Functional diversity of RSH proteins, key regulators of bacterial alarmone (p)ppGpp metabolism

The bacterial stringent response refers to the adaptive reaction that bacteria exhibit when faced with adverse environmental conditions, altering their metabolism and reducing the growth rate to enhance survival and adaptability. The rapid accumulation of guanosine tetraphosphate (ppGpp) and guanosine pentaphosphate (pppGpp), collectively referred to as (p)ppGpp in this article, mediates the stringent response, playing a crucial role in microbial adaptation to environmental changes. The levels of (p)ppGpp within bacteria are regulated by RelA/SpoT homologue (RSH) proteins, which include small alarmone synthetases (SASs), small alarmone hydrolases (SAHs), and bifunctional proteins such as Rel. Furthermore, recent studies have identified a new bacterial alarmone, adenosine tetraphosphate (ppApp) and adenosine pentaphosphate (pppApp), collectively referred to as (p)ppApp, which is involved in the regulation of various biological processes in bacteria. The enzymes involved in (p)ppGpp metabolism vary among different bacterial species. This study systematically classifies and reviews the structural and biochemical characteristics of the known RSH proteins and summarizes their biochemical functions, aiming to promote further exploration and development in this field.