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

TitleLactate Dehydrogenase C Produces S-2-Hydroxyglutarate in Mouse Testis.
Publication TypeJournal Article
Year of Publication2016
AuthorsTeng, X, Emmett, MJ, Lazar, MA, Goldberg, E, Rabinowitz, JD
JournalACS Chem Biol
Date Published2016 Sep 16
KeywordsAnimals, DNA Methylation, Glutarates, Humans, Isoenzymes, L-Lactate Dehydrogenase, Male, Metabolomics, Mice, Mice, Inbred C57BL, Mice, Knockout, Substrate Specificity, Testis

<p>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.</p>

Alternate JournalACS Chem Biol
PubMed ID27333189
PubMed Central IDPMC5317044
Grant ListF30 DK104513 / DK / NIDDK NIH HHS / United States
P30 DK019525 / DK / NIDDK NIH HHS / United States
R01 CA163591 / CA / NCI NIH HHS / United States
R37 DK043806 / DK / NIDDK NIH HHS / United States