Abstract

The role of NAD⁺ metabolism in health and disease is of increased interest as the use of niacin (nicotinic acid) has emerged as a major therapy for treatment of hyperlipidemias and with the recognition that nicotinamide can protect tissues and NAD⁺ metabolism in a variety of disease states, including ischemia/reperfusion. In addition, a growing body of evidence supports the view that NAD⁺ metabolism regulates important biological effects, including lifespan. NAD⁺ exerts potent effects through the poly(ADP-ribose) polymerases, mono-ADP-ribosyltransferases, and the recently characterized sirtuin enzymes. These enzymes catalyze protein modifications, such as ADP-ribosylation and deacetylation, leading to changes in protein function. These enzymes regulate apoptosis, DNA repair, stress resistance, metabolism, and endocrine signaling, suggesting that these enzymes and/or NAD⁺ metabolism could be targeted for therapeutic benefit. This review considers current knowledge of NAD⁺ metabolism in humans and microbes, including new insights into mechanisms that regulate NAD⁺ biosynthetic pathways, current use of nicotinamide and nicotinic acid as pharmacological agents, and opportunities for drug design that are directed at modulation of NAD⁺ biosynthesis for treatment of human disorders and infections.