Experimental and Structural Evidence that Herpes 1 Kinase and Cellular DNA Polymerase(s) Discriminate on the Basis of Sugar Pucker
Two isomers of methanocarba (MC) thymidine (T), one an effective antiherpes agent with the pseudosugar moiety locked in the North (N) hemisphere of the pseudorotational cycle (1a, N-MCT) and the other an inactive isomer locked in the antipodean South (S) conformation (1b, S-MCT) were used to determi...
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Published in | Journal of the American Chemical Society Vol. 126; no. 2; pp. 543 - 549 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
Washington, DC
American Chemical Society
21.01.2004
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Subjects | |
Online Access | Get full text |
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Summary: | Two isomers of methanocarba (MC) thymidine (T), one an effective antiherpes agent with the pseudosugar moiety locked in the North (N) hemisphere of the pseudorotational cycle (1a, N-MCT) and the other an inactive isomer locked in the antipodean South (S) conformation (1b, S-MCT) were used to determine whether kinases and polymerases discriminate between their substrates on the basis of sugar conformation. A combined solid-state and solution conformational analysis of both compounds, coupled with the direct measurement of mono-, di-, and triphosphate levels in control cells, cells infected with the Herpes simplex virus, or cells transfected with the corresponding viral kinase gene (HSV-tk), suggests that kinases prefer substrates that adopt the S sugar conformation. On the other hand, the cellular DNA polymerase(s) of a murine tumor cell line transfected with HSV-tk incorporated almost exclusively the triphosphate of the locked N conformer (N-MCTTP), notwithstanding the presence of higher triphosphate levels of the S-conformer (S-MCTTP). |
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Bibliography: | istex:4C20F3325275CDEC2E0F97FE59DABED53D4B7D37 ark:/67375/TPS-9DZ7WJH8-3 ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2 |
ISSN: | 0002-7863 1520-5126 |
DOI: | 10.1021/ja037929e |