Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2020 Oct 1.
Published in final edited form as: Curr Genet. 2019 Apr 16;65(5):1113–1119. doi: 10.1007/s00294-019-00972-0

Cross-talk in NAD+ metabolism – insights from Saccharomyces cerevisiae

Christol James Theoga Raj 1, Su-Ju Lin 1,*
PMCID: PMC6744962  NIHMSID: NIHMS1527157  PMID: 30993413

Abstract

NAD+ (nicotinamide adenine dinucleotide) is an essential metabolite involved in a myriad of cellular processes. The NAD+ pool is maintained by three biosynthesis pathways, which are largely conserved from bacteria to human with some species-specific differences. Studying the regulation of NAD+ metabolism has been difficult due to the dynamic flexibility of NAD+ intermediates, the redundancy of biosynthesis pathways, and the complex interconnections among them. The budding yeast Saccharomyces cerevisiae provides an efficient genetic model for the isolation and study of factors that regulate specific NAD+ biosynthesis pathways. A recent study has uncovered a putative cross-regulation between the de novo NAD+ biosynthesis and copper homeostasis mediated by a copper-sensing transcription factor Mac1. Mac1 appears to work with the Hst1-Sum1-Rfm1 complex to repress the expression of de novo NAD+ biosynthesis genes. Here we extend the discussions to include additional nutrient- and stress-sensing pathways that have been associated with the regulation of NAD+ homeostasis. NAD+ metabolism is an emerging therapeutic target for several human diseases. NAD+ preservation also helps ameliorate age-associated metabolic disorders. Recent findings in yeast contribute to the understanding of the molecular basis underlying the cross-regulation of NAD+ metabolism and other signaling pathways.

Keywords: NAD+ metabolism, Sir2 family, nutrient signaling, stress signaling, transcription, gene silencing

Introduction

NAD+ and its derivatives NADH, NADP+ and NADPH (pyridine nucleotides) are essential cofactors involved in various redox reactions. NAD+ also contributes to the regulation of chromatin structure, DNA repair, circadian rhythm and lifespan (Chini et al. 2016; Imai and Guarente 2014; Kato and Lin 2014a; Nikiforov et al. 2015; Yoshino et al. 2018). Several human diseases have been associated with aberrant NAD+ metabolism, including diabetes, cancer, and neuron degeneration (Canto et al. 2015; Chini et al. 2016; Garten et al. 2015; Liu et al. 2018; Nikiforov et al. 2015; Poyan Mehr et al. 2018; Schwarcz et al. 2012; Verdin 2015; Yang and Sauve 2016; Yoshino et al. 2018). Administration of NAD+ precursors such as nicotinamide mononucleotide (NMN), nicotinamide (NAM), nicotinic acid riboside (NaR) and nicotinamide riboside (NR) has been shown to increase NAD+ levels and ameliorate associated deficiencies in various model systems including human cells (Belenky et al. 2007; Brown et al. 2014; Canto et al. 2015; Chini et al. 2016; Garten et al. 2015; Lin et al. 2016; Liu et al. 2018; Poyan Mehr et al. 2018; Verdin 2015; Williams et al. 2017; Yang and Sauve 2016; Yoshino et al. 2018). However, the molecular mechanisms underlying the beneficial effects of NAD+ precursor treatments are not completely understood. For example, it remains unclear how eukaryote cells transport and utilize NAD+ precursors. Also, signaling pathways and cellular processes that contribute to the regulation of NAD+ homeostasis remain largely unknown. Studying NAD+ homeostasis is complicated by the dynamic flexibility of precursors cells use to generate NAD+. For example, NAM can replenish NAD+ pools either by entering the salvage pathway or by de-repressing the de novo pathway (Fig. 1). NAM also inhibits the activity of NAD+ consuming Sir2 family proteins (Bitterman et al. 2002; Jackson et al. 2003). Recent studies in budding yeast S. cerevisiae have helped shed some light on the regulation of NAD+ homeostasis.

Fig. 1. NAD+ biosynthesis pathways in budding yeast Saccharomyces cerevisiae.

