FIG. 4.

NAD⁺ biosynthetic pathways in mammals. Four building blocks may be used for NAD⁺ synthesis: L-tryptophan, NA, NR, and NAM. The de novo pathway uses L-tryptophan to generate, through several intermediate steps, quinolinate. Quinolinate is sequentially converted to NAMN, NAAD, and NAD⁺ by the action of QPRT, NMNATs, and NADS, respectively. In the Preiss-Handler pathway, NAPRT converts NA to NAMN, which is then used by NMNATs. NR can enter the salvage pathway either by the action of NRK, which generates NMN, or by the reaction catalyzed by PNP, which generates NAM. NAM is subsequently converted to NMN by NAMPT, the rate-limiting step in the salvage pathway. NRKs can also convert NAR to NAMN. All the biosynthetic pathways converge at the level of dinucleotide formation catalyzed by the NMNATs. NMNATs use NAMN and NMN with similar efficiency. NAD⁺-consuming reactions catalyzed by PARPs, CD38, and sirtuins release NAM that may be use to resynthesize NAD⁺ in the salvage pathway. NA, nicotinic acid; NAD⁺, nicotinamide adenine dinucleotide; NAAD, nicotinic acid adenine dinucleotide; NADS, NAD⁺ synthetase; NAM, nicotinamide; NAR, nicotinic acid riboside; NR, nicotinamide riboside; NRK, NR kinase; NMN, nicotinamide mononucleotide; NAMN, nicotinic acid mononucleotide; NAMPT, nicotinamide phosphoribosyltransferase; NAPRT, nicotinic acid phosphoribosyltransferase; NMNAT, nicotinamide mononucleotide adenylyl transferase; PNP, purine nucleoside phosphorylase; QPRT, quinolinate phosphoribosyltransferase.