol. Chem., 239 (1964),pp. 269-274
[86]	Okazaki, R., Kornberg, A. J. Biol. Chem., 239 (1964),pp. 275-284
[87]	Osaki, T., Tanio, Y., Tachibana, I. et al. Gene therapy for carcinoembryonic antigen-producing human lung cancer cells by cell type-specific expression of herpes simplex virus thymidine kinase gene Cancer Res., 54 (1994),pp. 5258-5261
[88]	Peters, G.J.
[89]	Piskur, J., Sandrini, M.P., Knecht, W. et al. Animal deoxyribonucleoside kinases: ‘forward’ and ‘retrograde’ evolution of their substrate specificity FEBS Lett., 560 (2004),pp. 3-6
[90]	Rainov, N.G. A phase III clinical evaluation of herpes simplex virus type 1 thymidine kinase and ganciclovir gene therapy as an adjuvant to surgical resection and radiation in adults with previously untreated glioblastoma multiforme Hum. Gene Ther., 11 (2000),pp. 2389-2401
[91]	Rejiba, S., Bigand, C., Parmentier, C. et al. Gemcitabine-based chemogene therapy for pancreatic cancer using Ad-dCK::UMK GDEPT and TS/RR siRNA strategies Neoplasia, 11 (2009),pp. 637-650
[92]	Ribot, E.J., Miraux, S., Konsman, J.P. et al. NMR Biomedicine, 24 (2011),pp. 1361-1368
[93]	Sabini, E., Hazra, S., Konrad, M. et al. Structural basis for activation of the therapeutic L-nucleoside analogs 3TC and troxacitabine by human deoxycytidine kinase Nucl. Acids Res., 35 (2007),pp. 186-192
[94]	Sabini, E., Hazra, S., Konrad, M. et al. Nonenantioselectivity property of human deoxycytidine kinase explained by structures of the enzyme in complex with L- and D-nucleosides J. Med. Chem., 50 (2007),pp. 3004-3014
[95]	Sabini, E., Hazra, S., Konrad, M. et al. Elucidation of different binding modes of purine nucleosides to human deoxycytidine kinase J. Med. Chem., 51 (2008),pp. 4219-4225
[96]	Sabini, E., Hazra, S., Ort, S. et al. Structural basis for substrate promiscuity of dCK J. Mol. Biol., 378 (2008),pp. 607-621
[97]	Sabini, E., Ort, S., Monnerjahn, C. et al. Structure of human dCK suggests strategies to improve anticancer and antiviral therapy Nat. Struc. Biol., 10 (2003),pp. 513-519
[98]	Sandrini, M.P., Clausen, A.R., On, S.L. et al. Nucleoside analogues are activated by bacterial deoxyribonucleoside kinases in a species-specific manner J. Antimicrobial Chemother., 60 (2007),pp. 510-520
[99]	Sandrini, M.P., Piskur, J. Deoxyribonucleoside kinases: two enzyme families catalyze the same reaction Trends Biochem. Sci., 30 (2005),pp. 225-228
[100]	Sandrini, M.P., Soderbom, F., Mikkelsen, N.E. et al. J. Mol. Biol., 369 (2007),pp. 653-664
[101]	Segura-Pena, D., Lichter, J., Trani, M. et al. Quaternary structure change as a mechanism for the regulation of thymidine kinase 1-like enzymes Structure, 15 (2007),pp. 1555-1566
[102]	Segura-Pena, D., Lutz, S., Monnerjahn, C. et al. Binding of ATP to TK1-like enzymes is associated with a conformational change in the quaternary structure J. Mol. Biol., 369 (2007),pp. 129-141
[103]	Serra, I., Conti, S., Piškur, J. et al. Adv. Synth. Catal., 356 (2014),pp. 563-570
[104]	Skovgaard, T., Uhlin, U., Munch-Petersen, B. FEBS J., 279 (2012),pp. 1777-1787
[105]	Soltysova, A., Altanerova, V., Altaner, C. Cancer stem cells Neoplasma, 52 (2005),pp. 435-440
[106]	Soriano, E.V., Clark, V.C., Ealick, S.E. Structures of human deoxycytidine kinase product complexes Acta Crystallogr. D Biol. Crystallogr., 63 (2007),pp. 1201-1207
[107]	Szatmari, T., Huszty, G., Desaknai, S. et al. Adenoviral vector transduction of the human deoxycytidine kinase gene enhances the cytotoxic and radiosensitizing effect of gemcitabine on experimental gliomas Cancer Gene Ther., 15 (2008),pp. 154-164
