D‐2‐hydroxyglutaric aciduria: Case report and biochemical studies

Chalmers, R. A.; Lawson, A. M.; Watts, R. W. E.; Kamerling, J.P.; Hey, Edmund; Ogilvie, D. M.

doi:10.1007/bf02312516

Cited by 124 publications

(87 citation statements)

References 24 publications

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“…This autosomal recessive neurometabolic disorder results in the accumulation of 2HG isomers (51,52). These compounds are metabolic intermediates in reactions catalyzed by malate dehydrogenase and hydroxyacid-oxoacid transhydrogenase (53,54), and accumulation of 2HG affects some metabolic processes, such as the TCA cycle and branched-chain amino acid metabolism (55,56).…”

Section: Figure 3 Interacting Genes and Energy Metabolism-related Mementioning

confidence: 99%

Mitochondrial Citrate Transporter-dependent Metabolic Signature in the 22q11.2 Deletion Syndrome

Napoli

Tassone

Wong

et al. 2015

Journal of Biological Chemistry

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Background:The most common microdeletion congenital disorder, 22qDS, is the second risk factor for schizophrenia. Results: Plasma metabolomics in 22qDS consisted of an oxidative phosphorylation-to-glycolysis shift with altered 2-hydroxyglutaric acid, cholesterol, and fatty acid concentrations. Conclusion: Despite the haploinsufficiency of ϳ30 genes, the 22qDS metabolic signature chiefly reflected deficits in the mitochondrial citrate transporter. Significance: Biochemical profiling of 22qDS unveiled the impact of SLC25A1 haploinsufficiency.

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Section: Figure 3 Interacting Genes and Energy Metabolism-related Mementioning

confidence: 99%

Mitochondrial Citrate Transporter-dependent Metabolic Signature in the 22q11.2 Deletion Syndrome

Napoli

Tassone

Wong

et al. 2015

Journal of Biological Chemistry

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“…The five carbon dicarboxylic acid D-2HG is normally found in human urine, and is an intermediate in the synthesis of 5-aminolaevulinate and porphyrin for heme synthesis, as well as metabolism of hydroxy-lysine (Lindahl et al, 1967;Chalmers et al, 1980). Our current understanding of the metabolic origin and fate of D-2HG in mammalian cells is rather limited.…”

Section: D-2hg As a Potential Biomarker Of Cancers Harboring Idh1 Andmentioning

confidence: 99%

Cancer-associated IDH mutations: biomarker and therapeutic opportunities

et al. 2010

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The discovery of somatic mutations in the isocitrate dehydrogenase (IDH) enzymes through a genome-wide mutational analysis in glioblastoma represents a milestone event in cancer biology. The nature of the heterozygous, point mutations mapping to arginine residues involved in the substrate binding inspired several research teams to investigate their impact on the biochemical activity of these enzymes. Soon, it became clear that the mutations identified impaired the ability of IDH1 and IDH2 to catalyze the conversion of isocitrate to a-ketoglutarate (aKG), whereas conferring a gain of a novel enzymatic activity leading to the reduction of aKG to the metabolite D2-hydroxyglutarate (D-2HG). Across glioma as well as several hematologic malignancies, mutations in IDH1 and IDH2 have shown prognostic value. Several hypotheses implicating the elevated levels of D-2HG and tumorigenesis, and the therapeutic potential of targeting mutant IDH enzymes will be discussed.

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“…The interest in 2HG increased when it was found to accumulate in urine of patients with suspected inborn errors of metabolism (4,5). Most 2-hydroxyglutaric aciduria patients present elevations of either or in their extracellular fluids, and the clinical phenotype depends on the configuration of the accumulated organic acid.…”

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confidence: 99%

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

Becker-Kettern

Paczia

Conrotte

et al. 2016

Journal of Biological Chemistry

122

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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 dld3⌬ knock-out strain accumulates millimolar levels of D-2HG, whereas a dld2⌬ 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 ␣-ketoglutarate. Depletion of D-lactate levels in the dld3⌬, but not in the dld2⌬ mutant, led to the discovery of a new type of enzymatic activity, carried by Dld3, to convert D-2HG to ␣-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 ␣-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. 2-Hydroxyglutarate (2HG)3 is a 5-carbon dicarboxylic acid that was first detected in human urine in the late 1970s (1).Because of the hydroxyl group on the second carbon, 2HG exists under two enantiomeric configurations (L or D) that can be separated by gas or liquid chromatography after derivatization with another chiral compound and that can therefore be differentially assayed in biological samples using GC-MS or LC-MS methods (2, 3). The interest in 2HG increased when it was found to accumulate in urine of patients with suspected inborn errors of metabolism (4, 5). Most 2-hydroxyglutaric aciduria patients present elevations of either L-2HG or D-2HG in their extracellular fluids, and the clinical phenotype depends on the configuration of the accumulated organic acid. More recently, cases of "combined D,L-hydroxyglutaric aciduria" have been reported (6).2-Hydroxyglutaric acidurias remained enigmatic diseases because neither L-2HG nor D-2HG are intermediates of any known metabolic pathway, and the causal gene deficiencies were only discovered many years after the first patient case reports. It is now established that L-2-hydroxyglutaric aciduria is caused by loss-of-function mutations in the L2HGDH gene, encoding a specific L-2HG dehydrogenase, whereas in many cases D-2-hydroxyglutaric aciduria results from loss-of-function mutations in the D2H...

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D‐2‐hydroxyglutaric aciduria: Case report and biochemical studies

Cited by 124 publications

References 24 publications

Mitochondrial Citrate Transporter-dependent Metabolic Signature in the 22q11.2 Deletion Syndrome

Mitochondrial Citrate Transporter-dependent Metabolic Signature in the 22q11.2 Deletion Syndrome

Cancer-associated IDH mutations: biomarker and therapeutic opportunities

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

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