Saccharomyces cerevisiae Forms D-2-Hydroxyglutarate and Couples Its Degradation to D-Lactate Formation via a Cytosolic Transhydrogenase.

The Journal of Biological Chemistry
Julia Becker-KetternCarole L Linster

Abstract

The D or L form of 2-hydroxyglutarate (2HG) accumulates in certain rare neurometabolic disorders, and high D-2-hydroxyglutarate (D-2HG) levels are also found in several types of cancer. Although 2HG has been detected in Saccharomyces cerevisiae, its metabolism in yeast has remained largely unexplored. Here, we show that S. cerevisiae actively forms the D enantiomer of 2HG. Accordingly, the S. cerevisiae genome encodes two homologs of the human D-2HG dehydrogenase: Dld2, which, as its human homolog, is a mitochondrial protein, and the cytosolic protein Dld3. Intriguingly, we found that a dld3Δ knock-out strain accumulates millimolar levels of D-2HG, whereas a dld2Δ knock-out strain displayed only very moderate increases in D-2HG. Recombinant Dld2 and Dld3, both currently annotated as D-lactate dehydrogenases, efficiently oxidized D-2HG to α-ketoglutarate. Depletion of D-lactate levels in the dld3Δ, but not in the dld2Δ mutant, led to the discovery of a new type of enzymatic activity, carried by Dld3, to convert D-2HG to α-ketoglutarate, namely an FAD-dependent transhydrogenase activity using pyruvate as a hydrogen acceptor. We also provide evidence that Ser3 and Ser33, which are primarily known for oxidizing 3-phosphoglycerate i...Continue Reading

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Citations

Oct 24, 2017·Nucleic Acids Research·Kenneth W EllensCarole L Linster
Aug 12, 2018·The FEBS Journal·Julia Becker-KetternCarole L Linster
May 17, 2019·Scientific Reports·Raffaela S BergerKatja Dettmer
Jan 9, 2019·Frontiers in Molecular Biosciences·Gregory A Grant
Aug 23, 2017·Proceedings of the National Academy of Sciences of the United States of America·Wen ZhangPing Xu
Apr 10, 2018·Metabolomics : Official Journal of the Metabolomic Society·Daqiang PanBernd Kammerer
Jun 3, 2021·International Journal of Molecular Sciences·Vítězslav PlocekZdena Palková

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