Nicotinamide adenine dinucleotide (NAD+) biosynthetic and salvage pathway (NAD+ pathway)

The Nicotinamide adenine dinucleotide (NAD+) biosynthetic and salvage pathway is a fundamental metabolic network that regulates the availability of NAD+, a vital coenzyme for redox reactions and a substrate for signaling enzymes (Navas & Verdin, 2021). In mammalian cells, the salvage pathway is the primary route for NAD+ production, converting nicotinamide into nicotinamide mononucleotide (NMN) via the rate-limiting enzyme nicotinamide phosphoribosyltransferase (NAMPT) (Galli et al., 2020). This pathway plays a pivotal role in maintaining genomic stability, energy metabolism, and circadian rhythms by providing the necessary NAD+ for PARPs and sirtuins (Cantó et al., 2015). Dysregulation of NAD+ metabolism is a hallmark of several pathologies, including cancer, where elevated NAMPT levels support the high energy demands and DNA repair capacity of malignant cells. Consequently, NAMPT inhibitors have been developed as potential anti-cancer agents to induce metabolic collapse and apoptosis in tumors. Conversely, NAD+ levels naturally decline with age, contributing to metabolic decline and neurodegeneration, which has led to the investigation of NAD+ precursors like nicotinamide riboside (NR) as therapeutic supplements (Verdin, 2015). Therapeutic strategies targeting this pathway thus range from enzymatic inhibition to substrate supplementation, depending on the disease context.

Other names

NAD+ metabolismNicotinamide salvage pathwayNAD+ biosynthesisPreiss-Handler pathwayDe novo NAD+ synthesis pathwayNicotinamide adenine dinucleotide metabolism

The pathway is targeted either through the inhibition of rate-limiting enzymes like nicotinamide phosphoribosyltransferase (NAMPT) to deplete NAD+ levels in cancer cells, or through the supplementation of precursors like nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) to restore NAD+ levels in aging and metabolic diseases.