Ultrasensitive regulation of anapleurosis via allosteric activation of PEP carboxylase

Nat Chem Biol. 2012 Apr 22;8(6):562-8. doi: 10.1038/nchembio.941.


Anapleurosis is the filling of the tricarboxylic acid cycle with four-carbon units. The common substrate for both anapleurosis and glucose phosphorylation in bacteria is the terminal glycolytic metabolite phosphoenolpyruvate (PEP). Here we show that Escherichia coli quickly and almost completely turns off PEP consumption upon glucose removal. The resulting buildup of PEP is used to quickly import glucose if it becomes available again. The switch-like termination of anapleurosis results from depletion of fructose-1,6-bisphosphate (FBP), an ultrasensitive allosteric activator of PEP carboxylase. E. coli expressing an FBP-insensitive point mutant of PEP carboxylase grow normally when glucose is steadily available. However, they fail to build up PEP upon glucose removal, grow poorly when glucose availability oscillates and suffer from futile cycling at the PEP node on gluconeogenic substrates. Thus, bacterial central carbon metabolism is intrinsically programmed with ultrasensitive allosteric regulation to enable rapid adaptation to changing environmental conditions.

Publication types

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

MeSH terms

  • Allosteric Regulation
  • Allosteric Site
  • Escherichia coli K12 / enzymology
  • Escherichia coli K12 / growth & development
  • Escherichia coli K12 / metabolism*
  • Escherichia coli Proteins / genetics
  • Escherichia coli Proteins / metabolism*
  • Fructosediphosphates / metabolism
  • Fructosediphosphates / pharmacology
  • Gluconeogenesis
  • Glucose / metabolism
  • Glucose / pharmacology
  • Phosphoenolpyruvate / metabolism*
  • Phosphoenolpyruvate Carboxylase / genetics
  • Phosphoenolpyruvate Carboxylase / metabolism*


  • Escherichia coli Proteins
  • Fructosediphosphates
  • Phosphoenolpyruvate
  • Phosphoenolpyruvate Carboxylase
  • Glucose
  • fructose-1,6-diphosphate