biostudies-literatureUnknown16(12)Ahmad SGuanosine penta- and tetraphosphate [(p)ppGpp] and their adenosine analogs [(p)ppApp] are bacterial second messengers known as alarmones. Members of the RelA-SpoT homolog (RSH) family synthesize (p)ppGpp to mediate the stringent response during nutrient starvation, whereas (p)ppApp synthetases have been identified as bactericidal toxins in diverse contexts including type VI secretion systems, toxin-antitoxin modules, and phages. Although alarmone synthesis has traditionally been viewed as a cytoplasmic process, early studies in Streptomyces suggested the existence of secreted alarmone synthetases. Here, we identify SaEAS, an exported alarmone synthetase (EAS) from Streptomyces albidoflavus, as the long-mysterious source of extracellular alarmone symBioe0222725https://www.ebi.ac.uk/biostudies/studies/S-EPMC12691689biostudies-literatureBacteria export alarmone synthetases that produce (p)ppApp and (p)ppGpp.PMC12691689Schiefer VGuedez AGAdewale AThakar HWang BAhmad SManisa BTsang KKBullen NPKim YWhitney JCfalseBacteria export alarmone synthetases that produce (p)ppApp and (p)ppGpp.Guanosine penta- and tetraphosphate [(p)ppGpp] and their adenosine analogs [(p)ppApp] are bacterial second messengers known as alarmones. Members of the RelA-SpoT homolog (RSH) family synthesize (p)ppGpp to mediate the stringent response during nutrient starvation, whereas (p)ppApp synthetases have been identified as bactericidal toxins in diverse contexts including type VI secretion systems, toxin-antitoxin modules, and phages. Although alarmone synthesis has traditionally been viewed as a cytoplasmic process, early studies in Streptomyces suggested the existence of secreted alarmone synthetases. Here, we identify SaEAS, an exported alarmone synthetase (EAS) from Streptomyces albidoflavus, as the long-mysterious source of extracellular alarmone sy2025-01-01T00:00:00Z2025 Dec2026-06-06T00:19:48.479Z2026-05-23T03:14:10.382ZS-EPMC126916894122223810.1128/mbio.02227-25