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Deoxyribonucleotide Kinases

Analysis of genes and enzymes involved in metabolism of nucleic acids precursors

Deoxyribonucleoside kinases

Deoxyribonucleoside kinases catalyse the phosphorylation of deoxyribonucleosides (dN) to the corresponding deoxyribonucleoside monophosphates (dNMP). They are the key enzymes in the salvage of deoxyribonucleosides originating extracellularly or from intracellular breakdown of DNA. Subsequently, dNMPs are phosphorylated into diphosphates (dNDP) and triphosphates (dNTP), which are direct precursors of DNA. In humans, the salvage pathway is extremely important for activation of several antiviral and anti-cancer drugs. Apparently, the salvage pathways in other animals and in plants have a similar potential, to activate biocides and drugs. However, this potential has so far not been exploited. Deoxyribonucleoside kinases exhibit a great diversity among the analysed organisms. Mammals have four deoxyribonucleoside kinases with overlapping specificities: cytoplasmic thymidine kinase 1 (TK1) phosphorylates only thymidine; mitochondrial thymidine kinase 2 (TK2) phosphorylates thymidine and deoxycytidine; cytoplasmic deoxycytidine kinase (dCK) phosphorylates deoxyadenosine, deoxyguanosine and deoxycytidine; and mitochondrial deoxyguanosine kinase (dGK) phosphorylates only the purine dNs, deoxyadenosine and deoxyguanosine. The situation in other vertebrates is less understood. In insects, our group has discovered that there is only one deoxyribonucleoside kinase, (DmdNK), capable of phosphorylating all four natural substrates.

Deoxiribonukleoside kinase from Drosophila

The structure of the ultra-fast Drosophila deoxyribonucleoside kinase (DmdNK). This dimeric enzyme can phosphorylate a wide range of substrates and has been isolated and characterized in our laboratory. It has a number of interesting properties which are now applied in the enzymatic synthesis of several nucleoside monophosphate analogs and in anti-cancer gene-therapy, using the kinase gene as a suicide gene.

The 3D structure of this enzyme, a dimer, has been determined by laboratories in Uppsala and Roskilde in collaboration with our group and has become the model to understand the structure-function relationship among other kinases, including the human ones.

To study the evolution, diversity and practical use of deoxyribonucleoside kinase, our group has and is currently studying deoxyribonucleoside kinases from bacteria, insects, plants, amphibians and birds.

Relevant publications from our group

1. Larsen, N. B., Munch-Petersen, B. & Piskur, J. (2014) Tomato Thymidine Kinase Is Subject to Inefficient TTP Feedback Regulation, Nucleosides, nucleotides & nucleic acids. 33, 287-90.

2. Konrad, A., Lai, J., Mutahir, Z., Piskur, J. & Liberles, D. A. (2014) The phylogenetic distribution and evolution of enzymes within the thymidine kinase 2-like gene family in metazoa, Journal of molecular evolution. 78, 202-16.

3. Clausen, A. R., Mutahir, Z., Munch-Petersen, B. & Piskur, J. (2014) Plants salvage deoxyribonucleosides in mitochondria, Nucleosides, nucleotides & nucleic acids. 33, 291-5.

4. Andersson Rasmussen, A., Kandasamy, D., Beck, H., Crosby, S. D., Bjornberg, O., Schnackerz, K. D. & Piskur, J. (2014) Global expression analysis of the yeast Lachancea (Saccharomyces) kluyveri reveals new URC genes involved in pyrimidine catabolism, Eukaryotic cell. 13, 31-42.

5. Mutahir, Z., Clausen, A. R., Andersson, K. M., Wisen, S. M., Munch-Petersen, B. & Piskur, J. (2013) Thymidine kinase 1 regulatory fine-tuning through tetramer formation, The FEBS journal. 280, 1531-41.

6. Tinta, T., Christiansen, L. S., Konrad, A., Liberles, D. A., Turk, V., Munch-Petersen, B., Piskur, J. & Clausen, A. R. (2012) Deoxyribonucleoside kinases in two aquatic bacteria with high specificity for thymidine and deoxyadenosine, FEMS microbiology letters. 331, 120-7.

