ppGpp Coordinates Nucleotide and Amino-Acid Synthesis in E. coli During Starvation

Boyuan Wang, Robert A. Grant, Michael T. Laub

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

(p)ppGpp is a nucleotide messenger universally produced in bacteria following nutrient starvation. In E. coli, ppGpp inhibits purine nucleotide synthesis by targeting several different enzymes, but the physiological significance of their inhibition is unknown. Here, we report the structural basis of inhibition for one target, Gsk, the inosine-guanosine kinase. Gsk creates an unprecedented, allosteric binding pocket for ppGpp by restructuring terminal sequences, which restrains conformational dynamics necessary for catalysis. Guided by this structure, we generated a chromosomal mutation that abolishes Gsk regulation by ppGpp. This mutant strain accumulates abnormally high levels of purine nucleotides following amino-acid starvation, compromising cellular fitness. We demonstrate that this unrestricted increase in purine nucleotides is detrimental because it severely depletes pRpp and essential, pRpp-derived metabolites, including UTP, histidine, and tryptophan. Thus, our results reveal the significance of ppGpp's regulation of purine nucleotide synthesis and a critical mechanism by which E. coli coordinates biosynthetic processes during starvation.

Original languageEnglish (US)
Pages (from-to)29-42.e10
JournalMolecular cell
Volume80
Issue number1
DOIs
StatePublished - Oct 1 2020
Externally publishedYes

Keywords

  • amino-acid synthesis
  • Gsk
  • ppGpp
  • pRpp
  • purine nucleotide synthesis
  • stringent response

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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