Original Publication: Imai S, Guarente L. NAD+ and Sirtuins in Aging and Disease. Trends in cell biology. 2014;24(8):464-471. doi:10.1016/j.tcb.2014.04.002.
NAD+ as an essential compound for many enzymatic processes
Nicotinamide adenine dinucleotide (NAD+) was discovered more than a century ago by Sir Arthur Harden as a low molecular weight substance present in a boiled yeast extract, which could stimulate fermentation and alcohol production in vitro 1. Subsequent studies over the next several decades determined that the structure of NAD+ comprised two covalently joined mononucleotides (nicotinamide mononucleotide or NMN, and AMP), and identified the keystone function of NAD+ and NADH as enzyme cofactors mediating hydrogen transfer in oxidative or reductive metabolic reactions 1.
For an extended period, NAD+ thus appeared in biochemistry textbooks with the sole function of a cofactor of enzymes serving metabolic pathways in cells. More recently, NAD+ has been associated with biochemical reactions other than hydrogen transfer, serving as a cosubstrate for bacterial DNA ligase 2, poly-ADP-ribose polymerase or PARP 3, CD38/157 ectoenzymes 4, and class III NAD+-dependent deacylases or sirtuins 5. In all of these newer examples, NAD+ is cleaved at the glycosidic bond between nicotinamide and ADP ribose (Figure 1, described in detail, below). For the ligase, ADP ribose is transferred to the 5′ hydroxyl of DNA to be ligated. For PARP, ADP ribose is serially transferred to arginine side chains in itself, histones, and other proteins at sites of DNA damage. For CD38/157, NAD+ is provided through the connexin 43 hemichannels and hydrolyzed extracellularly. These enzymes also generate cyclic ADP-ribose, a strong Ca2+ inducer. Lastly, for sirtuins, NAD+ cleavage catalyzes the removal of acetyl or acyl groups from lysines of sirtuin substrate proteins accompanied by their transfer to ADP ribose.