7. Konrad, A., Yarunova, E., Tinta, T., Piskur, J. & Liberles, D. A. (2012) The global distribution and evolution of deoxyribonucleoside kinases in bacteria, Gene. 492, 117-20.

8. Konrad, A., Piskur, J. & Liberles, D. A. (2012) The evolution of catalytic residues and enzyme mechanism within the bacterial nucleoside phosphorylase superfamily 1, Gene. 510, 154-61.

9. Clausen, A. R., Girandon, L., Ali, A., Knecht, W., Rozpedowska, E., Sandrini, M. P., Andreasson, E., Munch-Petersen, B. & Piskur, J. (2012) Two thymidine kinases and one multisubstrate deoxyribonucleoside kinase salvage DNA precursors in Arabidopsis thaliana, The FEBS journal. 279, 3889-97.

10. Tran, T. H., Christoffersen, S., Allan, P. W., Parker, W. B., Piskur, J., Serra, I., Terreni, M. & Ealick, S. E. (2011) The crystal structure of Streptococcus pyogenes uridine phosphorylase reveals a distinct subfamily of nucleoside phosphorylases, Biochemistry. 50, 6549-58.

11. Rasmussen, A., Lv, Y., Schnackerz, K. D. & Piskur, J. (2011) A new expression vector for production of enzymes in the yeast Saccharomyces (Lachancea) kluyveri, Nucleosides, nucleotides & nucleic acids. 30, 1227-32.

12. Mutahir, Z., Larsen, N. B., Christiansen, L. S., Andersson, K. M., Rico, R., Wisen, S. M., Clausen, A. R., Munch-Petersen, B. & Piskur, J. (2011) Characterization of oligomeric and kinetic properties of tomato thymidine kinase 1, Nucleosides, nucleotides & nucleic acids. 30, 1223-6.

13. Khan, Z., Knecht, W., Willer, M., Rozpedowska, E., Kristoffersen, P., Clausen, A. R., Munch-Petersen, B., Almqvist, P. M., Gojkovic, Z., Piskur, J. & Ekstrom, T. J. (2010) Plant thymidine kinase 1: a novel efficient suicide gene for malignant glioma therapy, Neuro-oncology. 12, 549-58.

14. Clausen, A. R., Al Meani, S. A. & Piskur, J. (2010) Pasteurella multocida thymidine kinase 1 efficiently activates pyrimidine nucleoside analogs, Nucleosides, nucleotides & nucleic acids. 29, 359-62.

15. Christoffersen, S., Serra, I., Terreni, M. & Piskur, J. (2010) Nucleoside phosphorylases from clostridium perfringens in the synthesis of 2',3'-dideoxyinosine, Nucleosides, nucleotides & nucleic acids. 29, 445-8.

16. Bjornberg, O., Vodnala, M., Domkin, V., Hofer, A., Rasmussen, A., Andersen, G. & Piskur, J. (2010) Ribosylurea accumulates in yeast urc4 mutants, Nucleosides, nucleotides & nucleic acids. 29, 433-7.

17. Knecht, W., Mikkelsen, N. E., Clausen, A. R., Willer, M., Eklund, H., Gojkovic, Z. & Piskur, J. (2009) Drosophila melanogaster deoxyribonucleoside kinase activates gemcitabine, Biochemical and biophysical research communications. 382, 430-3.

18. Hebrard, C., Cros-Perrial, E., Clausen, A. R., Dumontet, C., Piskur, J. & Jordheim, L. P. (2009) Bacterial deoxyribonucleoside kinases are poor suicide genes in mammalian cells, Nucleosides, nucleotides & nucleic acids. 28, 1068-75.

19. Schnackerz, K. D., Andersen, G., Dobritzsch, D. & Piskur, J. (2008) Degradation of pyrimidines in Saccharomyces kluyveri: transamination of beta-alanine, Nucleosides, nucleotides & nucleic acids. 27, 794-9.

