Thymidylate kinase

Entecavir, telbivudine, clevudine, and the other nucleoside analogues (Fig. 4aa) need to be phosphorylated to their 5 -triphosphate form to be antivirally active (Fig. 8). This again implies three phosphorylation steps based successively on a nucleoside kinase, nucleoside 5 -monophosphate kinase, and nucleoside 5 -diphosphate kinase. These reactions have been characterized only in a few cases, that is, thymidylate kinase in the metabolism of clevudine (Hu et al. 2005). 

Deoxy-5 -fluorothymidine (838) was prepared by Langen and Kowol-jj. 796,797 fpQjyj 5 -0-tosyl precursor by treatment with fluoride. Compound 838 cannot be phosphorylated enzymically owing to the lack of OH-5, but it inhibits the growth of carcinoma cells. This was explained as follows the thymidine 5 -monophosphate (thymidylate) kinase in carcinoma cells, catalyzing the transformation of thymidine 5 -monophosphate into the diphosphate, is inhibited by 838, thus preventing the synthesis of... 

Figure 7.4 Illustration of the Elastic Network Model for thymidylate kinase (cut-off = 8 Angstroms).

Acyclovir (9.9) shows a unique specificity and lack of toxicity in HSV-1, HSV-2, and varicella (chickenpox, shingles) viral infections. A guanine derivative, acyclovir lacks the pentose of similar compounds and is phosphorylated at the alcoholic OH by the viral thymidylate kinase only. Consequently, it is not activated in uninfected cells additionally. 

Additional information <3> (<3> thymidylate kinase is the product of the CDC8 gene [12]) [12]... 

Tamiya, N. Yusa, T. Yamaguchi, Y Tsukifuji, R. Kuroiwa, N. Moriyama, Y. Fujimura, S. Co-purification of thymidylate kinase and cytosolic thymidine kinase from human term placenta by affinity chromatography. Biochim. Biophys. Acta, 995, 28-35 (1989)... 

Bone, R. Cheng, Y.C. Wolfenden, R. Inhibition of adenosine and thymidylate kinases by bisubstrate analogs. J. Biol. Chem., 261, 16410-16413 (1986)... 

Jong, A.Y.S. Campbell, J.L. Characterization of Saccharomyces cerevisiae thymidylate kinase, the CDC8 gene product. General properties, kinetic analysis, and subcellular localization. J. Biol. Chem., 259, 14394-14398 (1984)... 

Chen, M.C. Walker, J. Prusoff, W.H. Kinetic studies of herpes simplex virus type 1-encoded thymidine and thymidylate kinase, a multifunctional enzyme. J. Biol. Chem., 254, 10747-10753 (1979)... 

Smith, L.K. Eakin, R.E. Partial purification and characterization of thymidylate kinase from embryonic chick liver. Arch. Biochem. Biophys., 167, 61-71 (1975)... 

Cheng, Y.C. Prusoff, W.H. Mouse ascites sarcoma 180 thymidylate kinase. General properties, kinetic analysis, and inhibition studies. Biochemistry, 12, 2612-2619 (1973)... 

Ostermann, N. Segura-Pena, D. Meier, C. Veit, T. Monnerjahn, C. Konrad, M. Lavie, A. Structures of human thymidylate kinase in complex with prodrugs implications for the structure-based design of novel compounds. Biochemistry, 42, 2568-2577 (2003)... 

Petit, C.M. Koretke, K.K. Characterization of Streptococcus pneumoniae thymidylate kinase steady-state kinetics of the forward reaction and isothermal titration calorimetry. Biochem. J., 363, 825-831 (2002)... 

Fioravanti, E. Haouz, A. Ursby, T. Munier-Lehmann, H. Delarue, M. Bourgeois, D. Mycobacterium tuberculosis thymidylate kinase structural studies of intermediates along the reaction pathway. J. Mol. Biol., 327, 1077-1092 (2003)... 

Jacobsson, B. Britton, S. Tornevik, Y. Eriksson, S. Decreas in thymidylate kinase activity in peripheral blood mononuclear cells from HIV-infected individuals. Biochem. Pharmacol., 56, 389-395 (1998)... 

Munier-lehmann, H. Chaffotte, A. Pochet, S. Labesse, G. Thymidylate kinase of Mycobacterium tuberculosis a chimera sharing properties common to eukaryotic and bacterial enzymes. Protein Sci., 10, 1195-1205 (2001)... 

T. Goody, R.S. Lavie, A. Insights into the phosphoryltransfer mechanism of human thymidylate kinase gained from crystal structures of enzyme complexes along the reaction coordinate. Structure, 8, 629-642 (2000)... 

AZTTP on DNA polymerase of the host cell is much weaker. The effect of AZT is further increased by the accumulation of considerable amounts of AZTMP in cells. This monophosphate inhibits thymidylate kinase, with a consequent decrease in the concentration of dTTP in the cell. With less competition from dTTP there is more efficient incorporation of AZTTP into viral DNA by the reverse transcriptase. 2, 3 -Dideoxyinosine (ddl) is under trial for use against AIDS and is similarly incorporated into viral DNA by the reverse transcriptase with chain termination. 

Figure 2.4 Catabolism of a known inhibitor of thymidylate kinases (A) into component parts A1, A2 and A3.

P. falciparum Thymidylate Kinase (PfTMK). PfTMK is involved in nucleotide synthesis in the parasite. As nucleotide synthesis pathways are indispensable for most organisms, it has been proposed... 

Kandeel M, Kitade Y (2008) Molecular characterization, heterologous expression and kinetic analysis of recombinant Plasmodium falciparum thymidylate kinase. J Biochem 144(2/245-250... 

Thymidylate kinase the lost chemotherapeutic target. Nucleic Acids Symp Ser (Oxf) 53 283-284... 

The inhibitory action of the antifolates may be reversed either by changing the medium (Adams, 1969a, b), or more conveniently by additions of thymidine to the medium when dTTP is synthesised using the enzymes thymidine and thymidylate kinase (see Fig. 11.7). 

Cells that have been preincubated with deoxyuridine, then exposed to [ H] thymidine, incorporate little or none of the labeled material into DNA. This is because of both dilution of the labeled material in the larger intracellular pool of newly synthesized TMP and also inhibition of thymidylate kinase by thymidine triphosphate. 

Antiviral Thymidine kinase and thymidylate kinase Idoxuridine... 

---