Figure 1. Primary pathways of NAD metabolism.

There are two major pathways contributing to NAD synthesis: de novo synthesis and salvage from precursors. The de novo pathway of NAD synthesis converts tryptophan to quinolinic acid (QA) via the kynurenine pathway. The salvage pathways recycle nicotinamide mononuclotide (NMN), nicotinamide riboside (NR), nicotinamide (NAM) and nicotinic acid (NA) in various cellular compartments including the nucleus and mitochondria. These precursors are present in the extracellular milieu and may be transported across the plasma membrane where they are utilized. Extracellular NAD is cleaved by nucleotide phosphatases (CD73) or glycohydrolases (CD38 and CD157). Cleavage by CD73 yields NMN which CD73 can then re-cleave to yield NR. Cleavage by CD38 or CD157 yields NAM. NAM is also produced within cells by NAD⁺-consuming enzymes such as sirtuins, PARPS and SARM1. NAM and NR are converted to NMN by NAMPT and NRKs respectively. NMN and NAMN then are converted to NAD and NAAD respectively and NAAD is amidated by NADS to yield NAD. Cellular NAD levels may be boosted by activators of the salvage pathway (green) or by inhibitors of enzymes that consume NAD⁺ such as CD38, PARPs, and SARM1 (red).