Metabolism, Activity, and Targeting of D- and L-2-Hydroxyglutarates

Abstract

Isocitrate dehydrogenases (IDH1/2) are frequently mutated in multiple types of human cancer, resulting in neomorphic enzymes that convert α-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG). The current view on the mechanism of IDH mutation holds that 2-HG acts as an antagonist of α-KG to competitively inhibit the activity of α-KG-dependent dioxygenases, including those involved in histone and DNA demethylation. Recent studies have implicated 2-HG in activities beyond epigenetic modification. Multiple enzymes have been discovered that lack mutations but that can nevertheless produce 2-HG promiscuously under hypoxic or acidic conditions. Therapies are being developed to treat IDH-mutant cancers by targeting either the mutant IDH enzymes directly or the pathways sensitized by 2-HG.

Figure 1. Metabolism and Targets of 2-Hydroxyglutarate (2-HG)

The thick and thin arrows represent the primary and promiscuous reactions, respectively. FAD, flavin adenine dinucleotide; FADH2, reduced form of FAD; NADP, nicotinamide adenine dinucleotide phosphate; NADPH, reduced form of NADP. Additional abbreviations are listed in Table 1.

Figure 2. Production of 2-Hydroxyglutarate (2-HG) by Promiscuous Enzymatic Reactions

The thick and thin arrows represent the primary and promiscuous reactions, respectively. PHDGH, phosphoglycerate dehydrogenase; 3PG, 3-phosphoglycerate; 3PHP, 3-phosphohydroxypyruvate. Additional abbreviations are listed in Figure 1.