Review articles
Reconstructing eukaryotic NAD metabolism Anthony Rongvaux, Fabienne Andris, ´ ric Van Gool, and Oberdan Leo* Fre´de
Summary In addition to its well-known role as a coenzyme in oxidation–reduction reactions, the distinct role of NAD as a precursor for molecules involved in cell regulation has been clearly established. The involvement of NAD in these regulatory processes is based on its ability to function as a donor of ADP-ribose; NAD synthesis is therefore required to avoid depletion of the intracellular pool. The rising interest in the biosynthetic routes leading to NAD formation and the highly conserved nature of the enzymes involved prompted us to reconstruct the NAD biosynthetic routes operating in distinct eukaryotic organisms. The evidence obtained from biochemical and computational analysis provides a good example of how complex metabolic pathways may evolve. In particular, it is proposed that the development of several NAD biosynthetic routes during evolution has led to partial functional
Laboratoire de Physiologie Animale, Universite´ Libre de Bruxelles, Belgium. Funding agencies: The Belgian Program in Interuniversity Poles of Attraction initiated by the Belgian State, Prime Minister’s office, Science Policy Programming and by a Research Concerted Action of the Communaute´ Franc¸aise de Belgique. The scientific responsibility is assumed by its authors. A.R. is a research fellow of the Fonds National de la Recherche Scientifique and F.V.G. is supported by a grant from the Fonds pour la formation a` la Recherche dans l’Industrie et dans l’Agriculture. *Correspondence to: Oberdan Leo, Laboratoire de Physiologie Animale, Universite´ Libre de Bruxelles, Rue Jeener et Brachet, 12, B - 6041 Gosselies, Belgium. E-mail:
[email protected] DOI 10.1002/bies.10297 Published online in Wiley InterScience (www.interscience.wiley.com).
Abbreviations: IDO, indoleamine 2,3-dioxygenase; Na, nicotinic acid; NaAD, nicotinic acid adenine dinucleotide; NAD, nicotinamide adenine dinucleotide; NADS, NAD synthase; NAm, nicotinamide; NaMN, nicotinic acid mononucleotide; NaMNAT, nicotinic acid mononucleotide adenylyltransferase; NAmPRTase, nicotinamide phosphoribosyltransferase; NaPRTase, nicotinic acid phosphoribosyltransferase; NDase, nicotinamidase; NMN, nicotinamide mononucleotide; NMNAT, nicotinamide mononucleotide adenylyltransferase; PARP, poly(ADP-ribose)polymerase; PRPP, phosphoribosyl pyrophosphate; QPRTase, quinolinic acid phosphoribosyltransferase; TDO, tryptophan 2,3dioxygenase.
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redundancy, allowing a given pathway to freely acquire novel functions unrelated to NAD biosynthesis. BioEssays 25:683–690, 2003. ß 2003 Wiley Periodicals, Inc. Introduction Nicotinamide adenine dinucleotide (NAD) has been known for several decades to play a major role as a coenzyme in numerous oxidation–reduction reactions. The chemistry of this molecule allows it to readily accept and donate electrons in reactions catalysed by dehydrogenases, leading in particular to the generation of ATP, a molecule universally required for most energy-consuming cellular processes. Recently, the distinct role of NAD as a precursor for molecules involved in regulatory processes has also been recognized. NAD can indeed serve as a substrate for covalent protein modification catalysed by enzymes identified as ADP-ribosyl transferases.(1) Originally discovered in prokaryotes (numerous bacterial toxins such as the diphteria toxin belong to this family of enzymes), a number of eukaryotic ADP-ribosyl transferases have now been identified and cloned. During ADP-ribosylation, the ADP-ribose moiety of NAD is enzymatically transferred onto an acceptor protein, a reaction known to profoundly affect the target protein effector function.(2) The identification of cyclic ADP-ribose (cADPR) as an important signaling molecule regulating intracellular calcium homeostasis has uncovered a novel role for NAD in cellular physiology.(3) cADPR is generated following NAD cleavage by NAD glycohydrolases/ADP-ribosyl cyclases, a class of enzymes found in a variety of organisms.(4) Recently, an additional class of ‘‘NAD-consuming’’ proteins has been described. This group of enzymes known as the Sir2 (silent information regulator 2) family has diverse functions in yeast including gene silencing. Sir2 and several of its mammalian homologues display NAD-dependent deacetylase activity.(5,6) These enzymes catalyze a unique reaction in which the cleavage of NAD and the deacetylation of substrate are coupled to the formation of O-acetyl-ADP-ribose, a novel metabolite exhibiting biological effects when microinjected in living cells.(7,8) Members of this family have attracted great interest following the demonstration that Sir2 and its homologs play a role in cell longevity in both yeast and Caenorhabditis elegans.(9,10) The available data indicate that the effector function of this protein requires adequate levels of intracel-