[108]	Tanaka, H., Arakawa, H., Yamaguchi, T. et al. A ribonucleotide reductase gene involved in a p53-dependent cell-cycle checkpoint for DNA damage Nature, 404 (2000),pp. 42-49
[109]	Tang, W., He, Y., Zhou, S. et al. J. Exp. Clin. Canc. Res., 28 (2009),p. 155
[110]	Tinta, T., Christiansen, L.S., Konrad, A. et al. Deoxyribonucleoside kinases in two aquatic bacteria with high specificity for thymidine and deoxyadenosine FEMS Microbiol. Lett., 331 (2012),pp. 120-127
[111]	Wang, L., Hellman, U., Eriksson, S. Cloning and expression of human mitochondrial deoxyguanosine kinase cDNA FEBS Lett., 390 (1996),pp. 39-43
[112]	Wang, L., Karlsson, A., Arner, E.S. et al. Substrate specificity of mitochondrial 2'-deoxyguanosine kinase. Efficient phosphorylation of 2-chlorodeoxyadenosine J. Biol. Chem., 268 (1993),pp. 22847-22852
[113]	Wang, L., Munch-Petersen, B., Herrstrom Sjoberg, A. et al. Human thymidine kinase 2: molecular cloning and characterisation of the enzyme activity with antiviral and cytostatic nucleoside substrates FEBS Lett., 443 (1999),pp. 170-174
[114]	Wang, L., Westberg, J., Bolske, G. et al. Novel deoxynucleoside-phosphorylating enzymes in mycoplasmas: evidence for efficient utilization of deoxynucleosides Mol. Microbiol., 42 (2001),pp. 1065-1073
[115]	Welin, M., Kosinska, U., Mikkelsen, N.E. et al. Structures of thymidine kinase 1 of human and mycoplasmic origin Proc. Natl. Acad. Sci. USA, 101 (2004),pp. 17970-17975
[116]	Welin, M., Skovgaard, T., Knecht, W. et al. FEBS J., 272 (2005),pp. 3733-3742
[117]	Welin, M., Wang, L., Eriksson, S. et al. Structure-function analysis of a bacterial deoxyadenosine kinase reveals the basis for substrate specificity J. Mol. Biol., 366 (2007),pp. 1615-1623
[118]	Vernejoul, F., Ghenassia, L., Souque, A. et al. Gene therapy based on gemcitabine chemosensitization suppresses pancreatic tumor growth Mol. Ther., 14 (2006),pp. 758-767
[119]	Vernis, L., Piskur, J., Diffley, J.F. Nucl. Acids Res., 31 (2003),p. e120
[120]	Westphal, M., Yla-Herttuala, S., Martin, J. et al. Adenovirus-mediated gene therapy with sitimagene ceradenovec followed by intravenous ganciclovir for patients with operable high-grade glioma (ASPECT): a randomised, open-label, phase 3 trial Lancet Oncol., 14 (2013),pp. 823-833
[121]	Voges, J., Reszka, R., Gossmann, A. et al. Imaging-guided convection-enhanced delivery and gene therapy of glioblastoma Ann. Neurol., 54 (2003),pp. 479-487
[122]	Xu, F., Li, S., Li, X.L. et al. Phase I and biodistribution study of recombinant adenovirus vector-mediated herpes simplex virus thymidine kinase gene and ganciclovir administration in patients with head and neck cancer and other malignant tumors Cancer Gene Ther., 16 (2009),pp. 723-730
[123]	Young, J.D., Yao, S.Y., Baldwin, J.M. et al. The human concentrative and equilibrative nucleoside transporter families, SLC28 and SLC29 Mol. Aspects Med., 34 (2013),pp. 529-547
[124]	Zhang, N., Dong, X., Sun, Y. et al. Oncology Rep., 29 (2013),pp. 960-966
[125]	Zhang, N., Zhao, L., Ma, S. et al. Int. J. Mol. Med., 30 (2012),pp. 659-665
[126]	Zhang, N.Q., Zhao, L., Ma, S. et al. Asian Pacific J. Cancer Prev., 13 (2012),pp. 2121-2127
[127]	Zhang, Y., Morar, M., Ealick, S.E. Structural biology of the purine biosynthetic pathway Cell. Mol. Life Sci., 65 (2008),pp. 3699-3724
[128]	Zhang, Y., , Ealick, S.E. The structure of human deoxycytidine kinase in complex with clofarabine reveals key interactions for prodrug activation Acta Crystallogr. D Biol. Crystallogr., 62 (2006),pp. 133-139
[129]	Zhu, Z., Ma, S., Zhao, L. et al. Int. J. Oncol., 38 (2011),pp. 745-753
[130]	Zhu, Z., Mao, L., Zhao, L. et al. Cancer Biol. Ther., 11 (2011),pp. 874-882