Journal Article

Enantioselectivity of human AMP, dTMP and UMP-CMP kinases

Julie A.C. Alexandre, Béatrice Roy, Dimitri Topalis, Sylvie Pochet, Christian Périgaud and Dominique Deville-Bonne

in Nucleic Acids Research

Volume 35, issue 14, pages 4895-4904
Published in print July 2007 | ISSN: 0305-1048
Published online July 2007 | e-ISSN: 1362-4962 | DOI: http://dx.doi.org/10.1093/nar/gkm479
Enantioselectivity of human AMP, dTMP and UMP-CMP kinases

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l-Nucleoside analogues such as lamivudine are active for treating viral infections. Like d-nucleosides, the biological activity of the l-enantiomers requires their stepwise phosphorylation by cellular or viral kinases to give the triphosphate. The enantioselectivity of NMP kinases has not been thoroughly studied, unlike that of deoxyribonucleoside kinases. We have therefore investigated the capacity of l-enantiomers of some natural (d)NMP to act as substrates for the recombinant forms of human uridylate-cytidylate kinase, thymidylate kinase and adenylate kinases 1 and 2. Both cytosolic and mitochondrial adenylate kinases were strictly enantioselective, as they phosphorylated only d-(d)AMP. l-dTMP was a substrate for thymidylate kinase, but with an efficiency 150-fold less than d-dTMP. Both l-dUMP and l-(d)CMP were phosphorylated by UMP-CMP kinase although much less efficiently than their natural counterparts. The stereopreference was conserved with the 2-azido derivatives of dUMP and dUMP while, unexpectedly, the 2-azido-d-dCMP was a 4-fold better substrate for UMP-CMP kinase than was CMP. Docking simulations showed that the small differences in the binding of d-(d)NMP to their respective kinases could account for the differences in interactions of the l-isomers with the enzymes. This in vitro information was then used to develop the in vivo activation pathway for l-dT.

Journal Article.  5846 words.  Illustrated.

Subjects: Chemistry ; Biochemistry ; Bioinformatics and Computational Biology ; Genetics and Genomics ; Molecular and Cell Biology

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