Metal ion-assisted stacking interactions and the facilitated hydrolysis of nucleoside 5′-triphosphates

The self-association properties of the common nucleosides and nucleotides are summarized; if defined via their nucleobases they decrease in the order, adenine > guanine > hypoxanthine > cytosine greater than or similar to uracil. Next, some aspects of the metal ion-promoted dephosphorylation of nucleoside 5'-triphosphates (NTPs) are reviewed. It is shown that the dephosphorylation rate in the presence of Cu2+ decreases in the series, ATP > GTP > ITP > pyrimidine-NTPs. Similarly, addition of AMP, GMP or IMP (decreasing order of effectiveness) to a Cu2+/ATP system facilitates the dephosphorylation reaction further because one of the two ATPs in the stacked reactive intermediate, occurring in low concentration, [Cu-2(ATP)](2)(OH)(-), has a structural role and this 'enzyme'-like ATP(4-) can be replaced by one of the mentioned nucleoside 5'-monophosphates. These results demonstrate how weak interactions, i.e. aromatic-ring stacking, can govern the reactivity of a system. Next to stacking, the purine(N7)-metal ion interaction allowing bridging and stabilization of the stack by inclusion of the phosphate group(s) is important; therefore, addition of tubercidin 5'-monophosphate (= 7-deaza-AMP(2-)) to Cu2+/ATP inhibits the reactivity of the system. The structural delicacy of the reactive intermediate is further emphasized by the inhibiting effects of 1,N-6-ethenoadenosine 5'-monophosphate (epsilon-AMP(2-)) and adenosine 5'-monophosphate N(1)-oxide; in contrast, the dianion of the antiviral 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA(2-)) mimics AMP(2-) exceedingly well and facilitates even further the Cu2+-promoted dephosphorylation of ATP.