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DOI: 10.1039/A901233H (Paper) Reference Section for: Chem. Commun., 1999, 743-744

Why is the antiviral nucleotide analogue 9-[2-(phosphonomethoxy)ethyl]adenine in its diphosphorylated form (PMEApp4–) initially a better substrate for polymerases than (2′-deoxy)adenosine 5′-triphosphate (dATP4–/ATP4–)? Considerations on the mechanism of nucleic acid polymerases

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Helmut Sigel, Bin Song, Claudia A. Blindauer, Larisa E. Kapinos, Fridrich Gregáň and Nadja Prónayová

Abstract

The observation that the antivirally active PMEA in its diphosphorylated form (PMEApp4–) is initially a better substrate for polymerases than dATP4– (ATP4–) can be rationalized by (i) the increased basicity of the phosphonyl group (compared to a phosphoryl group) and (ii) the participation of the ether O atom of PMEApp4– in metal ion binding; both effects together favor M2+ binding at the α group and thus its nucleophilic attack.

References

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  17. Estimated value; see ref. 15a.
  18. It may be added that PMEApp is a poorer substrate than ATP for ATPases4 and this agrees with the above conclusions because for ATPases, like for kinases,7,8 a M(α,β)–M(γ)-like coordination is desirable. Clearly, M(α,β) binding of M2+ will be somewhat inhibited by the five-membered chelate formed with the a group and the ether O atom.
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