Genes of the Rel/Spo homolog (RSH) superfamily synthesize and/or hydrolyse the modified nucleotides pppGpp/ppGpp (collectively referred to as (p)ppGpp) and are prevalent across diverse bacteria and in plant chloroplasts. Bacteria accumulate (p)ppGpp in response to nutrient deprivation (generically called the stringent response) and elicit appropriate adaptive responses mainly through the regulation of transcription. Although at different concentrations (p)ppGpp affect the expression of distinct set of genes, the two well-characterized responses are reduction in expression of the protein synthesis machinery and increase in the expression of genes coding for amino acid biosynthesis. In Escherichia coli, the cellular (p)ppGpp level inversely correlates with the growth rate and increasing its concentration decreases the steady state growth rate in a defined growth medium. Since change in growth rate must be accompanied by changes in cell cycle parameters set through the activities of the DNA replication and cell division apparatus, (p)ppGpp could coordinate protein synthesis (cell mass increase) with these processes. Here we review the role of (p)ppGpp in bacterial cell cycle regulation.

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.