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lular NAD, suggesting a possible link between NAD levels (and thus metabolic energy flow of the cell) and aging.(11) In marked contrast to its role in energy metabolism during which NAD is rapidly interconverted between its oxidized and reduced forms without net consumption, the involvement of NAD in these regulatory cellular processes is based on its ability to function as a donor of ADP-ribose, requiring NAD resynthesis to avoid depletion of the intracellular NAD pool. This dual role of NAD in both energy metabolism and protein modification has been shown to have important physiological consequences, as demonstrated by numerous studies performed on the role of the nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1). PARP1 is an abundant enzyme of eukaryotic cells that is implicated in the response to DNA injury (see Ref. 12 for review). In response to DNA damage caused by environmental genotoxic agents and endogenous cellular reactions, PARP-1 binds to DNA strand breaks and catalyses the transfer of successive units of the ADP-ribose moiety (up to 200 units) from NAD to other nuclear proteins including itself. As a consequence, excessive activation of PARP-1 depletes the cellular NAD and ATP pools. The increasing role of ‘‘NAD-consuming’’ enzymes in the regulation of important cellular functions raises interest therefore in the biosynthetic routes leading to NAD formation. According to a widely accepted concept, a combination of de novo and salvage pathways contributes to the biosynthesis of NAD. De novo biosynthetic pathways generally refer to the set of reactions that supply a product from low molecular weight compounds (often an energetically expensive, multistep pathway) while the salvage pathway allows the recycling of metabolites derived from normal cellular catabolism. The information relative to mammalian NAD metabolism has been mostly derived from studies performed on liver cells, known to exhibit robust NAD biosynthesis. In these cells, NAD can be synthesized from tryptophan (generally referred to as the ‘‘de novo pathway’’) and nicotinamide and nicotinic acid (thought to represent the ‘‘salvage pathways’’). Most genes and enzymes involved in these complex pathways have been identified in the last few years from several living organisms ranging from bacteria to mammals, leading to the possible reconstruction of this important metabolic pathway using computational sequence analysis. This information led us to reevaluate the respective role of de novo and salvage pathways of NAD biosynthesis in distinct living organisms, with particular emphasis on the role of tryptophan, nicotinic acid and nicotinamide as NAD precursors in eukaryotes.
NAD biosynthesis and tryptophan catabolism Tryptophan is an essential aromatic amino acid and it is the rarest of the 20 amino acids in proteins. Its role as a NAD precursor was first suggested by nutritional studies indicating that diets supplemented with tryptophan were able to cure human pellagra, a disease characterized by a nicotinamide deficiency.(13) Since then, numerous studies have demonstrated the role of tryptophan as NAD precursor in most living organisms, including mammals.(14) About 90% of Ltryptophan in mammals is degraded through the so-called kynurenine pathway generating a number of biologically active compounds,(15) including quinolinic acid, a precursor of NAD (Fig. 1). The primary site of L-tryptophan catabolism in mammals is believed to be the liver, a tissue that specifically expresses the tryptophan 2,3-dioxygenase (TDO), the first and rate-limiting enzyme of this pathway in this organ. This enzyme catalyses the reaction of L-tryptophan with molecular oxygen to yield N-formyl-kynurenine,(16) which is further hydrolyzed into L-kynurenine. TDO controls serum tryptophan homeostasis and is induced following ingestion of tryptophan, representing in fact the first example of an inducible enzyme discovered in mammals.(17) L-kynurenine is channeled into nicotinamide-containing nucleotides by subsequent reactions leading to quinolinic acid (see Ref. 18). Quinolinic acid is converted to nicotinic acid mononucleotide (NaMN) by a quinolinic acid phosphoribosyltransferase (QPRTase)(19) and converges to the Preiss-Handler pathway leading to NAD (see below). The indoleamine 2,3-dioxygenase (IDO) represents a second tryptophan catabolizing enzyme,(20) distinguished from TDO by substrate specificity, expression pattern and inducibility. IDO displays a broader specificity as it catalyzes the breakdown of a variety of compounds containing an indole ring, including D-tryptophan, 5-hydroxytryptophan and serotonin. This enzyme is ubiquitously expressed in non-hepatic tissues, with the lung, the placenta and the immune system having the highest activity.