(p)ppGpp and Its Homologs: Enzymatic and Mechanistic Diversity Among the Microbes

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Background

Among various bacterial stress responses is the stringent response, characterized by rapid synthesis of guanosine tetraphosphate (ppGpp) and guanosine pentaphosphate (pppGpp) alarmones, jointly referred to as (p)ppGpp. This synthesis is triggered by a variety of environmental stresses, including nutrient starvation for carbon, amino acids, phosphate, iron, and fatty acids; further also heat shock, oxidative and osmotic stress, as well as perturbations of intracellular metabolic processes. The onset of the stringent response depends on several enzymes that sense stress and alter the balance between the rates of (p)ppGpp synthesis and hydrolysis to elevate (p)ppGpp which then provokes adjustments (at transcriptional, metabolic or other levels) crucial for recovery and stress survival, or ensuring survival of pathogens in their hosts. Recently regulatory effects and enzymes catalyzing synthesis or hydrolysis of (p)ppApp, a structural analog of (p)ppGpp, have also become of interest.

The (p)ppGpp metabolism of E. coli is a well-studied example, typical for other γ- and β-proteobacteria, with predominately only RelA (a monofunctional synthetase) and SpoT (a bifunctional enzyme with a strong hydrolase and weak synthetase activity) present. More recently, there have been major advances documenting diversities in (p)ppGpp metabolism in other bacteria. Firmicutes, α-, δ-, and ε-proteobacteria possess but a single bifunctional enzyme, called RSH (for RelA/SpoT-homologs), along with varying numbers of small alarmone synthetases (SAS) or hydrolases (SAH), each devoid of large regulatory domains. Of all the microbial enzymes, only SAHs have orthologs in metazoa and humans (Mesh-1 enzymes). Although there are apparently parallel outcomes to the onset and maintenance of the stringent response, it seems the enzymes and mechanisms mediating responses to the environmental cues are different and many remain unknown. In addition, it has been reported recently that (p)ppGpp homologs, such as pGpp and (p)ppApp, may be also metabolized by these enzymes. The goal of this Research Topic is to understand new enzymatic, mechanistic and structural features of diversity underpinning alarmone metabolism of different bacteria. This is key for the advancement of basic research as well as for the development of new, direly needed anti-microbial strategies.

In this Research Topic, we welcome both original research and mini-reviews. The focus is on new examples of enzymes and regulatory processes discovered as part of the widespread microbial diversity as well as new features of even well studied alarmone sensors and metabolism. Virtually all research approaches are welcome, including biochemistry, bioinformatics, crystallography, genetics, and molecular physiology. The aim is to document microbial diversity as it relates to the following:

• the enzymes that synthesize and hydrolyze (p)ppGpp and (p)ppApp alarmones;
• mechanisms that sense both external and internal sources of metabolic stress, in relation to alarmones;
• regulatory responses mediated by the alarmones (p)ppGpp and (p)ppApp.

Keywords: RSH, SAS, SAH, (p)ppGpp, (p)ppApp

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

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