Nicotinamide adenine dinucleotide-dependent enzymes (NAD-dependent enzymes)

Nicotinamide adenine dinucleotide (NAD)-dependent enzymes are a vast and diverse superfamily of proteins that utilize NAD+ or its reduced form, NADH, as essential cofactors or substrates to drive biochemical transformations. This group encompasses oxidoreductases critical for cellular respiration and metabolic pathways like glycolysis and the TCA cycle, as well as signaling enzymes such as sirtuins (SIRTs), poly(ADP-ribose) polymerases (PARPs), and ADP-ribosyl cyclases like CD38 (Cantó et al., 2015, Cell Metabolism). These enzymes are fundamental to maintaining cellular homeostasis, regulating energy production, DNA repair, gene expression via epigenetic modifications, and calcium-mediated signaling (Covarrubias et al., 2021, Nature Reviews Molecular Cell Biology). Given their central role in physiology, dysregulation of NAD-dependent enzymes is implicated in a wide array of pathologies, including oncogenesis, neurodegeneration, and metabolic syndrome. Therapeutic strategies targeting this class include the use of PARP inhibitors for DNA repair-deficient cancers and the development of sirtuin modulators or CD38 inhibitors to address aging and inflammatory conditions (Lord & Ashworth, 2017, Science). However, the ubiquity of NAD+ in cellular processes presents a significant challenge for achieving drug selectivity and minimizing systemic toxicity.

Other names

NAD+-dependent enzymesNAD(H)-dependent enzymesNicotinamide adenine dinucleotide-linked enzymesNAD-consuming enzymes

Inhibition of enzymatic activity through competitive binding at the NAD+ site or modulation of the cellular NAD+ pool (Lord & Ashworth, 2017, Science; Cantó et al., 2015, Cell Metabolism).