ArticleThe Journal of biological chemistry2016
Saccharomyces cerevisiae Forms D-2-Hydroxyglutarate and Couples Its Degradation to D-Lactate Formation via a Cytosolic Transhydrogenase.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 86 citations in OpenAlex.
- Molecular mechanisms of transhydrogenase activity and allosteric regulation in eukaryotic type II PHGDH Ser33.Nature communications · 2026Article
- The return of metabolism: biochemistry and physiology of glycolysis.Biological reviews of the Cambridge Philosophical Society · 2026Review
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- Substitution of ZnACS omega · 2025Article
- A genetically encoded biosensor for point-of-care and live-cell detection of D-2-hydroxyglutarate.Nature communications · 2025Article
- Transcriptional response of Saccharomyces cerevisiae to lactic acid enantiomers.Applied microbiology and biotechnology · 2024Article
- Activation of the yeast Retrograde Response pathway by adaptive laboratory evolution with S-(2-aminoethyl)-L-cysteine reduces ethanol and increases glycerol during winemaking.Microbial cell factories · 2024Article
- 2-Hydroxyglutarate modulates histone methylation at specific loci and alters gene expression via Rph1 inhibition.Life science alliance · 2024Article
- Bridging the gap: linking Torulaspora delbrueckii genotypes to fermentation phenotypes and wine aroma.FEMS yeast research · 2024Article
- Engineering transcriptional regulation of pentose metabolism in Rhodosporidium toruloides for improved conversion of xylose to bioproducts.Microbial cell factories · 2023Article
- High-throughput Saccharomyces cerevisiae cultivation method for credentialing-based untargeted metabolomics.Analytical and bioanalytical chemistry · 2023Article
- High-throughput metabolomics for the design and validation of a diauxic shift model.NPJ systems biology and applications · 2023Article
- The Pseudomonas aeruginosa PAO1 metallo flavoprotein d-2-hydroxyglutarate dehydrogenase requires ZnThe Journal of biological chemistry · 2023Article
- Uncovering ZnThe Journal of biological chemistry · 2023Article
- No Chance to Survive:Antibiotics (Basel, Switzerland) · 2023Article
- A Selective Fluorescent l-Lactate Biosensor Based on an l-Lactate-Specific Transcription Regulator and Förster Resonance Energy Transfer.Biosensors · 2022Article
- Metabolic reprogramming and epigenetic modifications on the path to cancer.Protein & cell · 2022Review
- Revealing a New Family of D-2-Hydroxyglutarate Dehydrogenases inMicroorganisms · 2022Article
- A D-2-hydroxyglutarate biosensor based on specific transcriptional regulator DhdR.Nature communications · 2021Article
- Genomic-, phenotypic-, and toxicity-based safety assessment and probiotic potency of Bacillus coagulans IDCC 1201 isolated from green malt.Journal of industrial microbiology & biotechnology · 2021Article
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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 in the main serine biosynthesis pathway, in addition reduce α-ketoglutarate to D-2HG using NADH and represent major intracellular sources of D-2HG in yeast. Based on our observations, we propose that D-2HG is mainly formed and degraded in the cytosol of S. cerevisiae cells in a process that couples D-2HG metabolism to the shuttling of reducing equivalents from cytosolic NADH to the mitochondrial respiratory chain via the D-lactate dehydrogenase Dld1.
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