A conserved phosphatase destroys toxic glycolytic side products in mammals and yeast

Nat Chem Biol. 2016 Aug;12(8):601-7. doi: 10.1038/nchembio.2104. Epub 2016 Jun 13.


Metabolic enzymes are very specific. However, most of them show weak side activities toward compounds that are structurally related to their physiological substrates, thereby producing side products that may be toxic. In some cases, 'metabolite repair enzymes' eliminating side products have been identified. We show that mammalian glyceraldehyde 3-phosphate dehydrogenase and pyruvate kinase, two core glycolytic enzymes, produce 4-phosphoerythronate and 2-phospho-L-lactate, respectively. 4-Phosphoerythronate strongly inhibits an enzyme of the pentose phosphate pathway, whereas 2-phospho-L-lactate inhibits the enzyme producing the glycolytic activator fructose 2,6-bisphosphate. We discovered that a single, widely conserved enzyme, known as phosphoglycolate phosphatase (PGP) in mammals, dephosphorylates both 4-phosphoerythronate and 2-phospho-L-lactate, thereby preventing a block in the pentose phosphate pathway and glycolysis. Its yeast ortholog, Pho13, similarly dephosphorylates 4-phosphoerythronate and 2-phosphoglycolate, a side product of pyruvate kinase. Our work illustrates how metabolite repair enzymes can make up for the limited specificity of metabolic enzymes and permit high flux in central metabolic pathways.

MeSH terms

  • Glycolates / chemistry
  • Glycolates / metabolism*
  • Glycolates / toxicity
  • Glycolysis* / drug effects
  • HCT116 Cells
  • Humans
  • Lactates / chemistry
  • Lactates / metabolism*
  • Lactates / toxicity
  • Pentose Phosphate Pathway / drug effects
  • Phosphoric Monoester Hydrolases / deficiency
  • Phosphoric Monoester Hydrolases / metabolism*
  • Phosphorylation
  • Pyruvate Kinase / metabolism
  • Saccharomyces cerevisiae / enzymology
  • Saccharomyces cerevisiae / metabolism*
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Substrate Specificity
  • Sugar Acids / chemistry
  • Sugar Acids / metabolism*
  • Sugar Acids / toxicity


  • 4-phosphoerythronate
  • Glycolates
  • Lactates
  • Saccharomyces cerevisiae Proteins
  • Sugar Acids
  • 2-phospholactic acid
  • Pyruvate Kinase
  • Pho13 protein, S cerevisiae
  • phosphoglycolate phosphatase
  • Phosphoric Monoester Hydrolases
  • phosphoglycolate