Abstract
Two (p)ppGpp nucleotide analogs, sometimes abbreviated simply as ppGpp, are widespread in bacteria and plants. Their name alarmone reflects a view of their function as intracellular hormone-like protective alarms that can increase a 100-fold when sensing any of an array of physical or nutritional dangers, such as abrupt starvation, that trigger lifesaving adjustments of global gene expression and physiology. The diversity of mechanisms for stress-specific adjustments of this sort is large and further compounded by almost infinite microbial diversity. The central question raised by this review is whether the small basal levels of (p)ppGpp functioning during balanced growth serve very different roles than alarmone-like functions. Recent discoveries that abrupt amino acid starvation of Escherichia coli, accompanied by very high levels of ppGpp, occasion surprising instabilities of transfer RNA (tRNA), ribosomal RNA (rRNA), and ribosomes raises new questions. Is this destabilization, a mode of regulation linearly related to (p)ppGpp over the entire continuum of (p)ppGpp levels, including balanced growth? Are regulatory mechanisms exerted by basal (p)ppGpp levels fundamentally different than for high levels? There is evidence from studies of other organisms suggesting special regulatory features of basal levels compared to burst of (p)ppGpp. Those differences seem to be important even during bacterial infection, suggesting that unbalancing the basal levels of (p)ppGpp may become a future antibacterial treatment. A simile for this possible functional duality is that (p)ppGpp acts like a car’s brake, able to stop to avoid crashes as well as to slow down to drive safely.
Highlights
Specialty section: This article was submitted to Microbial Physiology and Metabolism, a section of the journal Frontiers in Microbiology
Whether NADPH is the bona fide substrate of Mesh1 is still a matter of debate, considering that the Drosophila version did not reduce the cellular pools of NADPH when expressed in Escherichia coli (Zhu and Dai, 2019)
To avoid futile cycles of synthesis and hydrolysis, this bifunctional enzyme balances both activities by undergoing conformational changes that activate one activity while inhibiting the other, as shown by structural studies made with the RelA/SpoT Homologue (RSH) catalytic region of Streptococcus equisimilis or Thermus thermophilus (Mechold et al, 2002; Hogg et al, 2004; Tamman et al, 2020)
Summary
Specialty section: This article was submitted to Microbial Physiology and Metabolism, a section of the journal Frontiers in Microbiology. While sudden burst of (p)ppGpp during stress, starvation, or stationary phase, will stop cellular growth, and cells will go into survival mode (alarmone); the low basal levels, during exponential phase, in absence of starvation, (p)ppGpp will meld the external conditions with the bacterial growth, maintaining the homeostasis of cellular components and macromolecules, acting as a secondary messenger (Figure 2).
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