Z-Nucleotides Formation in Human and Rat Cells

Little is known about the formation and role of Z-nucleotides (ZMP,ZDP,ZTP) in rat and human cells. In cells having an active purine de novo biosynthesis pathway, ZMP (AICA-riboside monophosphoribonucleoside) is formed naturally as one of the final intermediates in IMP biosynthesis. ZMP, when synthesized by this pathway, is then efficiently formylated by 5-amino-4-imidazole-carboxamide 5′ribonucleotide transformylase (EC 2.1.2.3) and therefore the intracellular level of ZMP is usually very low and is not detectable by HPLC (1–3). ZMP can also be formed when cells with an active or absent de novo purine biosynthesis pathway are exposed to acadesine (AICA-riboside) or RICA-base. ZMP is formed from acadesine after phosphorylation, whereas formation from AICA-base requires the transfer of the phosphoribosyl group from PRPP. It has already been established that adenosine kinase (AK) is responsible for the phosphorylation of acadesine to ZMP, and AK inhibited or AK deficient cells are unable to metabolize acadesine (4–7). ZMP, when formed from acadesine, can be further metabolized by alternative pathways depending on its intracellular concentrations (2). At low ZMP concentrations, metabolism of ZMP follows predominantly the steps of de novo synthesis of IMP and other purines. At intermediate concentrations of ZMP, net retrograde flux through adenylosuccinate lyase results in sZMP (5-amino-4imidazole-N-succinocarboxamide ribonucleotide) formation, while at high ZMP concentrations, accumulation of ZMP, ZDP and ZTP becomes significant.