Fig. 1

Open in a new tab

NAD+ can be synthesized de novo or salvaged from intermediates and small precursors such as NA, NAM and NR. Yeast cells also release and re-uptake these precursors. The de novo NAD+ synthesis (left panel) is mediated by Bna2,7,4,5,1,6 proteins leading to the production of NaMN. The NA/NAM salvage pathway (center panel) also produces NaMN, which is then converted to NaAD and NAD+ by Nma1/2 and Qns1, respectively. NR salvage (right panel) connects to the NA/NAM salvage pathway by Urh1, Pnp1 and Meu1. NR turns into NMN by Nrk1, which is then converted to NAD+ by Nma1, Nma2 and Pof1. For clarity, this model centers on NA/NAM salvage (highlighted with bold black arrows) because standard growth media contain abundant NA. Arrows with dashed lines indicate the mechanisms of these pathways remain largely unclear. NA, nicotinic acid. NAM, nicotinamide. NR, nicotinamide riboside. QA, quinolinic acid. L-TRP, L-tryptophan. NFK, N-formylkynurenine. L-KYN, L-kynurenine. 3-HK, 3-hydroxykynurenine. 3-HA, 3-hydroxyanthranilic acid. NaMN, nicotinic acid mononucleotide. NaAD, deamido-NAD+. NMN, nicotinamide mononucleotide. Abbreviations of protein names are shown in parentheses. Bna2, tryptophan 2,3-dioxygenase. Bna7, kynurenine formamidase. Bna4, kynurenine 3-monooxygenase. Bna5, kynureninase. Bna1, 3-hydroxyanthranilate 3,4-dioxygenase. Bna6, quinolinic acid phosphoribosyl transferase. Nma1/2, NaMN/NMN adenylyltransferase. Qns1, glutamine-dependent NAD+ synthetase. Npt1, nicotinic acid phosphoribosyl transferase. Pnc1, nicotinamide deamidase. Sir2 family, NAD+- dependent protein deacetylases. Urh1, Pnp1 and Meu1, nucleosidases. Nrk1, NR kinase. Isn1 and Sdt1, nucelotidases. Pho8 and Pho5, phosphatases. Pof1, NMN adenylyltransferase. Tna1, NA and QA transporter. Nrt1, NR transporter.

Overview of NAD+ biosynthesis

Cellular NAD+ pool is maintained by three major NAD+ biosynthesis pathways (Fig.1), which are largely conserved from bacteria to humans. One pathway may dominate the others depending on the availability of specific NAD+ precursors and the expression levels of specific NAD+ biosynthesis enzymes. For example, nicotinic acid (NA) is the primary NAD+ precursor present in standard yeast growth media, and NA/NAM salvage (Fig. 1, center panel) is the major NAD+ synthesis route until NA is depleted (Bedalov et al. 2003; Sporty et al. 2009). During NA/NAM salvage, yeast cells recycle NAM from NAD+ consusmption reactions (catalyzed by Sir2 family proteins) or uptake NA from the environment via NA transporter Tna1 (Llorente and Dujon 2000), leading to nicotinic acid mononucleotide (NaMN) production. NaMN is converted to deamido-NAD+ (NaAD) by NaMN adenylyltransferases (Nma1/2) (Emanuelli et al. 1999), which is turned into NAD+ by the glutamine-dependent NAD+ synthetase (Qns1) (Bieganowski et al. 2003) (Fig. 1, center panel). Unlike higher eukaryotes including mammals, yeasts do not possess NAM phosphorybosyltransferase (NAMPT) (Revollo et al. 2004), the enzyme that converts NAM to NMN. Instead, NAM is deamidated to NA by Pnc1, and shunted into NA/NAM salvaging (Ghislain et al. 2002).

