INHIBITION OF DE NOVO PURINE SYNTHESIS BY METHYLTHIOADENOSINE: 72

Abstract

De novo purine synthesis in human B lymphoblast cell lines was inhibited by methylthioadenosine (MTA) or adenine in the medium. Two human leukemic T-cell lines lacking methylthio-adenosine phosphorylase (MTAP) activity showed increased rates of de novo purine synthesis which were resistant to inhibition by MTA but were inhibited by adenine in a similar fashion to MTAP+ cells. The presence of MTA in culture media inhibited growth in a dose-dependent manner in MTAP+ and MTAP− cell lines. Similar inhibition of growth was effected by the presence of adenine in the medium. These results suggest that the inhibition of de novo purine synthesis by MTA is due to cleavage of the MTA to adenine by the MTAP enzyme. The adenine so formed can be converted to 5'-AMP in a PRPP-dependent reaction catalysed by the purine salvage enzyme APRT. Inhibition of growth of the MTAP− cell lines by MTA suggests that MTA may also exert effects on cell metabolism by a mechanism unrelated to its degradation.