Evolution reveals a glutathione-dependent mechanism of 3-hydroxypropionic acid tolerance

Metab Eng. 2014 Nov;26:57-66. doi: 10.1016/j.ymben.2014.09.004. Epub 2014 Sep 28.


Biologically produced 3-hydroxypropionic acid (3 HP) is a potential source for sustainable acrylates and can also find direct use as monomer in the production of biodegradable polymers. For industrial-scale production there is a need for robust cell factories tolerant to high concentration of 3 HP, preferably at low pH. Through adaptive laboratory evolution we selected S. cerevisiae strains with improved tolerance to 3 HP at pH 3.5. Genome sequencing followed by functional analysis identified the causal mutation in SFA1 gene encoding S-(hydroxymethyl)glutathione dehydrogenase. Based on our findings, we propose that 3 HP toxicity is mediated by 3-hydroxypropionic aldehyde (reuterin) and that glutathione-dependent reactions are used for reuterin detoxification. The identified molecular response to 3 HP and reuterin may well be a general mechanism for handling resistance to organic acid and aldehydes by living cells.

Keywords: 3-hydroxypropionic acid; 3-hydroxypropionic aldehyde (reuterin); Adaptive laboratory evolution; Saccharomyces cerevisiae; Tolerance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Proliferation / drug effects
  • Cell Proliferation / genetics
  • Directed Molecular Evolution / methods*
  • Dose-Response Relationship, Drug
  • Drug Tolerance / genetics
  • Escherichia coli / drug effects
  • Escherichia coli / genetics*
  • Genetic Enhancement / methods*
  • Glutathione / genetics
  • Glutathione / metabolism*
  • Lactic Acid / administration & dosage
  • Lactic Acid / analogs & derivatives*
  • Saccharomyces cerevisiae / drug effects
  • Saccharomyces cerevisiae / genetics*


  • Lactic Acid
  • hydracrylic acid
  • Glutathione