D-2-hydroxyacid dehydrogenase (2HADH)

D-2-hydroxyacid dehydrogenase (2HADH) is a diverse family of oxidoreductases that catalyze the stereospecific, NAD(P)(H)-dependent reversible reduction of 2-ketocarboxylic acids to their corresponding D-2-hydroxycarboxylic acids. In humans, this family includes several enzymes with distinct metabolic roles, such as D-2-hydroxyglutarate dehydrogenase (D2HGDH), glyoxylate reductase/hydroxypyruvate reductase (GRHPR), D-lactate dehydrogenase (LDHD), 3-phosphoglycerate dehydrogenase (PHGDH), and the C-terminal binding proteins (CtBP1 and CtBP2). These enzymes are critical for metabolite repair and detoxification; for example, D2HGDH metabolizes the oncometabolite D-2-hydroxyglutarate, while GRHPR prevents the accumulation of glyoxylate, which otherwise leads to toxic oxalate production. Mutations in these enzymes are linked to rare metabolic disorders such as D-2-hydroxyglutaric aciduria and primary hyperoxaluria type II. In oncology, members like PHGDH and CtBP are significant therapeutic targets; PHGDH is often overexpressed in breast and lung cancers to support the serine biosynthesis pathway, while CtBPs act as transcriptional corepressors that promote cell survival and epithelial-mesenchymal transition. Consequently, small-molecule inhibitors of PHGDH and CtBP are under active investigation as potential anti-cancer agents.

Other names

D-isomer specific 2-hydroxyacid dehydrogenaseD-2-hydroxy acid dehydrogenase(R)-2-hydroxy-acid:acceptor 2-oxidoreductase2HADH familyD-isomer-specific 2-hydroxyacid dehydrogenase

Competitive inhibition of enzyme activity, disruption of metabolic pathways such as serine biosynthesis, and inhibition of transcriptional corepression by blocking the dehydrogenase domain of CtBP proteins.