20. Lundgren, S., Lohkamp, B., Andersen, B., Piskur, J. & Dobritzsch, D. (2008) The crystal structure of beta-alanine synthase from Drosophila melanogaster reveals a homooctameric helical turn-like assembly, Journal of molecular biology. 377, 1544-59.

21. Clausen, A. R., Girandon, L., Knecht, W., Survery, S., Andreasson, E., Munch-Petersen, B. & Piskur, J. (2008) A multisubstrate deoxyribonucleoside kinase from plants, Nucleic acids symposium series (2004), 489-90.

22. Beck, H., Dobritzsch, D. & Piskur, J. (2008) Saccharomyces kluyveri as a model organism to study pyrimidine degradation, FEMS yeast research. 8, 1209-13.

23. Andersen, G., Bjornberg, O., Polakova, S., Pynyaha, Y., Rasmussen, A., Moller, K., Hofer, A., Moritz, T., Sandrini, M. P., Merico, A. M., Compagno, C., Akerlund, H. E., Gojkovic, Z. & Piskur, J. (2008) A second pathway to degrade pyrimidine nucleic acid precursors in eukaryotes, Journal of molecular biology. 380, 656-66.

24. Andersen, B., Lundgren, S., Dobritzsch, D. & Piskur, J. (2008) A recruited protease is involved in catabolism of pyrimidines, Journal of molecular biology. 379, 243-50.

25. Sandrini, M. P., Soderbom, F., Mikkelsen, N. E. & Piskur, J. (2007) Dictyostelium discoideum salvages purine deoxyribonucleosides by highly specific bacterial-like deoxyribonucleoside kinases, Journal of molecular biology. 369, 653-64.

26 Sandrini, M. P., Shannon, O., Clausen, A. R., Bjorck, L. & Piskur, J. (2007) Deoxyribonucleoside kinases activate nucleoside antibiotics in severely pathogenic bacteria, Antimicrobial agents and chemotherapy. 51, 2726-32.

27. Sandrini, M. P., Clausen, A. R., On, S. L., Aarestrup, F. M., Munch-Petersen, B. & Piskur, J. (2007) Nucleoside analogues are activated by bacterial deoxyribonucleoside kinases in a species-specific manner, The Journal of antimicrobial chemotherapy. 60, 510-20.

28. Piskur, J., Schnackerz, K. D., Andersen, G. & Bjornberg, O. (2007) Comparative genomics reveals novel biochemical pathways, Trends in genetics : TIG. 23, 369-72.

29. Lundgren, S., Andersen, B., Piskur, J. & Dobritzsch, D. (2007) Crystallization and preliminary X-ray data analysis of beta-alanine synthase from Drosophila melanogaster, Acta crystallographica Section F, Structural biology and crystallization communications. 63, 874-7.

30.  Lundgren, S., Andersen, B., Piskur, J. & Dobritzsch, D. (2007) Crystal structures of yeast beta-alanine synthase complexes reveal the mode of substrate binding and large scale domain closure movements, The Journal of biological chemistry. 282, 36037-47.

31. Kosinska, U., Carnrot, C., Sandrini, M. P., Clausen, A. R., Wang, L., Piskur, J., Eriksson, S. & Eklund, H. (2007) Structural studies of thymidine kinases from Bacillus anthracis and Bacillus cereus provide insights into quaternary structure and conformational changes upon substrate binding, The FEBS journal. 274, 727-37.

32. Knecht, W., Rozpedowska, E., Le Breton, C., Willer, M., Gojkovic, Z., Sandrini, M. P., Joergensen, T., Hasholt, L., Munch-Petersen, B. & Piskur, J. (2007) Drosophila deoxyribonucleoside kinase mutants with enhanced ability to phosphorylate purine analogs, Gene therapy. 14, 1278-86.

33. Andersen, G., Andersen, B., Dobritzsch, D., Schnackerz, K. D. & Piskur, J. (2007) A gene duplication led to specialized gamma-aminobutyrate and beta-alanine aminotransferase in yeast, The FEBS journal. 274, 1804-17.

