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
Volume11
Issue9
Pagination2420-7
Date Published2016 Sep 16
ISSN1554-8937
Abstract

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.

DOI10.1021/acschembio.6b00290
Alternate JournalACS Chem. Biol.
PubMed ID27333189
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