(21) Curiously, IDO synthesis does not appear to be sensitive to tryptophan levels but responds to inflammatory stimuli including interferon-g, bacterial and viral products.(22–24) A decrease in TDO activity occurs concomitantly with IDO induction, suggesting a coordinate shift in tryptophan degradation from the liver to extrahepatic tissues during an immune response.(25) The physiological significance of this dichotomy is not completely elucidated but novel functions of IDO in immune regulation that appear unrelated to its contribution to NAD biosynthesis have emerged from the
Figure 1. The NAD biosynthetic pathways: Four metabolic routes allow NAD synthesis from three distinct precursors (L-tryptophan, nicotinic acid and nicotinamide). TDO, tryptophan 2,3-dioxygenase; IDO, indoleamine 2,3-dioxygenase; QPRTase, quinolinic acid phosphoribosyltransferase; NaPRTase, nicotinic acid phosphoribosyltransferase; NAmPRTase, nicotinamide phosphoribosyltransferase; NaMNAT, nicotinic acid mononucleotide adenylyltransferase; NMNAT, nicotinamide mononucleotide adenylyltransferase; NADS, NAD synthase; NDase, nicotinamidase.
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Figure 1.
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recent literature.(26–31) As stated earlier, tryptophan is the rarest essential amino acid, and therefore represents a likely target for cellular regulatory mechanisms. The observation that IDO expression is induced upon infection is compatible with the putative role of this enzyme in limiting proliferation of pathogens by depleting an essential amino acid in their microenvironment.(32,33) A similar biostatic effect has been invoked to explain the suppressive role of IDO-expressing cells during pregnancy and inflammation. Both animal and human studies have demonstrated the immunosuppressive role of IDO-expressing cells (in the placenta and by subsets of lymphoid cells belonging to the macrophage/dendritic cell family) in diverting T lymphocyte responses toward tolerance.(26–28) Recently, however, three independent studies have suggested that the ability of IDO-expressing cells to suppress immune responses is related to their capacity to secrete or release into the extracellular milieu several tryptophan metabolites (including kynurenine, 3-hydroxykynurenine and 3-hydroxyanthranilic acid) able to actively induce Tcell apoptosis in vitro.(29–31) The mechanism by which IDO-expressing cells suppress immune responses appears therefore to be related to the production of several, tryptophanderived bioactive compounds and not to tryptophan depletion per se. Collectively these observations point to an important immunoregulatory function for IDO, and are difficult to reconcile with a major role of tryptophan catabolism in repleting intracellular NAD in extra-hepatic tissues. In agreement with this hypothesis, a substantial increase in the concentration of quinolinic acid in the central nervous system and in lymphoid sites has been detected in a number of inflammatory diseases.(34,35) Similarly, the quinolinic acid phosphoribosyltransferase (QPRTase) enzymatic activity was only detected in liver and kidneys of normal rats, indicating that most
peripheral tissues lack the ability to functionally connect tryptophan catabolism to NAD biosynthesis.(36) The analysis of sequence databases reveals that only mammals express two distinct proteins (TDO and IDO, see gray box 1 in Table 1) able to catabolize tryptophan into the kynurenin pathway. These observations suggest that the tryptophan catabolic pathway has been diverted in extrahepatic tissues from its original role as a de novo pathway for NAD biosynthesis to a novel immune-related role. The decrease in TDO activity during infection could therefore be instrumental in making tryptophan available to IDO-expressing tissues for immunoregulatory purposes. In these tissues, therefore, nicotinic acid and nicotinamide probably represent the major precursors of NAD biosynthesis. Niacin and NAD metabolism Similarly to tryptophan, the role of niacin (or vitamin B3) as a NAD precursor was discovered by the ability of this vitamin to act as an anti-pellagra factor.(37) Niacin is the generic name used to indicate both nicotinic acid and nicotinamide, two distinct molecular species either of which may act as a precursor for NAD in most living organisms through distinct enzyme-catalyzed reactions.
