METAL ION-ASSISTED STACKING INTERACTIONS AND THE FACILITATED HYDROLYSIS OF NUCLEOSIDE 5'-TRIPHOSPHATES

The self-association properties of the common nucleosides and nucleoti des 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 depho sphorylation of nucleoside 5'-triphosphates (NTPs) are reviewed. It is shown that the dephosphorylation rate in the presence of Cu2+ decreas es in the series, ATP > GTP > ITP > pyrimidine-NTPs. Similarly, additi on of AMP, GMP or IMP (decreasing order of effectiveness) to a Cu2+/AT P system facilitates the dephosphorylation reaction further because on e of the two ATPs in the stacked reactive intermediate, occurring in l ow concentration, [Cu-2(ATP)](2)(OH)(-), has a structural role and thi s 'enzyme'-like ATP(4-) can be replaced by one of the mentioned nucleo side 5'-monophosphates. These results demonstrate how weak interaction s, i.e. aromatic-ring stacking, can govern the reactivity of a system. Next to stacking, the purine(N7)-metal ion interaction allowing bridg ing 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 emphas ized by the inhibiting effects of 1,N-6-ethenoadenosine 5'-monophospha te (epsilon-AMP(2-)) and adenosine 5'-monophosphate N(1)-oxide; in con trast, the dianion of the antiviral 9-[2-(phosphonomethoxy)ethyl]adeni ne (PMEA(2-)) mimics AMP(2-) exceedingly well and facilitates even fur ther the Cu2+-promoted dephosphorylation of ATP.