34. Zameitat, E., Gojkovic, Z., Knecht, W., Piskur, J. & Loffler, M. (2006) Biochemical characterization of recombinant dihydroorotate dehydrogenase from the opportunistic pathogenic yeast Candida albicans, The FEBS journal. 273, 3183-91.

35. Sandrini, M. P., Clausen, A. R., Munch-Petersen, B. & Piskur, J. (2006) Thymidine kinase diversity in bacteria, Nucleosides, nucleotides & nucleic acids. 25, 1153-8.

36. Lohkamp, B., Andersen, B., Piskur, J. & Dobritzsch, D. (2006) Purification, crystallization and X-ray diffraction analysis of dihydropyrimidinase from Dictyostelium discoideum, Acta crystallographica Section F, Structural biology and crystallization communications. 62, 36-8.

37. Lohkamp, B., Andersen, B., Piskur, J. & Dobritzsch, D. (2006) The crystal structures of dihydropyrimidinases reaffirm the close relationship between cyclic amidohydrolases and explain their substrate specificity, The Journal of biological chemistry. 281, 13762-76.

38. Legent, K., Mas, M., Dutriaux, A., Bertrandy, S., Flagiello, D., Delanoue, R., Piskur, J. & Silber, J. (2006) In vivo analysis of Drosophila deoxyribonucleoside kinase function in cell cycle, cell survival and anti-cancer drugs resistance, Cell cycle (Georgetown, Tex). 5, 740-9.

39. Clausen, A. R., Matakos, A., Sandrini, M. P. & Piskur, J. (2006) Thymidine kinases in archaea, Nucleosides, nucleotides & nucleic acids. 25, 1159-63.

40. Andersen, G., Merico, A., Bjornberg, O., Andersen, B., Schnackerz, K. D., Dobritzsch, D., Piskur, J. & Compagno, C. (2006) Catabolism of pyrimidines in yeast: a tool to understand degradation of anticancer drugs, Nucleosides, nucleotides & nucleic acids. 25, 991-6.

41. Sandrini, M. P. & Piskur, J. (2005) Deoxyribonucleoside kinases: two enzyme families catalyze the same reaction, Trends in biochemical sciences. 30, 225-8.

42. Dobritzsch, D., Andersen, B. & Piskur, J. (2005) Crystallization and X-ray diffraction analysis of dihydropyrimidinase from Saccharomyces kluyveri, Acta crystallographica Section F, Structural biology and crystallization communications. 61, 359-62.

43. Zameitat, E., Knecht, W., Piskur, J. & Loffler, M. (2004) Two different dihydroorotate dehydrogenases from yeast Saccharomyces kluyveri, FEBS letters. 568, 129-34.

44. Piskur, J., Sandrini, M. P., Knecht, W. & Munch-Petersen, B. (2004) Animal deoxyribonucleoside kinases: 'forward' and 'retrograde' evolution of their substrate specificity, FEBS letters. 560, 3-6.

45. Gojkovic, Z., Knecht, W., Zameitat, E., Warneboldt, J., Coutelis, J. B., Pynyaha, Y., Neuveglise, C., Moller, K., Loffler, M. & Piskur, J. (2004) Horizontal gene transfer promoted evolution of the ability to propagate under anaerobic conditions in yeasts, Molecular genetics and genomics : MGG. 271, 387-93.

46. Vernis, L., Piskur, J. & Diffley, J. F. (2003) Reconstitution of an efficient thymidine salvage pathway in Saccharomyces cerevisiae, Nucleic acids research. 31, e120.

47. Mikkelsen, N. E., Johansson, K., Karlsson, A., Knecht, W., Andersen, G., Piskur, J., Munch-Petersen, B. & Eklund, H. (2003) Structural basis for feedback inhibition of the deoxyribonucleoside salvage pathway: studies of the Drosophila deoxyribonucleoside kinase, Biochemistry. 42, 5706-12.

48. Lundgren, S., Gojkovic, Z., Piskur, J. & Dobritzsch, D. (2003) Yeast beta-alanine synthase shares a structural scaffold and origin with dizinc-dependent exopeptidases, The Journal of biological chemistry. 278, 51851-62.

