NADH-dependent dehydrogenase and oxidoreductase

NADH-dependent dehydrogenases and oxidoreductases represent a vast and diverse superfamily of enzymes that facilitate the transfer of electrons between substrates and the nicotinamide adenine dinucleotide (NAD+/NADH) cofactor (UniProt, 2024). These enzymes are fundamental to cellular metabolism, playing critical roles in glycolysis, the citric acid cycle, and the mitochondrial electron transport chain (Wikipedia, 2024). Because they govern energy production and redox balance, specific members of this class are frequently targeted in the treatment of various conditions, including cancer, bacterial infections, and metabolic disorders (Valvona et al., 2016; Vilchèze and Jacobs, 2007). For instance, the biguanide metformin targets mitochondrial Complex I, while the antitubercular drug isoniazid inhibits the NADH-dependent enoyl-ACP reductase InhA (Bridges et al., 2014). However, the high degree of structural conservation in the NADH-binding domain, often characterized by the Rossmann fold, presents significant challenges for achieving drug selectivity (Rao and Rossmann, 1973). Therapeutic modulation of these enzymes can lead to profound changes in cellular bioenergetics, making them both potent and high-risk targets for drug development.

Other names

NAD-dependent oxidoreductaseNADH-linked dehydrogenaseNicotinamide adenine dinucleotide-dependent enzyme

Drugs targeting this class typically act as competitive or non-competitive inhibitors of the enzyme active site or the NADH/NAD+ cofactor binding pocket (Rossmann fold), thereby halting critical metabolic fluxes or electron transport (Bridges et al., 2014; Vilchèze and Jacobs, 2007).