FIG. 2.
The NAD+ metabolome. l-TRYP, NA, NAM, NMN, NR, and NAR can be used as precursors for NAD+ synthesis. (A) l-TRYP is catabolized to N-formylkynurenine (N-f-KYN) by IDO or TDO. (B) N-f-KYN is catabolized by arylformidase to form KYN. (C) KATs catabolize KYN to form KA. (D) Kynurenine 3-hydroxylase uses KYN as a substrate to form 3-HK. (E) Kynureninase then forms 3-HAA, which is converted to 2-amino-3-carboxymuconate semialdehyde (not shown) by (F) 3-HAAO. (G) This product is then converted to picolinic acid by picolinic acid carboxylase. (H) Alternatively, the semialdehyde undergoes spontaneous condensation and rearrangement to form QUIN, which forms NAMN by (I) QPRT. (U) NAMN undergoes adenylylation by NMNAT1-3 to form NAAD, which forms NAD+ by (M) glutamine-dependent NAD+ synthetases. NA is used by the Preiss–Handler pathway. (L) NAMN is formed by NAPRT following addition of 5-phosphoribose group from PRPP to NA. (P) NAMPT forms NMN by addition of phosphoribose moiety to NAM. (U) NMN is then converted to NAD+ via the catalytic activity of NMNAT1-3. (N) NAM is also produced as a by-product of NAD-dependent enzymes, for example, PARPs, sirtuins, and CD38. (O) NAM can also be converted to NA by bacterial nicotinamidases. (J) NR is phosphorylated to form NMN by NRK1/NRK2, which is then subsequently converted to NAD+ by NMNAT1-3. (J) NAR can also be used to form NAMN by NRK1/NRK2 or (K) NA by purine nucleoside phosphorylase. (Q) NAM is methylated NNMT to MeNAM and modulates the efficiency of NAD-dependent biological processes. (T) NAD+ can be reduced to form NADH. (R) NAD+ can also undergo phosphorylation to NADP+ (S) and then further reduction to NADPH. 3-HAA, 3-hydroxyanthranilic acid; 3-HAAO, 3-hydroxyanthranilic acid oxygenase; KA, kynurenic acid; KATs, kynurenine aminotransferases; KYN, kynurenine; l-TRYP, l-tryptophan; MeNAM, N-methylnicotinamide; NA, nicotinic acid; NAAD, nicotinic acid adenine dinucleotide; NAM, nicotinamide; NAMN, nicotinic acid mononucleotide; NAMPT, nicotinamide phosphoribosyltransferase; NAPRT, nicotinic acid phosphoribosyltransferase; NAR, nicotinic acid riboside; NMN, nicotinamide mononucleotide; NMNAT, nicotinamide mononucleotide adenylyltransferase; NNMT, nicotinamide N-methyltransferase; NR, nicotinamide riboside; NRK, nicotinamide riboside kinase; PRPP, 5-phosphoribosyl-1-pyrophosphate; QPRT, quinolinic acid phosphoribosyltransferase; TDO, tryptophan 2,3-dioxygenase.
