49. Knecht, W., Petersen, G. E., Sandrini, M. P., Sondergaard, L., Munch-Petersen, B. & Piskur, J. (2003) Mosquito has a single multisubstrate deoxyribonucleoside kinase characterized by unique substrate specificity, Nucleic acids research. 31, 1665-72.

50. Gojkovic, Z., Rislund, L., Andersen, B., Sandrini, M. P., Cook, P. F., Schnackerz, K. D. & Piskur, J. (2003) Dihydropyrimidine amidohydrolases and dihydroorotases share the same origin and several enzymatic properties, Nucleic acids research. 31, 1683-92.

51. Dobritzsch, D., Gojkovic, Z., Andersen, B. & Piskur, J. (2003) Crystallization and preliminary X-ray analysis of beta-alanine synthase from the yeast Saccharomyces kluyveri, Acta crystallographica Section D, Biological crystallography. 59, 1267-9.

52. Ullrich, A., Knecht, W., Piskur, J. & Loffler, M. (2002) Plant dihydroorotate dehydrogenase differs significantly in substrate specificity and inhibition from the animal enzymes, FEBS letters. 529, 346-50.

53. Knecht, W., Sandrini, M. P., Johansson, K., Eklund, H., Munch-Petersen, B. & Piskur, J. (2002) A few amino acid substitutions can convert deoxyribonucleoside kinase specificity from pyrimidines to purines, The EMBO journal. 21, 1873-80.

54. Knecht, W., Petersen, G. E., Munch-Petersen, B. & Piskur, J. (2002) Deoxyribonucleoside kinases belonging to the thymidine kinase 2 (TK2)-like group vary significantly in substrate specificity, kinetics and feed-back regulation, Journal of molecular biology. 315, 529-40.

55. Gojkovic, Z., Sandrini, M. P. & Piskur, J. (2001) Eukaryotic beta-alanine synthases are functionally related but have a high degree of structural diversity, Genetics. 158, 999-1011.

56. Munch-Petersen, B., Knecht, W., Lenz, C., Sondergaard, L. & Piskur, J. (2000) Functional expression of a multisubstrate deoxyribonucleoside kinase from Drosophila melanogaster and its C-terminal deletion mutants, The Journal of biological chemistry. 275, 6673-9.

57. Knecht, W., Munch-Petersen, B. & Piskur, J. (2000) Identification of residues involved in the specificity and regulation of the highly efficient multisubstrate deoxyribonucleoside kinase from Drosophila melanogaster, Journal of molecular biology. 301, 827-37.

58. Knecht, W., Munch-Petersen, B. & Piskur, J. (2000) Polyclonal antibodies against the ultrafast multisubstrate deoxyribonucleoside kinase from Drosophila melanogaster, Advances in experimental medicine and biology. 486, 263-6.

59. Munch-Petersen, B., Piskur, J. & Sondergaard, L. (1998) Four deoxynucleoside kinase activities from Drosophila melanogaster are contained within a single monomeric enzyme, a new multifunctional deoxynucleoside kinase, The Journal of biological chemistry. 273, 3926-31.

60. Munch-Petersen, B., Piskur, J. & Sondergaard, L. (1998) The single deoxynucleoside kinase in Drosophila melanogaster, Dm-dNK, is multifunctional and differs from the mammalian deoxynucleoside kinases, Advances in experimental medicine and biology. 431, 465-9.

61. Gojkovic, Z., Paracchini, S. & Piskur, J. (1998) A new model organism for studying the catabolism of pyrimidines and purines, Advances in experimental medicine and biology. 431, 475-9.

62. Piskur, J., Sondergaard, L., Gojkovic, Z., Stokbro, B., Hjulsager, C., Davidson, J., DeMoll, E., Rawls, J. & Bahn, E. (1994) Observed resistance to pyrimidine analogs and sensitivity to uracil in Drosophila is attributed to deregulation of pyrimidine metabolism, Advances in experimental medicine and biology. 370, 559-65.

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