The Roles of 2-Hydroxyglutarate

Abstract

2-Hydroxyglutarate (2-HG) is structurally similar to α-ketoglutarate (α-KG), which is an intermediate product of the tricarboxylic acid (TCA) cycle; it can be generated by reducing the ketone group of α-KG to a hydroxyl group. The significant role that 2-HG plays has been certified in the pathophysiology of 2-hydroxyglutaric aciduria (2HGA), tumors harboring mutant isocitrate dehydrogenase 1/2 (IDH1/2mt), and in clear cell renal cell carcinoma (ccRCC). It is taken as an oncometabolite, raising much attention on its oncogenic mechanism. In recent years, 2-HG has been verified to accumulate in the context of hypoxia or acidic pH, and there are also researches confirming the vital role that 2-HG plays in the fate decision of immune cells. Therefore, 2-HG not only participates in tumorigenesis. This text will also summarize 2-HG’s identities besides being an oncometabolite and will discuss their enlightenment for future research and clinical treatment.

Metabolomic Changes in Naturally MAP-Infected Holstein–Friesian Heifers Indicate Immunologically Related Biochemical Reprogramming

“…The compound 2-hydroxyglutarate is produced from the TCA intermediate α-ketoglut arate using isocitrate dehydrogenase (IDH) 1 or 3-phosphoglycerate dehydrogenase [26]. Due to its structural similarity to α-ketoglutarate, it can also be produced, at low levels, from malate dehydrogenase (MDH) (which converts malate to oxaloacetate) or lactate dehydrogenase [27]. The accumulation of 2-hydroxyglutarate is a feature of glioblastoma and acute myeloid leukaemia and has been suggested to contribute to carcinogenesis through epigenetic changes and altered immune responses [28].…”

Embryonic developmental arrest in the annual killifish Austrolebias charrua: A proteomic approach to diapause III

“…Although this may be of great importance for diapause embryos since they must overcome stressors, another factor must be considered. The alpha-ketoglutarate obtained by GDH could produce2-hydroxyglutarate in a reaction catalyzed by 3-phosphoglycerate dehydrogenase (PHGDH) or by the action of malate dehydrogenase [ 42 , 43 ] Of the two enzymes, the only one present in the current work was the malate dehydrogenase (but without reaching the required levels to be considered differentially expressed). Interestingly, a metabolomic analysis carried out in Austrofundulus limnaeus embryos suffering from dehydration stress during their diapause detected the metabolite 2-hydroxyglutarate [ 44 ].…”

Metabolic Reprogramming: A Friend or Foe to Cancer Therapy?

“…Similarly, pyruvate has proven ability to inhibit HDAC1/HDAC3 and induce apoptosis [134]; however, many cancers upregulate the LDH-A (lactate-deydrogenase-A) gene [135] to enhance the conversion of pyruvate to lactate and overcome these pro-apoptotic effects. In many respects the metabolite 2-hydroxyglutarate, an intermediate in the TCA cycle can be considered a 'classical' oncometabolite which exerts its pro-tumourigenic function through epigenetic effects, hypoxia regulation and immunosuppressive activity (expertly reviewed in [136]). Notably, silencing or inhibition of class-I HDACs have been observed to manipulate the expression of key players in both the intrinsic and extrinsic apoptotic pathways [137,138].…”