Experimental and Structural Evidence that Herpes 1 Kinase and Cellular DNA Polymerase(s) Discriminate on the Basis of Sugar Pucker

Victor E. Marquez, Tsipi Ben-Kasus, Joseph J. Barchi, Karen M. Green, Marc C. Nicklaus, Riad Agbaria

Research output: Contribution to journalArticlepeer-review

86 Scopus citations

Abstract

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).

Original languageEnglish
Pages (from-to)543-549
Number of pages7
JournalJournal of the American Chemical Society
Volume126
Issue number2
DOIs
StatePublished - 21 Jan 2004

ASJC Scopus subject areas

  • Catalysis
  • Chemistry (all)
  • Biochemistry
  • Colloid and Surface Chemistry

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