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

Abstract

The observation that the antivirally active PMEA in its diphosphorylated form (PMEApp^4–) is initially a better substrate for polymerases than dATP^4– (ATP^4–) 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 PMEApp^4– in metal ion binding; both effects together favor M²⁺ binding at the α group and thus its nucleophilic attack.