From nicotinic acid to NAD The biosynthetic pathway leading from nicotinic acid to NAD (Fig. 1), the so-called ‘‘Preiss-Handler pathway’’,(38) appears well conserved through evolution (see white box in Table 1 and Fig. 2). Nicotinic acid phosphoribosyltransferase (NaPRTase) is an ATP-dependent enzyme able to synthesize nicotinic acid mononucleotide (NaMN) and pyrophosphate from nicotinic acid (Na) and phosphoribosyl pyrophosphate (PRPP). NaMN is converted to desamido-NAD (NaAD) by a nicotinic acid
Table 1. Genes coding for putative enzymes were searched in the genomic databases using Blast algorithm(66) Tryptophan catabolism
IDO TDO QPRTase Eukaryotes
Prokaryotes
Homo sapiens (Hs) Mus musculus (Mm) Caenorhabditis elegans (Ce) Drosophila melanogaster (Dm) Arabidopsis thaliana (At) Saccharomyces cerevisiae (Sc) Escherischia coli (Ec) Mycobacterium tuberculosis (Mt)
þ þ þ
þ þ þ þ
þ þ þ þ þ þ
(1) (2)
From Na to NAD
NaPRTase NADS þ þ þ þ þ þ þ þ
þ þ þ þ þ þ þ þ
From NAm to NAD NaMNAT/ NMNAT NAmPRTase NDase þ þ þ þ þ þ þ þ
þ þ
(3) þ þ þ þ þ þ
Accession numbers, IDO, Hs, P14902; Mm, P28776; Sc, S57097. TDO, Hs, P48775; Mm, P48776; Ce, Q09474; Dm, NP_511113. QPRTase, Hs, Q15274; Mm, NP_598447; At, AAM63914; Sc, P43619; Ec, AAC73220; Mt, NP_216112. NaPRTase, Hs, AAH06284; Mm, XP_128286; Ce, NP_500265; Dm, AAF51037; At, AAM13003; Sc, P39683; Ec, Q8XDE8; Mt, NP_335010. NADS, Hs, BAB14034; Mm, NP_084497; Ce, T19420; Dm, Q9VYA0; At, NP_175906; Sc, P38795; Ec, P18843; Mt, NP_336996. NaMNAT/NMNAT, Hs, AAG33632, AAG60615 and AAK52726; Mm, XP_131855 and AAH05737; Ce, P91851; Dm, AAL90149; At, NP_200392; Sc, P53204; Ec, P52085; Mt, O86328. NAmPRTase, Hs, P43490; Mm, AAH04059. NDase, Ce, NP_499876; Dm, AAM52663; At, AAM61357; Sc, P53184; Ec, P21369; Mt, B70944.
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Figure 2. Schematic representation of NAD metabolism in different organisms and mammalian organs. A: Mammalian liver; B: mammalian macrophage; C: yeast; D: Drosophila melanogaster and Caenorhabditis elegans. Red boxes indicate compounds used as NAD precursors. Blue arrows represent enzymes present and expressed in the organ/organism but not functionally connected to NAD metabolism. The gray arrow represents an enzyme not expressed in the considered cell type.
mononucleotide adenylyltransferase (NaMNAT). NaAD is finally converted into NAD by a NAD synthase (NADS).(18,38) The three enzymatic activities and/or the corresponding genes have been found in numerous prokaryotes and eukaryotes, including mammals, suggesting the universal nature of the metabolic pathway linking nicotinic acid to NAD biosynthesis (Table 1).
