Direct regulation of GTP homeostasis by (p)ppGpp: a critical component of viability and stress resistance

Mol Cell. 2012 Oct 26;48(2):231-41. doi: 10.1016/j.molcel.2012.08.009. Epub 2012 Sep 13.


Cells constantly adjust their metabolism in response to environmental conditions, yet major mechanisms underlying survival remain poorly understood. We discover a posttranscriptional mechanism that integrates starvation response with GTP homeostasis to allow survival, enacted by the nucleotide (p)ppGpp, a key player in bacterial stress response and persistence. We reveal that (p)ppGpp activates global metabolic changes upon starvation, allowing survival by regulating GTP. Combining metabolomics with biochemical demonstrations, we find that (p)ppGpp directly inhibits the activities of multiple GTP biosynthesis enzymes. This inhibition results in robust and rapid GTP regulation in Bacillus subtilis, which we demonstrate is essential to maintaining GTP levels within a range that supports viability even in the absence of starvation. Correspondingly, without (p)ppGpp, gross GTP dysregulation occurs, revealing a vital housekeeping function of (p)ppGpp; in fact, loss of (p)ppGpp results in death from rising GTP, a severe and previously unknown consequence of GTP dysfunction.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / metabolism*
  • Bacillus subtilis* / metabolism
  • Bacillus subtilis* / physiology
  • Cell Survival / genetics
  • Escherichia coli / metabolism
  • Guanosine Triphosphate / metabolism*
  • Humans
  • Pyrophosphatases / metabolism
  • Stress, Physiological


  • Amino Acids
  • Guanosine Triphosphate
  • Pyrophosphatases

Associated data

  • GEO/GSE39758