Tyr-Asp inhibition of glyceraldehyde 3-phosphate dehydrogenase affects plant redox metabolism

EMBO J. 2021 Aug 2;40(15):e106800. doi: 10.15252/embj.2020106800. Epub 2021 Jun 22.


How organisms integrate metabolism with the external environment is a central question in biology. Here, we describe a novel regulatory small molecule, a proteogenic dipeptide Tyr-Asp, which improves plant tolerance to oxidative stress by directly interfering with glucose metabolism. Specifically, Tyr-Asp inhibits the activity of a key glycolytic enzyme, glyceraldehyde 3-phosphate dehydrogenase (GAPC), and redirects glucose toward pentose phosphate pathway (PPP) and NADPH production. In line with the metabolic data, Tyr-Asp supplementation improved the growth performance of both Arabidopsis and tobacco seedlings subjected to oxidative stress conditions. Moreover, inhibition of Arabidopsis phosphoenolpyruvate carboxykinase (PEPCK) activity by a group of branched-chain amino acid-containing dipeptides, but not by Tyr-Asp, points to a multisite regulation of glycolytic/gluconeogenic pathway by dipeptides. In summary, our results open the intriguing possibility that proteogenic dipeptides act as evolutionarily conserved small-molecule regulators at the nexus of stress, protein degradation, and metabolism.

Keywords: Arabidopsis; GAPDH; NADPH; central carbon metabolism; dipeptides.

MeSH terms

  • Arabidopsis / drug effects*
  • Arabidopsis / metabolism
  • Arabidopsis Proteins / chemistry
  • Arabidopsis Proteins / metabolism
  • Computer Simulation
  • Dipeptides / chemistry
  • Dipeptides / metabolism
  • Dipeptides / pharmacology*
  • Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / chemistry
  • Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / metabolism
  • Glyceraldehyde-3-Phosphate Dehydrogenases / antagonists & inhibitors*
  • Glyceraldehyde-3-Phosphate Dehydrogenases / metabolism
  • NADP / metabolism
  • Oxidation-Reduction
  • Oxidative Stress / drug effects
  • Pentose Phosphate Pathway / drug effects
  • Phosphoenolpyruvate Carboxykinase (ATP) / metabolism
  • Plant Proteins / antagonists & inhibitors
  • Plant Proteins / metabolism*
  • Seedlings / drug effects
  • Seedlings / metabolism
  • Tobacco / drug effects*
  • Tobacco / metabolism


  • Arabidopsis Proteins
  • Dipeptides
  • Plant Proteins
  • NADP
  • Glyceraldehyde-3-Phosphate Dehydrogenases
  • GAPC1 protein, Arabidopsis
  • Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)
  • Phosphoenolpyruvate Carboxykinase (ATP)