the sirtuin deacetylases, the adenosine diphosphate (ADP)-ribose transferases/poly(ADP-ribose) polymerases, and the cyclic ADP-ribose (cADPR) synthases. The ensuing protein modification and messenger generation play a spectrum of roles in gene-regulatory, signaling, metabolic and cellular homeostasis pathways, and also in aging and diseases. Unlike the reversible shuttling between oxidized and reduced forms, which do not change the overall coenzyme concentration, the activity of NAD-consuming enzymes requires the replenishing of the NAD pool. This heightens the importance of NAD biosynthesis and of its regulation. Several routes exist to synthesize NAD+ from various dietary sources. A de novo pathway, downstream of kynurenine metabolism of tryptophan degradation, uses quinolinic acid (QUIN) as the starting material. Others, described as salvage pathways and the primary source of NAD, use dietary niacin (vitamin B3) - nicotinic acid (NA) and its pyridine-nucleoside or amide forms of nicotinamide riboside (NR) and nicotinamide (NAM), respectively. NAM is also the product of the reactions carried out by the enzymes that use NAD+ as a substrate and which split the molecule at its N-glycosidic bond. The pathways of NAD synthesis employ distinct enzymes to process the various starting molecules, but they eventually converge in the final step(s). The de novo and salvage pathways are shown in the diagram for the NAD+ biosynthetic pathway; each route is described. The NAD+ consuming enzymes/reactions are briefly presented.

de novo NAD biosynthetic pathway
Kynurenine (KYN) metabolism is the major route of tryptophan degradation. The 2-amino-3-carboxymuconic 6-semialdehyde (ACMS) produced by one of the two arms of KYN metabolism spontaneously rearranges to QUIN. QUIN is the substrate for the quinolinate phosphoribosyltransferase (QPRT)-catalyzed reaction yielding nicotinic acid mononucleotide (NAMN). Nicotinamide mononucleotide (NMN) adenylyltransferases (NMNAT) catalyze the conversion of NAMN into nicotinic acid adenine dinucleotide (NAAD), which is then converted to NAD+ by NAD synthetase 1 (NADSYN1). There are three Nmnat enzymes with specific cellular localizations and tissue expression: Nmnat1 is primarily nuclear, Nmnat2 is cytosolic and Golgi-resident, Nmnat 3 is found in the cytosol and mitochondria. The three enzymes are also involved in the final step of NAD+ synthesis in the salvage pathways.

Salvage pathways of NAD biosynthesis
Nicotinamide (NAM), the by-product of reactions catalyzed by NAD+ consuming enzymes, is a major source of NAD synthesis in the salvage pathway. The others include the diet-derived nicotinic acid (NA) and nicotinamide riboside (NR). NA is converted to NAMN by nicotinic acid ribosyltransferase (NAPRT1) in what is known as the Preiss-Handler pathway. NAMN is further processed by the Nmnat enzymes, as described above. NR is converted to nicotinamide mononucleotide (NMN) by NR kinases Nmrk1 and Nmrk2 while NAM conversion to NMN is carried out by nicotinamide phosphoribosyltransferase, Nampt - the rate-limiting enzyme in the salvage pathway. Circadian clock proteins control the expression of Nampt. NMN is directly converted to NAD+ by the Nmnat enzymes.

NAD-consuming enzymes
The enzymes consuming NAD include the sirtuin deactylases, the adenosine diphosphate (ADP)-ribose transferases/poly(ADP-ribose) polymerases and the cyclic ADP-ribose (cADPR) synthases. The ensuing protein modification and messenger generation play a spectrum of roles in gene-regulatory, signaling, metabolic and cellular homeostasis pathways, and also in aging and diseases. There are three pathways of NAD utilization: the sirtuin mediated pathway and the ADP ribosylation pathways: mono and poly-ribosylation, and cyclic ribosylation. The enzymes are only briefly described here.
Sirtuins. The many deacetylases are grouped in class I, II and IV, and in class III, depending on whether they are the classical Zn2+ dependent or the NAD+ dependent enzymes, respectively. Class III is comprised of Sirtuin 1-7, that deacetylate histones and other proteins and some may also act as mono-ADP-ribosyl transferases.
PARPs. Mono(ADP-ribosylation) and poly(ADP-ribosylation) are posttranslational modifications of proteins carried out by members of poly(ADP-ribose) polymerases - PARPs, which catalyze the transfer of the ADP-ribose moiety of NAD to protein acceptors. There are currently about 17 members of the PARP family, the majority of which is involved in mono-ribosylation. Poly-ribosylation, which can add up to 200 units, drastically reduces the pool of available NAD. Several proteins are involved in the recognition of modified substrates, others participate in removing the modification.
CD38 and CD157. The CD38 and CD157 ectoenzymes are involved in the synthesis of cyclic ADP-ribose (cADPR). Like the poly-ribosylation reaction, the CD38-catalyzed reaction is highly NAD-consuming, yielding one molecule of cADPR for ~100 NAD hydrolyzed. cADPR and related NAADP are involved in calcium pathways by promoting its release from various stores.

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