NAD+ Precursor Metabolism and NAD+-Consuming Enzymes
Trp, NA, NAM, and NR are utilized through distinct metabolic pathways to form NAD+.
(A) NAD+ synthesis from NA, also known as the Preiss-Handler pathway, is initiated by the NAPRT, which uses PRPP to form NAMN. Together with ATP, NAMN is then converted into NAAD by the NMNAT1–3 enzymes. Finally, NAAD is transformed to NAD+ through an amidation reaction catalyzed by the NADSYN enzyme. (B) The de novo biosynthesis of NAD+ from Trp starts with the conversion of Trp to N-formylkynurenine by either IDO or TDO. After four reaction steps, N-formylkynurenine can be subsequently converted to the unstable ACMS, which can undergo nonenzymatic cyclization to quinolinic acid. The last step of the de novo biosynthesis component is comprised of the QPRT-catalyzed formation of NAMN, using PRPP as a co-substrate, which is converted to NAD+ via the remaining pathway described in (A). (C) ACMS can also be diverted away from NAD+ synthesis, by ACMSD, to form AMS and can then be oxidized via the glutarate pathway and TCA cycle to CO2 and water, or nonenzymatically converted to picolinic acid. (D) The synthesis of NAD+ from NAM or NR is more direct and relies on only two steps each. NAM is converted by the rate-limiting NAMPT to form NMN, using PRPP as cosubstrate. NMN is also the product of phosphorylation of NR by the NR kinases (NRK1 and NRK2). The subsequent conversion of NMN to NAD+ is catalyzed by the NMNAT enzymes. The blue boxes depict the three families of NAD+-consuming enzymes and some of the key processes to which they have been linked. ACMS, α-amino-β-carboxymuconate-ε-semialdehyde; ACMSD, ACMS decarboxylase; AMS, α-amino-β-muconate-ε-semialdehyde; IDO, indoleamine 2,3-dioxygenase; NA, nicotinic acid; NAAD, NA adenine dinucleotide; NADSYN, NAD+ synthetase; NAMN, NA mononucleotide; NAMPT, nicotinamide phosphoribosyltransferase; NAPRT, NA phosphoribosyltransferase; NMN, NAM mononucleotide; NMNAT, NMN adenylyltransferase; NR, nicotinamide riboside; NRK, NR kinase; PRPP, phosphoribosyl pyrophosphate; QPRT, quinolinate phosphoribosyltransferase; TDO, tryptophan 2,3-dioxygenase; Trp, Tryptophan.