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Promiscuity of lactate dehydrogenase A, malate dehydrogenase 1, and PHGDH and metabolism of 2-hydroxyglutarate

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2-Hydroxyglutarate (2-HG) derives from the promiscuity of lactate dehydrogenase A (LDHA), malate dehydrogenase 1 (MDH1), and PHGDH in the cytoplasm and malate dehydrogenase 2 (MDH2) in the mitochondria. Mutations of IDH1 and IDH2 endow them with neomorphic enzyme activity to convert alpha-KG to D-2HG (Dang et al 2009; Ward et al 2010; Showalter et al 2017; Du and Hu 2021). L-2HG and D-2HG are removed from the mitochondria by L2HGDH and D2HGDH, respectively. Abbreviations: D-2HG, D-2-hydroxyglutarate; D2HGDH, D-2-hydroxyglutarate dehydrogenase; FAD/FADH2, flavin adenine dinucleotide; 2-HG, 2-hydroxyglutarate; IDH, isocitrate dehydrogenase; L-2HG, L-2-hydroxyglutarate; L2HGDH, L-2-hydroxyglutarate dehydrogenase; LDHA, lactate dehydrogenase A; MDH, malate dehydrogenase; NAD+/NADH, nicotinamide adenine dinucleotide ; NADP+/NADPH, nicotinamide adenine dinucleotide phosphate; PHGDH, phosphoglycerate dehydrogenase.

References cited:
Dang L, White DW, Gross S, et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 2009;462(7274):739-44.
Du X, Hu H. The roles of 2-hydroxyglutarate. Front Cell Dev Biol 2021;9:651317.
Showalter MR, Hatakeyama J, Cajka T, et al. Replication study: The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Elife 2017;6:e26030.
Ward PS, Patel J, Wise DR, et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 2010;17(3):225-34.

(Source: Du X, Hu H. The roles of 2-hydroxyglutarate. Front Cell Dev Biol 2021;9:651317. Creative Commons Attribution License [CC BY].)