In Salmonella enterica, 2-methylcitrate blocks gluconeogenesis

J Bacteriol. 2010 Feb;192(3):771-8. doi: 10.1128/JB.01301-09. Epub 2009 Nov 30.


Strains of Salmonella enterica serovar Typhimurium LT2 lacking a functional 2-methylcitric acid cycle (2-MCC) display increased sensitivity to propionate. Previous work from our group indicated that this sensitivity to propionate is in part due to the production of 2-methylcitrate (2-MC) by the Krebs cycle enzyme citrate synthase (GltA). Here we report in vivo and in vitro data which show that a target of the 2-MC isomer produced by GltA (2-MC(GltA)) is fructose-1,6-bisphosphatase (FBPase), a key enzyme in gluconeogenesis. Lack of growth due to inhibition of FBPase by 2-MC(GltA) was overcome by increasing the level of FBPase or by micromolar amounts of glucose in the medium. We isolated an fbp allele encoding a single amino acid substitution in FBPase (S123F), which allowed a strain lacking a functional 2-MCC to grow in the presence of propionate. We show that the 2-MC(GltA) and the 2-MC isomer synthesized by the 2-MC synthase (PrpC; 2-MC(PrpC)) are not equally toxic to the cell, with 2-MC(GltA) being significantly more toxic than 2-MC(PrpC). This difference in 2-MC toxicity is likely due to the fact that as a si-citrate synthase, GltA may produce multiple isomers of 2-MC, which we propose are not substrates for the 2-MC dehydratase (PrpD) enzyme, accumulate inside the cell, and have deleterious effects on FBPase activity. Our findings may help explain human inborn errors in propionate metabolism.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Citrate (si)-Synthase / genetics
  • Citrate (si)-Synthase / metabolism
  • Citrates / pharmacology*
  • Fructose-Bisphosphatase / metabolism
  • Fructose-Bisphosphatase / physiology
  • Gluconeogenesis / drug effects*
  • Glucose / metabolism
  • Glucose / pharmacology
  • Hydro-Lyases / genetics
  • Hydro-Lyases / metabolism
  • Models, Biological
  • Propionates / pharmacology
  • Salmonella enterica / drug effects*
  • Salmonella enterica / genetics
  • Salmonella enterica / growth & development
  • Salmonella enterica / metabolism*


  • Bacterial Proteins
  • Citrates
  • Propionates
  • 2-methylcitric acid
  • Citrate (si)-Synthase
  • Fructose-Bisphosphatase
  • methylcitrate synthase
  • Hydro-Lyases
  • Glucose