title: Lactate Dehydrogenase C Produces S-2-Hydroxyglutarate in Mouse Testis.
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.
authors.affiliation: Lewis-Sigler Institute for Integrative Genomics, Princeton University , Princeton, New Jersey 08544, United States.|Department of Chemistry, Princeton University , Princeton, New Jersey 08544, United States.
authors.forename: Xin
authors.initials: X
authors.lastname: Teng
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Department of Genetics, Perelman School of Medicine at the University of Pennsylvania , Philadelphia, Pennsylvania 19104, United States.|The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania , Philadelphia, Pennsylvania 19104, United States.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Emmett
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Department of Genetics, Perelman School of Medicine at the University of Pennsylvania , Philadelphia, Pennsylvania 19104, United States.|The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania , Philadelphia, Pennsylvania 19104, United States.
authors.forename: Mitchell A
authors.initials: MA
authors.lastname: Lazar
authors.affiliation: Department of Molecular Biosciences, Northwestern University , Evanston, Illinois 60208, United States.
authors.forename: Erwin
authors.initials: E
authors.lastname: Goldberg
authors.affiliation: Lewis-Sigler Institute for Integrative Genomics, Princeton University , Princeton, New Jersey 08544, United States.|Department of Chemistry, Princeton University , Princeton, New Jersey 08544, United States.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Rabinowitz
mesh_terms: D000818:Animals; D019175:DNA Methylation; D005977:Glutarates / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D008297:Male; D055432:Metabolomics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013379:Substrate Specificity; D013737:Testis / Q000201:enzymology / Q000378:metabolism*
chemical_list: D005977:Glutarates; D007527:Isoenzymes; C019417:alpha-hydroxyglutarate; D007770:L-Lactate Dehydrogenase; C409673:lactate dehydrogenase C4