From nicotinamide to NAD Nicotinamide may represent the main source of NAD for most cells in mammals. In the absence of deliberate dietary supplementation, the nicotinamide concentration in human plasma has been determined to be fivefold higher than
nicotinic acid levels.(39) Moreover and as stated above, the cleavage of the ADP-ribose moiety of NAD by numerous enzymes leads to the concomitant release of nicotinamide, suggesting that recycling of nicotinamide to NAD represents a physiologically important homeostatic mechanism during active utilization of NAD as a substrate. In principle, nicotinamide could be recycled to NAD by two independent routes(18) (Fig. 1). Nicotinamide can be enzymatically converted to nicotinic acid by a nicotinamidase (NDase) and channeled through the previously described nicotinic acid pathway. Alternatively, it can be used as a substrate by a nicotinamide phosphoribosyltransferase (NAmPRTase), an enzyme catalyzing the condensation of nicotinamide with PRPP, to
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yield nicotinamide mononucleotide (NMN). NMN is further converted to NAD by a nicotinamide mononucleotide adenylyltransferase (NMNAT). Three distinct mammalian genes encoding proteins displaying both NMNAT and NaMNAT activities have been recently identified.(40–43) Each of these adenylyltransferases can use both NMN and NaMN as substrate, and is therefore capable to participate in the biosynthetic routes linking both nicotinamide and nicotinic acid to NAD. Noteworthy, each isoform appears to have a distinct cellular localisation, with the first isoform exclusively located in the nucleus while the two more recently identified proteins are present in the cytoplasm and mitochondria. We refer to NMNAT and NaMNAT as distinct enzymatic activities in Fig. 1, while the relevant genes are identified as single molecular entities termed NMNAT/NaMNAT in Table 1. The available evidence indicates therefore the existence of two distinct pathways to produce NAD from nicotinamide. The nicotinamidase enzymatic activity has been amply documented in several yeast and bacterial strains.(44–46) Reports of this activity in mammalian cells are conflicting, with some early works describing nicotinamidase activity in the liver(47,48) while the most recent literature suggests a lack of this enzyme in several mammalian tissues.(36,49,50) Indeed, while search in the available sequence databases revealed the presence of eukaryotic genes which represent likely candidates for nicotinamidases in yeast, C. elegans and Drosophila melanogaster, no gene products sharing significant sequence identity to the previously identified prokaryotic and yeast nicotinamidase genes have been found in mammals (see Table 1). In marked contrast, the occurrence of nicotinamide phosphoribosyltransferase activity in mammals has been clearly demonstrated in human erythrocytes.(51) Since then, this enzymatic activity has been found and partially purified from diverse animal and human tissues including liver, kidney, heart, brain, spleen and fibroblasts.(49,52–54) This enzymatic activity was shown to be specific for nicotinamide, as neither nicotinic acid nor quinolinic acid can be used as substrate by the NAmPRTase.(51) A prokaryotic gene (nadV) encoding this enzymatic activity has been recently identified in Haemophilus ducreyi, and shown to display significant homology with predicted proteins of unknown function in several prokaryotic and eukaryotic organisms.(55) Through a combination of biochemical and genetical approaches, we have recently demonstrated that the murine homologue of the prokaryotic nadV gene encodes the mammalian nicotinamide phosphoribosyltransferase,(56) possibly completing the identification of all enzymes involved in the mammalian salvage pathway allowing the recycling of nicotinamide into NAD. Modeling eukaryotic NAD biosynthesis pathways A multitude of genetical and biochemical studies have led to the molecular identification of most of the enzymes involved in
