Dehydrogenase superfamily (DH)

The dehydrogenase superfamily comprises a diverse group of oxidoreductase enzymes that facilitate the transfer of hydrogen atoms, typically as hydride ions, from a substrate to an electron acceptor such as NAD+, NADP+, or FAD. These enzymes are fundamental to cellular metabolism, playing indispensable roles in pathways such as glycolysis, the tricarboxylic acid (TCA) cycle, and the biosynthesis of steroids, fatty acids, and nucleotides [1, 3, 11]. Beyond their metabolic functions, many dehydrogenases are involved in the detoxification of endogenous and exogenous aldehydes, protecting cells from oxidative stress and chemical damage [2, 7]. In the context of drug discovery, the superfamily is highly significant as many of its members are validated therapeutic targets for cancer, infectious diseases, and metabolic disorders [1, 8]. For example, inhibitors of dihydroorotate dehydrogenase (DHODH) are used to treat autoimmune conditions and are being investigated for oncology, while aldehyde dehydrogenase (ALDH) inhibitors are used in managing alcohol dependence [2, 8]. However, the high degree of structural conservation among family members, particularly within the Rossmann fold used for cofactor binding, presents a major challenge for achieving drug selectivity and avoiding off-target toxicity [3, 7]. Additionally, several dehydrogenases serve as critical clinical biomarkers; for instance, elevated serum levels of lactate dehydrogenase (LDH) are used to diagnose myocardial infarction and monitor various malignancies [6, 12].

Other names

OxidoreductasesReductasesNAD-dependent dehydrogenasesNADP-dependent dehydrogenases

Inhibition of enzymatic activity by competing with substrates or cofactors (such as NAD+ or NADP+) to prevent the transfer of hydride ions during redox reactions [1, 3, 7].