ABSTRACT
The nucleotide derivatives (p)ppGpp, comprising ppGpp and pppGpp, are important signalling molecules thatcontrol various facets of gene regulation and protein synthesis in Escherichia coli. Their synthesis is catalysedby RelA (in response to amino acid limitation) and by SpoT (in response to the limitation of carbon source orfatty acids). SpoT is also a hydrolase for degradation of both ppGpp and pppGpp, while GppA catalyses theconversion of pppGpp to ppGpp. Here we provide evidence to show that pppGpp exerts heightened toxicitycompared to that by ppGpp. Thus, gppA spoT double mutants exhibited lethality under conditions in which thesingle mutants were viable. The extent of RelA-catalysed (p)ppGpp accumulation in the gppA spoT strain wassubstantially greater than that in its isogenic gppA? derivative. The data is interpreted in terms of a model inwhich toxicity of pppGpp in the gppA spoT mutants is mediated by its activation of RelA so as to result in avicious cycle of (p)ppGpp synthesis.