In the NR salvage cycle, NR is assimilated into NMN by the NR kinase Nrk1 (Bieganowski and Brenner 2004) or turned into NAM by nucleosidases Urh1/Pnp1/Meu1 (Belenky et al. 2007). NMN is converted to NAD+ via NMN adenylyltransferases (Nma1/2 and Pof1) (Emanuelli et al. 1999; Kato and Lin 2014b), whereas NAM merges into the NA/NAM salvage route (Fig. 1, right panel). Nrk1 can also convert nicotinic acid riboside (NaR), a deamidated form of NR, to NaMN (Belenky et al. 2007). The nucleotidases, Isn1 and Sdt1 (Bogan et al. 2009), and phosphatases, Pho5 and Pho8 (Lu et al. 2009; Lu and Lin 2011), also contribute to NR metabolism by converting NMN to NR.

In the de novo branch, tryptophan is converted to quinolinic acid (QA) through five steps of enzymatic reactions catalyzed sequentially by Bna2, Bna7, Bna4, Bna5 and Bna1 (Fig. 1, left panel) (Panozzo et al. 2002). QA is then phosphoribosylated by Bna6 producing NaMN, which is also the converging point of the de novo pathway and NA/NAM salvage. Because Bna2, Bna4 and Bna5 require molecular oxygen as a substrate (Panozzo et al. 2002), yeast cells grown under anaerobic conditions rely on the salvage pathways for NAD+ synthesis (Panozzo et al. 2002). The de novo pathway is also known as the kynurenine (KYN) pathway or tryptophan degradation pathway in mammals. In addition to becoming NAD+, KYN can be converted to kynurenic acid (KA), which in yeast is mediated by the Aro8/9 aminotransferases (Ohashi et al. 2017).

It has also been shown that small NAD+ precursors such as NR, NA, NAM and QA are released and re-uptake by yeast cells (Croft et al. 2018; Lu et al. 2009; Ohashi et al. 2013). This extended NAD+ precursor pool may confer metabolic flexibility in response to environmental changes. Uptake of NA, QA and NR is mediated by specific transporters Tna1 (NA and QA) (Llorente and Dujon 2000; Ohashi et al. 2013) and Nrt1 (NR) (Belenky et al. 2008) (Fig. 1, bottom). Transport of large NAD+ precursors, for example NMN, may require prior conversion to smaller precursors such as NR and NAM (Lu et al. 2009; Nikiforov et al. 2011). Release and re-uptake of NAD+ precursors have also been reported in human cells (Kulikova et al. 2015). Although transporters for specific NAD+ precursors in higher eukaryotes remain largely unclear, it was suggested that NR enters cells via the equilibrative nucleoside transporters (ENTs) (Ratajczak et al. 2016; Trammell et al. 2016), and that NA transport is likely mediated by specific carriers (Said et al. 2007). In a recently study, a Na+-dependent NMN transporter has been identified in mice (Grozio et al. 2019).

Regulation of NAD+ homeostasis

Given the complex interconnections among NAD+ biosynthetic pathways, studying the regulation of NAD+ homeostasis has been challenging. Based on the observations that yeast cells constantly release and re-uptake small NAD+ precursors (Lu et al. 2009; Ohashi et al. 2013), genetic screens targeting specific NAD+ biosynthesis pathways have been developed. Yeast mutants with altered release activities of specific NAD+ precursor(s) are likely defective in corresponding NAD+ biosynthetic pathway(s). These NAD+ precursor-specific screens have resulted in the identification of novel NAD+ homeostasis factors (Croft et al. 2018; James Theoga Raj et al. 2019; Kato and Lin 2014a; Lu and Lin 2011). For example, a QA release-specific reporter system targeting the de novo branch was employed in a recent study, which has identified Mac1 as a novel NAD+ homeostasis factor (James Theoga Raj et al. 2019). Mac1 is a copper-sensing transcription factor that activates copper transport genes during copper deprivation (Graden and Winge 1997; Gross et al. 2000; Jungmann et al. 1993). Interestingly, cells lacking MAC1 shared similar NAD+ phenotypes with the hst1Δ mutant and that deleting either MAC1 or HST1 was sufficient to abolish BNA gene repression (James Theoga Raj et al. 2019). Hst1 is a NAD+-dependent histone deacetylase previously reported to inhibit de novo NAD+ synthesis by repressing BNA gene expression when NAD+ is abundant (Bedalov et al. 2003) (Fig. 2). Mac1 proteins likely work with the Hst1-containing repressor complexes (Hst1-Rfm1-Sum1) formed at the BNA promoters to repress gene expression. Detailed mechanisms of how Mac1 proteins contribute to Hst1-mediated BNA gene repression remain to be determined.