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NAD biosynthesis. We have searched available genomic databases for the presence of homologues of these enzymes in several organisms. This information has been summarized in Table 1 and has been used to reconstruct the NAD metabolic pathways that are operative in distinct eukaryotic living organisms and/or cell types (as shown in Fig. 2). As previously discussed, only mammals express two distinct tryptophan catabolizing enzymes (TDO and IDO). Based on the available data, we would suggest that tryptophan catabolism only contributes to NAD biosynthesis in TDOexpressing tissues, while this metabolic pathway is linked to the generation of biologically active compounds unrelated to NAD in other tissues, as suggested by recent studies performed on cells of the immune system.(26–31) The mammalian liver can be considered as the prototypic organ in which most of previously described pathways leading to NAD synthesis appear to be operative. The biochemical pathways allowing tryptophan, nicotinamide and nicotinic acid to act as NAD precursor in this organ are shown in Fig. 2A. Note the role of TDO as the first tryptophan catabolizing enzyme and the presence of a NAmPRTase enabling the use of nicotinamide (partially produced from NAD degradation) to form NAD. In mammalian extra-hepatic tissues, tryptophan catabolism may have been diverted from NAD biosynthesis to a novel, immune-related role. This is represented in Fig. 2B, in which NAD biosynthesis in a macrophage is schematically represented. In this cell type, tryptophan catabolism initiated by IDO is not functionally connected to NAD biosynthesis, an assumption supported by the accumulation of quinolinic acid in macrophages of mice fed with kynurenine(57) and the absence of QPRTase activity in organs others than liver and kidney.(36) We therefore postulate that most mammalian tissues rely on an exogenous source of nicotinamide/nicotinic acid for NAD biosynthesis, hence explaining why these compounds represent essential nutrients in mammals. An interesting trend derives from our analysis, as genes coding for nicotinamidase and nicotinamide phosphoribosyltransferase appear to be mutually exclusive (see gray box 3 in Table 1). Thus, it is tempting to speculate that only one of the two independent nicotinamide routes has been kept functional in each organism. Several organisms (including bacteria, yeast, nematodes and insects) are able to convert nicotinamide into nicotinic acid converging into the PreissHandler pathway while others (microorganisms of the Pasteurellaceae family(55) and eukaryotes including vertebrates) use nicotinamide to yield NMN. These conclusions also suggest that the reported conversion of nicotinamide into nicotinic acid in mammals is most probably performed by microorganisms of the intestinal flora, or as a consequence of an infectious event.(36,58) Two additional eukaryotic NAD metabolic pathways are shown in Fig. 2C, D, representative respectively of yeast and nematodes/insects. A multitude of genetical and biochemical
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evidences concur to indicate that tryptophan, nicotinic acid and nicotinamide can serve as NAD precursors in yeasts.(59) In marked contrast to mammals however, nicotinamide is channeled through the nicotinic acid pathway by a nicotinamidase. Finally, in nematodes and insects (both the D. melanogaster and Anopheles gambiae genomes have been analysed with identical results), like in yeasts, a nicotinamidase is present in the nicotinamide salvage pathway. A particular feature in this animal group is the absence of genes homologous to the QPRTase (gray box 2 in Table 1), an essential enzyme linking tryptophan catabolism to the generation of NAD via NaMN. Moreover, mutations of two genes of the tryptophan catabolic pathway in Drosophila (the vermilion, Ref. 60, and cinnabar, Ref. 61, mutants, affecting respectively the tryptophan 2,3-dioxygenase and the kynurenine 3-monooxygenase genes) are known to affect eye color. Collectively, these observations strongly suggest that in these organisms, tryptophan catabolism does not participate to NAD biosynthesis. Conclusion The interest of this type of comparative analysis based on metabolic reconstruction from genomic data is that it provides important information on how complex metabolic pathways have evolved. Collectively, the available information suggests the development of several NAD biosynthetic routes during evolution, allowing NAD synthesis from three distinct precursors. The presence of these multiple metabolic routes may reflect differences in tissue distribution and/or intracellular compartmentalization of NAD metabolism in higher eukaryotes. It is also tempting to speculate that this partial functional overlap has allowed the acquisition of novel functions unrelated to NAD biosynthesis. In the present example it is suggested that the tryptophan catabolic pathway, while still devoted to NAD biosynthesis in the mammalian liver, has been freed during evolution to gain novel regulatory functions in several animal groups. In addition, these studies may also suggest possible targets for specific therapeutic intervention, as recently described in the field of antibiotics.