Document Detail

Stereoisomeric selectivity of human deoxyribonucleoside kinases.
MedLine Citation:
PMID:  10606535     Owner:  NLM     Status:  MEDLINE    
Deoxynucleoside kinases catalyze the 5'-phosphorylation of 2'-deoxyribonucleosides with nucleoside triphosphates as phosphate donors. One of the cellular kinases, deoxycytidine kinase (dCK), has been shown to phosphorylate several L-nucleosides that are efficient antiviral agents. In this study we investigated the potentials of stereoisomers of the natural deoxyribonucleoside to serve as substrates for the recombinant cellular deoxynucleoside kinases. The cytosolic thymidine kinase exhibited a strict selectivity and phosphorylated only beta-D-Thd, while the mitochondrial thymidine kinase (TK2) and deoxyguanosine kinase (dGK) as well as dCK all had broad substrate specificities. TK2 phosphorylated Thd and dCyd stereoisomers in the order: beta-D- > or = beta-L- >> alpha-D- > or = alpha-L-isomer. dCK activated both enantiomers of beta-dCyd, beta-dGuo, and beta-dAdo with similar efficiencies, and alpha-D-dCyd also served as a substrate. dGK phosphorylated the beta-dGuo enantiomers with no preference for the ribose configuration; alpha-L-dGuo was also phosphorylated, and beta-L-dAdo and beta-L-dCyd were substrates but showed reduced efficiencies. The anomers of the 2',3'-dideoxy-D-nucleosides (ddNs) were tested, and TK2 and dCK retained their low selectivities. Unexpectedly, alpha-dideoxycytidine (ddC) was a 3-fold better substrate for dCK than beta-ddC. Similarly, alpha-dideoxythymidine (ddT) was a better substrate for TK2 than beta-ddT. dGK did not accept any D-ddNs. Thus, TK2, dCK, and dGK, similar to herpes simplex virus type 1 thymidine kinase (HSV-1 TK), showed relaxed stereoselectivities, and these results substantiate the functional similarities within this enzyme family. Docking simulations with the Thd isomers and the active site of HSV-1 TK showed that the viral enzyme may in some respects serve as a model for studying the substrate specificities of the cellular enzymes.
J Wang; D Choudhury; J Chattopadhyaya; S Eriksson
Related Documents :
8245015 - A serine phosphorylation of nm23, and not its nucleoside diphosphate kinase activity, c...
25064455 - Heterozygous mutations in cyclic amp phosphodiesterase-4d (pde4d) and protein kinase a ...
15628745 - Phosphorylation of isocarbostyril- and difluorophenyl-nucleoside thymidine mimics by th...
10530775 - Inhibitory activity of nm23-h1 on invasion and colonization of human prostate carcinoma...
15044155 - Estrogen increases retrograde labeling of motoneurons: evidence of a nongenomic mechanism.
11822875 - Ap-1 transcription factor complex is a target of signals from both wnt-7a and n-cadheri...
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Biochemistry     Volume:  38     ISSN:  0006-2960     ISO Abbreviation:  Biochemistry     Publication Date:  1999 Dec 
Date Detail:
Created Date:  2000-01-19     Completed Date:  2000-01-19     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0370623     Medline TA:  Biochemistry     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  16993-9     Citation Subset:  IM    
Department of Veterinary Medical Chemistry, Swedish University of Agricultural Sciences, The Biomedical Centre, Uppsala.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Binding Sites
Computer Simulation
Deoxyribonucleosides / chemistry,  metabolism
Herpesvirus 1, Human / enzymology
Models, Molecular
Phosphotransferases (Alcohol Group Acceptor) / chemistry*,  metabolism*
Substrate Specificity
Thymidine / chemistry,  metabolism
Thymidine Kinase / chemistry,  metabolism
Reg. No./Substance:
0/Deoxyribonucleosides; 50-89-5/Thymidine; EC 2.7.1.-/Phosphotransferases (Alcohol Group Acceptor); EC 2.7.1.-/deoxyribonucleoside kinases; EC Kinase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Previous Document:  A functional spliced-variant of beta 2 subunit of Kv1 channels in C6 glioma cells and reactive astro...
Next Document:  Current knowledge of soft cheeses flavor and related compounds.