Fig. 2. A simplified model depicting the interactions of NAD+ metabolism and cellular signaling pathways.

Fig. 2

Open in a new tab

Under NA abundant conditions (standard growth media), NA/NAM salvage is the preferred NAD+ biosynthesis route, and BNA genes are repressed by the NAD+-dependent histone deacetylase Hst1. NAM contributes to NAD+ synthesis via NA/NAM salvage. NAM also de-represses BNA gene expression and de novo QA synthesis by inhibiting Hst1 activity. The copper-sensing transcription factor Mac1 appears to work in concert with the Hst1-containing repressor complex to repress BNA genes. Several nutrient sensing pathways including glucose sensing, amino acid sensing and phosphate (Pi) sensing pathways have also been connected to NAD+ metabolism. Dashed lines indicate the mechanisms of these pathways remain largely unclear.

The mechanisms of Mac1 regulation by copper help explain how may Mac1 function both as a transcription activator (for copper transport genes) and a co-repressor (for BNA genes). During copper deprivation, Mac1 proteins are stable and activate expression of copper transport genes. Upon copper repletion (nutritional level), copper binding to Mac1 results in a transcriptionally inactive state due to an intra-molecular interaction. When cells are exposed to high-copper conditions, Mac1 is quickly degraded to prevent excess copper import and toxicity (Jensen et al. 1998; Serpe et al. 1999; Zhu et al. 1998). Therefore, it is likely that under normal nutritional copper levels, the transcriptionally inactive (copper-bound) form of Mac1 works with the Hst1 complex to represses BNA genes. These studies also suggest copper stresses may impact de novo NAD+ biosynthesis via Mac1. Supporting this, high-copper stress conditions, which cause Mac1 degradation, also induce BNA gene expression and QA production. Interestingly, copper deprivation also increases BNA expression and QA production, suggesting copper may regulate de novo activity via additional stress-signaling mechanisms (Fig. 2).

Several stress- and nutrient-sensing pathways have also been associated with NAD+ metabolism (Fig. 2). Although these signaling pathways can increase the levels of specific NAD+ precursors, cellular NAD+ level does not always increase accordingly (Anderson et al. 2002; James Theoga Raj et al. 2019). It is possible that NAD+ is converted to other pyridine nucleotides, which may be critical for maintaining proper redox state and cellular function under stress. Also, since specific NAD+ intermediates as well as NAD+ biosynthesis enzymes have additional function in other cellular processes (Kato and Lin 2014a; Tsang and Lin 2015), it is anticipated that NAD+ homeostasis is under the control of multiple signaling pathways. Activation of the low phosphate (Pi)-sensing PHO pathway has been associated with increased NR metabolism (Lu and Lin 2011). Interestingly, PHO activation was also observed in the low-NAD+ npt1Δ mutant, suggesting a cross-regulation between low-NAD+ and low-Pi signaling (Lu and Lin 2011). Although the mechanisms remain unclear, coupling these pathways may be metabolically advantageous in certain conditions. For example, the Pi moiety of NAD+ derivatives is potential target for Pi scavenging during Pi limitation. PHO activation was also observed in the hst1Δ mutant (James Theoga Raj et al. 2019) and cells with reduced amino acid sensing activity (Tsang et al. 2015). Other signaling pathways that may play a role in NAD+ metabolism include PKA (cyclic-AMP activated protein kinase A), Sch9 (yeast Akt), and TOR (target of rapamycin) (Tsang and Lin 2015). Interestingly, these pathways appear to converge on Rim15 to regulate stress response transcription factors, Msn2 and Msn4 (Carroll et al. 2001; Swinnen et al. 2006; Wei et al. 2008). Msn2 and Msn4 have been shown to increase the expression of Pnc1, a NA/NAM salvaging enzyme (Medvedik et al. 2007), in response to various mild stresses including glucose and amino acid restriction (Anderson et al. 2003). Cells lacking Pnc1 accumulate excess NAM (Croft et al. 2018), which may result in inhibition of Sir2 and Hst1 activities (Bitterman et al. 2002; Jackson et al. 2003). It remains unclear whether these and yet-to-be-identified signaling pathways also regulate additional NAD+ homeostasis factors.

