Document Detail


Stereoisomeric selectivity of human deoxyribonucleoside kinases.
MedLine Citation:
PMID:  10606535     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
J Wang; D Choudhury; J Chattopadhyaya; S Eriksson
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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    
Affiliation:
Department of Veterinary Medical Chemistry, Swedish University of Agricultural Sciences, The Biomedical Centre, Uppsala.
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MeSH Terms
Descriptor/Qualifier:
Binding Sites
Computer Simulation
Deoxyribonucleosides / chemistry,  metabolism
Herpesvirus 1, Human / enzymology
Humans
Kinetics
Models, Molecular
Phosphorylation
Phosphotransferases (Alcohol Group Acceptor) / chemistry*,  metabolism*
Stereoisomerism
Substrate Specificity
Thymidine / chemistry,  metabolism
Thymidine Kinase / chemistry,  metabolism
Chemical
Reg. No./Substance:
0/Deoxyribonucleosides; 50-89-5/Thymidine; EC 2.7.1.-/Phosphotransferases (Alcohol Group Acceptor); EC 2.7.1.-/deoxyribonucleoside kinases; EC 2.7.1.21/Thymidine Kinase

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


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