Metabolism of γ-hydroxybutyrate to d-2-hydroxyglutarate in mammals: further evidence for d-2-hydroxyglutarate transhydrogenase

Struys, Eduard A.; Verhoeven, Nanda M.; Jansen, Erwin E.W.; Brink, H.J. ten; Gupta, Maneesh; Burlingame, T. G.; Quang, Lawrence S.; Maher, Timothy J.; Rinaldo, Piero; Snead, O. Carter; Goodwin, Amy K.; Weerts, Elise M.; Brown, Paul; Murphy, Tonya C.; Picklo, Mathew J.; Jakobs, C; Gibson, K. Michael

doi:10.1016/j.metabol.2005.09.009

Cited by 45 publications

(39 citation statements)

References 40 publications

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“…Hydrogen transfer between 2-HG/2-KG and GHB/SSA was confirmed by rat liver perfusion with [ 2 H 6 ]GHB, and M1 2-HG was labeled by 90% from [ 2 H 6 ]GHB. Hydrogen transfer between 2-HG and GHB by transhydrogenase was also reported by Struys et al (35).…”

Section: Discussionsupporting

confidence: 72%

“…GHB was not labeled from the perfusion with [3,[4][5][6][7][8][9][10][11][12][13] C 2 ]HNA, although 2-HG was M2-labeled in the perfusion with [3,4-13 C 2 ]HNA. Clearly, GHB production is coupled with the oxidation of 2-HG to 2-KG (35). In this experiment, OTHFPA-CoA catabolized from HNA/HNE was confirmed by perfusing rat livers with labeled and unlabeled OTHFPA.…”

Section: Resultsmentioning

confidence: 60%

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Catabolism of (2E)-4-Hydroxy-2-nonenal via ω- and ω-1-Oxidation Stimulated by Ketogenic Diet

Jin

Berthiaume

et al. 2014

Journal of Biological Chemistry

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Background: (2E)-4-hydroxy-2-nonenal (HNE) catabolism and its regulation remain to be fully investigated. Results: New catabolic pathways of HNE via -/-1-oxidation are elucidated and up-regulated in a ketogenic diet. Conclusion: HNE catabolism plays a major role in HNE disposal in certain organs. Significance: This work will further enhance our understanding of the metabolic fate of HNE and the roles of -and -1-oxidations in HNE disposal.

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Section: Discussionsupporting

confidence: 72%

Section: Resultsmentioning

confidence: 60%

Catabolism of (2E)-4-Hydroxy-2-nonenal via ω- and ω-1-Oxidation Stimulated by Ketogenic Diet

Jin

Berthiaume

et al. 2014

Journal of Biological Chemistry

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“…The prevailing hypothesis among the groups that study this metabolite in hydroxyglutaric aciduria is that 2-HG represents an error of normal metabolism that is corrected by the appropriate 2-HG dehydrogenase enzymes (264,289,290,314). The evidence for this comes from studies into the chemical origin of 2-HG in normal tissues; substrate labeling studies have indicated that the L-2-HG stereoisomer is derived from 2-OG that is aberrantly reduced by the downstream CAC enzyme malate dehydrogenase (25).…”

Section: Cyr and Domannmentioning

confidence: 99%

The Redox Basis of Epigenetic Modifications: From Mechanisms to Functional Consequences

Cyr

Domann

2011

Antioxidants & Redox Signaling

243

168

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Epigenetic modifications represent mechanisms by which cells may effectively translate multiple signaling inputs into phenotypic outputs. Recent research is revealing that redox metabolism is an increasingly important determinant of epigenetic control that may have significant ramifications in both human health and disease. Numerous characterized epigenetic marks, including histone methylation, acetylation, and ADP-ribosylation, as well as DNA methylation, have direct linkages to central metabolism through critical redox intermediates such as NAD + , S-adenosyl methionine, and 2-oxoglutarate. Fluctuations in these intermediates caused by both normal and pathologic stimuli may thus have direct effects on epigenetic signaling that lead to measurable changes in gene expression. In this comprehensive review, we present surveys of both metabolism-sensitive epigenetic enzymes and the metabolic processes that may play a role in their regulation. To close, we provide a series of clinically relevant illustrations of the communication between metabolism and epigenetics in the pathogenesis of cardiovascular disease, Alzheimer disease, cancer, and environmental toxicity. We anticipate that the regulatory mechanisms described herein will play an increasingly large role in our understanding of human health and disease as epigenetics research progresses. Antioxid. Redox Signal. 15, 551-589.

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“…However, because of their different three-dimensional spatial configurations, the two compounds are recognized by different enzymes. L-2-HG is formed from 2-KG by the side activity of L-malate dehydrogenase and is converted back to 2-KG by the catalytic action of L-2-hydroxyglutarate dehydrogenase (L-2-HGDH) [2,25,26]. An inherited deficiency of L-2-HGDH, caused by mutations in the gene L2HGDH located on chromosome region 14q22.1, results in the metabolic disorder L-2-HGA (OMIM #236792) [27][28][29].…”

Section: Discussionmentioning

confidence: 99%

Papillary thyroid carcinoma shows elevated levels of 2-hydroxyglutarate

et al. 2010

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Elevated levels of D: -2-hydroxyglutarate (D: -2-HG) occur in gliomas and myeloid leukemias associated with mutations of IDH1 and IDH2. L: -2-Hydroxyglutaric aciduria, an inherited metabolic disorder, predisposes to brain tumors. Therefore, we asked whether sporadic cancers, without IDH1 or IDH2 hot-spot mutations, show elevated 2-hydroxyglutarate levels. We retrieved 15 pairs of frozen papillary thyroid carcinoma (PTC) and adjacent non-neoplastic thyroid, and 14 pairs of hyperplastic nodule (HN) and adjacent non-hyperplastic thyroid. In all lesions, exon 4 sequencing confirmed the absence of known mutations of IDH1 and IDH2. We measured 2-hydroxyglutarate by liquid chromatography-tandem mass spectrometry. Compared to normal thyroid, PTCs had significantly higher D: -2-HG and L: -2-hydroxyglutarate (L: -2-HG) levels, and compared to HNs, PTCs had significantly higher D: -2-HG levels. D: -2-HG/L: -2-HG levels were not significantly different between HNs and normal thyroid. Further studies should clarify if elevated 2-hydroxyglutarate in PTC may be useful as cancer biomarker and evaluate the role of 2-hydroxyglutarate in cancer biology.

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Metabolism of γ-hydroxybutyrate to d-2-hydroxyglutarate in mammals: further evidence for d-2-hydroxyglutarate transhydrogenase

Cited by 45 publications

References 40 publications

Catabolism of (2E)-4-Hydroxy-2-nonenal via ω- and ω-1-Oxidation Stimulated by Ketogenic Diet

Catabolism of (2E)-4-Hydroxy-2-nonenal via ω- and ω-1-Oxidation Stimulated by Ketogenic Diet

The Redox Basis of Epigenetic Modifications: From Mechanisms to Functional Consequences

Papillary thyroid carcinoma shows elevated levels of 2-hydroxyglutarate

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