(62) Notably, many bacteria—like yeast, Drosophila and C. elegans—differ from mammals in the nicotinamide ‘‘salvage’’ pathway, as they express a nicotinamidase enabling these organisms to convert nicotinamide into nicotinic acid. The nicotinamidase gene may therefore provide an interesting target for drug development. Similarly, the level of intracellular NAD is thought to be involved in the development of tumors.(63) In keeping with this hypothesis, the human homologue of NAmPRTase (named PBEF) was found to be expressed at high levels in tumor cells,(64,65) suggesting that an increase in NAD turnover may confer a growth advantage to these cells. Collectively these findings suggest that a more thorough understanding of NAD biosynthesis may be important to decipher the link
between metabolism and various regulatory events in both health and disease. References 1. Ziegler M. New functions of a long-known molecule. Emerging roles of NAD in cellular signaling. Eur J Biochem 2000;267:1550–1564. 2. Koch-Nolte F, Reche P, Haag F, Bazan F. ADP-ribosyltransferases: plastic tools for inactivating protein and small molecular weight targets. J Biotechnol 2001;92:81–87. 3. Lee HC, Walseth TF, Bratt GT, Hayes RN, Clapper DL. Structural determination of a cyclic metabolite of NADþ with intracellular Ca2þmobilizing activity. J Biol Chem 1989;264:1608–1615. 4. Guse AH. Cyclic ADP-ribose. J Mol Med 2000;78:26–35. 5. Frye RA. Characterization of five human cDNAs with homology to the yeast SIR2 gene: Sir2-like proteins (sirtuins) metabolize NAD and may have protein ADP-ribosyltransferase activity. Biochem Biophys Res Commun 1999;260:273–279. 6. Imai S, Armstrong CM, Kaeberlein M, Guarente L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 2000;403:795–800. 7. Moazed D. Enzymatic activities of Sir2 and chromatin silencing. Curr Opin Cell Biol 2001;13:232–238. 8. Borra MT, O’Neill FJ, Jackson MD, Marshall B, Verdin E, Foltz KR, Denu JM. Conserved enzymatic production and biological effect of O-acetyl-ADP-ribose by silent information regulator 2-like NADþ-dependent deacetylases. J Biol Chem 2002;277:12632–12641. 9. Lin SJ, Defossez PA, Guarente L. Requirement of NAD and SIR2 for lifespan extension by calorie restriction in Saccharomyces cerevisiae. Science 2000;289:2126–2128. 10. Tissenbaum HA, Guarente L. Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature 2001;410:227–230. 11. Guarente L. Sir2 links chromatin silencing, metabolism, and aging. Genes Dev 2000;14:1021–1026. 12. D’Amours D, Desnoyers S, D’Silva I, Poirier GG. Poly(ADP-ribosyl)ation reactions in the regulation of nuclear functions. Biochem J 1999;342: 249–268. 13. Krehl WA, Trepley LJ, Sarma PS, Elvejhem CA. Growth retarding effect of corn in niacin-low rations and its counteraction by tryptophan. Science 1945;101:489–490. 14. Bender DA, Olufunwa R. Utilization of tryptophan, nicotinamide and nicotinic acid as precursors for nicotinamide nucleotide synthesis in isolated rat liver cells. Br J Nutr 1988;59:279–287. 15. Wolf H. Studies on tryptophan metabolism in man. Scand J Clin Lab Invest Suppl 1974;136:1–186. 16. Schutz G, Feigelson P. Purification and properties of rat liver tryptophan oxygenase. J Biol Chem 1972;247:5327–5332. 17. Knox WE, Mehler AH. The adaptive increase of the tryptophan peroxidase oxidase system of liver. Science 1951;113:237–238. 18. Magni G, Amici A, Emanuelli M, Raffaelli N, Ruggieri S. Enzymology of NADþ synthesis. Adv Enzymol Relat Areas Mol Biol 1999;73:135–182. 19. Nishizuka Y, Hayaishi O. Studies on the biosynthesis of nicotinamide adenine dinucleotide. I. Enzymatic synthesis of niacin ribonucleotides from 3-hydroxyanhranilic acid in mammalian tissues. J Biol Chem 1963; 238:3369–3377. 20. Shimizu T, Nomiyama S, Hirata F, Hayaishi O. Indoleamine 2,3dioxygenase. Purification and some properties. J Biol Chem 1978;253: 4700–4706. 21. Yamazaki F, Kuroiwa T, Takikawa O, Kido R. Human indolylamine 2,3dioxygenase. Its tissue distribution, and characterization of the placental enzyme. Biochem J 1985;230:635–638. 22. Yoshida R, Imanishi J, Oku T, Kishida T, Hayaishi O. Induction of pulmonary indoleamine 2,3-dioxygenase by interferon. Proc Natl Acad Sci USA 1981;78:129–132. 23. Yoshida R, Hayaishi O. Induction of pulmonary indoleamine 2,3dioxygenase by intraperitoneal injection of bacterial lipopolysaccharide. Proc Natl Acad Sci USA 1978;75:3998–4000. 24. Yoshida R, Urade Y, Tokuda M, Hayaishi O. Induction of indoleamine 2,3-dioxygenase in mouse lung during virus infection. Proc Natl Acad Sci USA 1979;76:4084–4086.
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