Molecular targets of guanine nucleotides in differentiation, proliferation and apoptosis

Guanine nucleotides are important substrates for macromolecular synthesis, cell signaling, and integration of metabolic status, and have an evolutionarily conserved role in differentiation, proliferation, and apoptosis. Bacteria, yeast, and mammalian cells are all dependent on an adequate supply of guanylates to maintain proliferation. Depletion of intracellular guanylates, especially by inhibition of de novo synthesis via the IMP dehydrogenase pathway, is a potent signal for inhibition of proliferation, as well as apoptosis. Growth inhibition by depletion of GTP is a conserved pathway from humans to Bacillus. IMPDH expression is downregulated by the p53 tumor suppressor gene. Many inhibitors of IMP dehydrogenase are used as clinical agents. These agents are antivirals (ribavirin), antitumor (tiazofurin [TR], selenazofurin [SR], and benzamide riboside [BR]), and immunosuppressants (mycophenolic acid [MPA]). The biochemical actions of IMP dehydrogenase inhibitors are well known, but correlation with in vivo activities is difficult because the extent of exogenous contributions to the nucleotide metabolic pathways is not fully known. IMPDH inhibitors are biochemically convenient in inhibiting parallel pathways, since excess reactants IMP and 5'-phospho-ribose-1'-pyrophosphate (PRPP) inhibit guanine salvage synthesis. IMPDH activity is a progression-linked key enzyme in tumorigenesis. The antitumor potential of IMPDH inhibitors is therefore particularly high.