Metal ion-binding properties of the antiviral nucleotide analogue 9-[2-(phosphonomethoxy)ethyl] adenine (PMEA). Why is its diphosphorylated form, PMEApp~(4-), initially a better substrate for nucleic acid polymerases than (2'-deoxy)adenosine 5'-triph

摘要

The metal ion-coordinating properties (Mg~(2+), Mn~(2+), Zn~(2+), etc. = M~(2+)) are summarized for (i) the dianion of 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA~(2-) = adenine (9)-CH_2CH_2-O-CH_2-PO_3~(2-)) and (ii) methylphosphonylphosphate (MePP~(3-) = CH_3P(O)_2~-O-PO_3~(2-)). The observed increased stability of the M(PMEA) complexes is mostly due to the formation of five-membered chelates involving the ether oxygen of the CH_2-O-CH_2-PO_3~(2-) residue; with some metal ions (Ni~(2+), Cu~(2+)) in addition an interaction with N3 of the adenine residue occure. The M(MePP)~- complexes are also somewhat more stable than those of diphosphate monoesters, like methyl diphosphate, because of the enhanced basicity of the phosphonyl unit. These two observations provide an explanation for the fact that diphosphorylated PMEA~(2-), an analogue of (d)ATP~(4-), is initially a better substrate for several nucleic acid polymerases than dATP~(4-). The higher basicity of the phosphonyl group and the formation of the five-membered chelates favor PMEA_(pp)~(4-) over dATP~(4-) because they facilitate the M(#alpha#)-M(#bate#,#gamma#) coordination pattern meeded for the enzyme-catalyzed incorporation of the substrate in the growing nucleic acid chain.