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Two P or Not Two P: Understanding Regulation by the Bacterial Second Messengers (p)ppGpp.

Under stressful growth conditions and nutrient starvation, bacteria adapt by synthesizing signaling molecules that profoundly reprogram cellular physiology. At the onset of this process, called the stringent response, members of the RelA/SpoT homolog (RSH) protein superfamily are activated by specific stress stimuli to produce several hyperphosphorylated forms of guanine nucleotides, commonly referred to as (p)ppGpp. Some bifunctional RSH enzymes also harbor domains that allow for degradation of (p)ppGpp by hydrolysis. (p)ppGpp synthesis or hydrolysis may further be executed by single-domain alarmone synthetases or hydrolases, respectively. The downstream effects of (p)ppGpp rely mainly on direct interaction with specific intracellular effectors, which are widely used throughout most cellular processes. The growing number of identified (p)ppGpp targets allows us to deduce both common features of and differences between gram-negative and gram-positive bacteria. In this review, we give an overview of (p)ppGpp metabolism with a focus on the functional and structural aspects of the enzymes involved and discuss recent findings on alarmone-regulated cellular effectors. Expected final online publication date for the Annual Review of Microbiology, Volume 75 is October 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.