Nicotinamide adenine dinucleotide-dependent dehydrogenase superfamily (NAD-dependent dehydrogenase superfamily)

The Nicotinamide adenine dinucleotide (NAD)-dependent dehydrogenase superfamily is a vast and diverse group of enzymes characterized by their ability to catalyze oxidation-reduction reactions using NAD+ or NADP+ as a cofactor. These enzymes typically share a common structural motif known as the Rossmann fold, which facilitates the binding of the nucleotide cofactor. Members of this superfamily, such as lactate dehydrogenase, alcohol dehydrogenase, and glyceraldehyde-3-phosphate dehydrogenase, play fundamental roles in primary metabolism, including glycolysis, the TCA cycle, and the pentose phosphate pathway. Because these enzymes are central to energy production and biosynthetic processes, they are frequently implicated in diseases like cancer, where metabolic reprogramming is a hallmark, and in various metabolic and infectious diseases. While the superfamily itself is too broad to be considered a single therapeutic target, many of its individual members are high-priority targets for drug development. Pharmacological intervention usually involves small-molecule inhibitors designed to block the catalytic activity of specific enzymes, though the high degree of structural conservation across the superfamily poses significant challenges for achieving selectivity and avoiding off-target effects.

Other names

NAD-binding proteinsRossmann fold dehydrogenasesNAD(P)-dependent oxidoreductasesNAD-linked dehydrogenases

Drugs typically act as competitive or non-competitive inhibitors of specific member enzymes, often by targeting the NAD+ binding pocket or the substrate-binding site to disrupt essential metabolic pathways or redox balance.