ppGpp

ppGpp, or guanosine tetraphosphate, is a small nucleotide alarmone produced by many bacteria in response to nutrient stress. It exists alongside the related molecule pppGpp, together referred to as (p)ppGpp. These molecules accumulate during amino acid limitation, carbon starvation, or other stresses and reprogram cellular physiology to prioritize survival over growth.

Biosynthesis and degradation: In many bacteria, including Escherichia coli, (p)ppGpp levels are controlled by RelA and SpoT enzymes. RelA is activated when the ribosome stalls due to uncharged tRNA at the A site during amino acid limitation and synthesizes (p)ppGpp. SpoT provides both synthetase and hydrolase activities, integrating diverse stress signals and balancing (p)ppGpp levels by degradation to GDP or related products when stress subsides.

Mode of action: (p)ppGpp exerts its effects primarily by interacting with RNA polymerase, often in cooperation with the transcription factor DksA. This reprograms promoter selectivity, typically downregulating ribosomal RNA and tRNA synthesis while upregulating amino acid biosynthesis, stress response, and maintenance pathways. The response is rapid and coordinates transcription with translation, metabolism, and replication to conserve resources.

Physiological significance: By limiting growth and reallocating resources, (p)ppGpp enables survival under nutrient scarcity and helps cells endure environmental fluctuations. It also influences virulence, biofilm formation, and antibiotic tolerance in certain pathogens, reflecting a central role in bacterial adaptability and stress management.

Distribution and evolution: (p)ppGpp signaling is widespread among bacteria and is also present in plant chloroplasts that retain RelA/SpoT homologs. The stringent response mediated by these molecules is a common strategy for coping with nutrient limitation.