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

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

Author information

1
Lewis-Sigler Institute for Integrative Genomics, Princeton University , Princeton, New Jersey 08544, United States.
2
Department of Chemistry, Princeton University , Princeton, New Jersey 08544, United States.
3
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.
4
The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania , Philadelphia, Pennsylvania 19104, United States.
5
Department of Molecular Biosciences, Northwestern University , Evanston, Illinois 60208, United States.

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.

PMID:
27333189
PMCID:
PMC5317044
DOI:
10.1021/acschembio.6b00290
[Indexed for MEDLINE]
Free PMC Article

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