ZTP (5-amino 4-imidazole carboxamide riboside 5'-triphosphate): a proposed alarmone for 10-formyl-tetrahydrofolate deficiency

Starvation of Salmonella typhimurium for folate in six different ways triggers the intracellular accumulation of a novel ribotide, 5-amino 4-imidazole carboxamide riboside 5'-triphosphate (ZTP). Numerous other starvations not involving folate do not cause ZTP to accumulate. We propose that ZTP is an alarmone for C-1-folate deficiency and present evidence that it is formed from ZMP, an intermediate in purine biosynthesis. ZMP accumulates rapidly in cells when 10-formyl-tetrahydrofolate, a substrate for ZMP transformylase, is depleted. We review previous evidence that Z-ribotides may be involved in physiological processes in many types of cells, including sporulation of Bacillus subtilis. We also discuss the implications of ZTP synthesis for chemotherapy and other pharmacological uses of antifolates and analogs of Z-ribosides.