Lactate Dehydrogenase C Produces S-2-Hydroxyglutarate in Mouse Testis

ACS Chem Biol. 2016 Sep 16;11(9):2420-7. doi: 10.1021/acschembio.6b00290. Epub 2016 Jul 7.


Metabolomics is a valuable tool for studying tissue- and organism-specific metabolism. In normal mouse testis, we found 70 μM S-2-hydroxyglutarate (2HG), more than 10-fold greater than in other tissues. S-2HG is a competitive inhibitor of α-ketoglutarate-dependent demethylation enzymes and can alter histone or DNA methylation. To identify the source of testis S-2HG, we fractionated testis extracts and identified the fractions that actively produced S-2HG. Through a combination of ion exchange and size exclusion chromatography, we enriched a single active protein, the lactate dehydrogenase isozyme LDHC, which is primarily expressed in testis. At neutral pH, recombinant mouse LDHC rapidly converted both pyruvate into lactate and α-ketoglutarate into S-2HG, whereas recombinant human LDHC only produced lactate. Rapid S-2HG production by LDHC depends on amino acids 100-102 being Met-Val-Ser, a sequence that occurs only in the rodent protein. Other mammalian LDH can also produce some S-2HG, but at acidic pH. Thus, polymorphisms in the Ldhc gene control testis levels of S-2HG, and thereby epigenetics, across mammals.

Publication types

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

MeSH terms

  • Animals
  • DNA Methylation
  • Glutarates / metabolism*
  • Humans
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • L-Lactate Dehydrogenase / genetics
  • L-Lactate Dehydrogenase / metabolism*
  • Male
  • Metabolomics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Substrate Specificity
  • Testis / enzymology
  • Testis / metabolism*


  • Glutarates
  • Isoenzymes
  • alpha-hydroxyglutarate
  • L-Lactate Dehydrogenase
  • lactate dehydrogenase C4