A bstract. A century after the identification of a coenzymatic activity for NAD+, NAD+ metabolism has come into the spotlight again due to the potential therapeutic relevance of a set of enzymes whose activity is tightly regulated by the balance between the oxidized and reduced forms of this metabolite. In fact, the actions of NAD+ have been extended from being an oxidoreductase cofactor for single enzymatic activities to acting as substrate for a wide range of proteins. These include NAD+-dependent protein deacetylases, poly(ADP-ribose) polymerases, and transcription factors that affect a large array of cellular functions. Through these effects, NAD+ provides a direct link between the cellular redox status and the control of signaling and transcriptional events. Of particular interest within the metabolic/endocrine arena are the recent results, which indicate that the regulation of these NAD+-dependent pathways may have a major contribution to oxidative metabolism and life span extension. In this review, we will provide an integrated view on: 1) the pathways that control NAD+ production and cycling, as well as its cellular compartmentalization; 2) the signaling and transcriptional pathways controlled by NAD+; and 3) novel data that show how modulation of NAD+-producing and -consuming pathways have a major physiological impact and hold promise for the prevention and treatment of metabolic disease.
NAD+, discovered over a century ago as a fermentation cofactor, has been extensively researched. Key discoveries, including those by Otto Warburg in the 1930s, highlighted its role in enzymatic reactions. Recently, NAD+-consuming proteins like sirtuins have been identified, showing NAD+’s function as a metabolic regulator linked to aging-related diseases such as type 2 diabetes and cancer.
This review covers NAD+ metabolism, including its biosynthesis from tryptophan and niacins (nicotinic acid, nicotinamide, and NAM riboside), its role in oxidoreductase reactions, and its potential as a therapeutic target for metabolic diseases.
