Human thymidine kinases

Use of these programs is documented in a multitude of publications trying to predict biological activity of compounds modulating the human carbonic anhy-drase [9, 10], G protein-coupled receptors (GPCRs) [10, 13, 25, 27, 30, 31], varicella-zoster virus and human thymidine kinases [32], cytochrome P-450-depen-dent lanosterol 14a-demethylase (P45014DM) [33], a sweet taste receptor [34], / -tubulin [35], ion channels [28, 36, 37] and others. 

A new series of 5-carboranyl-substituted-2 -deoxyuridine (25a) and deoxy-thymidine (25b) derivatives containing a range of alkyl spacers has been prepared to access a more effective use of boron neutron capture therapy. Evaluation of these derivatives as substrates for the human thymidine kinases TKl and TK2 showed that a decrease in the length of the spacer (from 8 methylene units to 4) between the carborane moiety and the pyrimidine base resulted in better substrate characteristics. 

Nucleotide bases (Fig. 7.16) have been derivatized by use of electrophilic organoiron complexes. The carbonyliron adducts 37 and 38 are typical examples [98]. A recent development in this field has led to the synthesis [99] of an extensive set of stmctures, including 39 which more closely resembles a nucleoside. The thymidine derivative 40 is an inhibitor of human thymidine kinase [100]. In the case of 41, the carbonylmetal component is attached at the heterocyclic base [101]. The carbonylmetal component can also be attached to dinucleotides by coordination at a phosphite, placed (as in 42) where the phosphate link would normally join the ribose rings [102]. The attachment of carbonylmetal labels to oligonucleotides for analysis by FTIR has also been described. The succini-midyl-based delivery strategy is the same as that used with proteins, as a... 

Shields AP, Grierson JR, Dohmen BM, MachuUa HJ, Stayanoff JC, Lawhom-Crews JM, Obradovich JE, Muzik O, Mangner TJ. Imaging proliferation in vivo with [E-18]ELT and positron emission tomography. Nat Med 1998 4 1334-1336. Sherley JL, Kelly TJ. Regulation of human thymidine kinase during the cell cycle. J Biol Chem 1988 263 8350-8358. 

McDougall, J. K., Kucherlapati, R., and Ruddle, F. H., 1973, Localization and induction of the human thymidine kinase gene by adenovirus type 12, Nature New Biol. 245 172. 

Al-Madhoun, A. S., Johnsamuel, J., Barth, R. F., Tjarks, W., and Eriksson, S. 2004. Evaluation of human thymidine kinase 1 substrates as new candidates for boron neutron capture therapy. Cancer Res., 64, 6280-86. 

Comparison of the substrate specificities of human thymidine kinase 1 and 2 and deoxycytidine kinase toward antiviral and cytostatic nucleoside analogues,... 

FIAC also strongly inhibits HCMV and Epstein-Barr vims (EBV) in vitro the two vimses known not to induce a specific viral thymidine kinase for their repHcation. However, HCMV may stimulate cellular kinases that can anabolize FIAC to its 5 -triphosphate, which specifically inhibits the HCMV-encoded DNA polymerase. This selective activity suggests that FIAC should be evaluated against HCMV infections. FIAC-ttiphosphate incorporated into DNA has shown strong in vitro activity against the DNA polymerases of human hepatitis B vims (HBV) and of woodchuck hepatitis vims (WHV) (37). 

The 2 -chloro and 2 -bromo congeners of either 748 (FIAC) or 758 (FMAU) are more cytotoxic than FIAC and FMAU, suggesting that these chloro and bromo nucleosides, in contrast to the 2 -fluoro compounds, are comparatively better substrates for deoxycytidine kinase of human lymphocytes than the substrates for viral-specific thymidine kinase. The disposition of the 2 -fluoro group may also be important from the biological viewpoint. It should be noted that the structural difference between RNA and DNA is at the 2 -position. The ribo type of analog (738) of FIAC is 10 times less effective in suppression of HSV replication than is FIAC. Thus Fox, and Watanabe and coworkers concluded that the 2 - up fluorine disposition and the species of the substituent at C-5 are the two important factors influencing antiviral activity. Nevertheless, the mechanism of action of 2 -deoxy-2 -fluorocytidine (737) on certain herpes viruses, including HSV-1... 

Mutagenesis Entacapone was mutagenic and clastogenic in the in vitro mouse lymphoma/thymidine kinase assay in the presence and absence of metabolic activation, and was clastogenic in cultured human lymphocytes in the presence of metabolic activation. 

The mouse lymphoma assay is in fact just one of several mammalian cell assays designed to determine increases in mutation rate. It focuses on the thymidine kinase (tk) assay in murine lymphoma cells (L5178Y), though tk data have also been produced from the human lymphoblastoid cell line TK6, and at the hgprt (hypox-anthine-guanine phosphoribosyl-transferase) locus in Chinese Hamster ovary or lung (V79) cells and mouse lymphoma cells. Since Ames mutation data and often... 

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)... 

Few pyrimidine bases are salvaged in human cells. However, the pyrimidine nucleosides uridine and cytidine can be salvaged by uri-dine-cytidine kinase, deoxycytidine can be salvaged by deoxycytidine kinase, and thymidine can be salvaged by the enzyme thymidine kinase. Each of these enzymes catalyzes the phosphorylation of a nucleoside(s) utilizing ATP, and forming UMP, CMP, dCMP, and TMP. 

Wagner, E.F., Stewart, TA., and Mintz, B. (1981) The human fi-globin gene and a functional viral thymidine kinase gene in developing mice. Proc. Natl. Acad. Sci. USA 78, 5016-5020. 

The liposome can enclose DNA less than 100 kb, although the trapping efficiency was 10-20% of added DNA amounts. We succeeded in transducing cultured mouse cells by introduction of a 45-kb plasmid containing the thymidine kinase gene [9], Recently, the full-length cDNA of human dystrophyn was introduced and expressed in the skeletal muscle and diaphragm of the mdx mouse [10]. 

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