The regulation of release and re-uptake of NAD+ metabolites also contributes to NAD+ homeostasis. It appears that yeast cells release and uptake small NAD+ precursors via different mechanisms. Yeast cells uptake low μM levels of NR, NA and QA via specific transporters Nrt1 (NR) and Tna1 (NA and QA) (Belenky et al. 2008; Llorente and Dujon 2000; Ohashi et al. 2013). When supplemented at high levels, these NAD+ precursors may enter cells by additional mechanisms. Interestingly, high μM levels of NA can hinder the re-uptake of released QA (James Theoga Raj et al. 2019) because QA and NA share the same transporter Tna1. Although it remains unclear how NAD+ metabolites are made and released from yeast cells, it was suggested that both vesicular trafficking and vacuolar function play a role (Croft et al. 2018; Kato and Lin 2014a; Lu and Lin 2010). Vacuolar degradation of NAD+ intermediates appears to coincide with NAD+ salvage. NAD+ metabolites may enter vacuole through vesicular transport and autophagy, which are then broken down into smaller precursors for storage or reuse. NAD+ precursors produced in the cytoplasm can also enter vacuole for storage. The equilibrative nucleoside transporter Fun26 (human lysosomal hENT homolog) controls the balance of NR and likely other nucleosides between the vacuole and the cytoplasm (Lu and Lin 2011). For example, excess cytoplasmic NR is released extracellularly or transported into the vacuole via Fun26 if not converted to NAD+. Likewise, stored vacuolar NR may re-enter cytoplasm to support NAD+ synthesis when needed. Interestingly, although a vacuolar storage pool for NAD+ precursors generated from the NA/NAM and NR salvage pathways has been observed, most excess QA (if not converted to NAD+) is released extracellularly (James Theoga Raj et al. 2019; Ohashi et al. 2013). In addition, wild type yeast cells appear to release very low level of NA (Croft et al. 2018). It is possible intracellular NA is efficiently converted into NaMN by Npt1 (Fig. 1). Supporting this, in a recent screen for mutants that release more NA and/or NAM, the npt1Δ mutant shows the most significant NA release phenotype (Croft et al. 2018). Together these studies demonstrate that compartmentalization of NAD+ metabolites as well as cellular processes also play important roles in the regulation of NAD+ homeostasis.

Conclusions and Perspectives

NAD+ metabolism is dynamic and flexible, which may help cells adapt to environmental changes. Due to this complex nature, factors regulating NAD+ metabolism and homeostasis are not completely understood. Although recent studies have identified novel regulators of NAD+ homeostasis in yeast, many questions remain unanswered. For example, it is unclear whether NA and/or NAD+ also repress the de novo pathway activity in other systems. Repression of de novo activity by NAD+ has been observed in bacteria (Chandler and Gholson 1972; Grose et al. 2005). In Salmonella, this repression is mediated by a tri-functional protein NadR, which can function as a NMNAT (central domain), a NAD+-sensing transcription repressor (N-terminal domain) of NAD+ biosynthesis genes, and a NR kinase (C-terminal domain) (Grose et al. 2005). In addition, NAM does not appear to de-repress de novo NAD+ synthesis activity in E. coli (Chandler and Gholson 1972), and instead it inhibits QA production. This is probably because NAM is efficiently converted to NAD+ in E coli. In yeast, NAM is deamidated into NA and later becomes NAD+ due to the lack of NAMPT. However, NAM is also a potent competitive inhibitor of the Sir2-family deacetylases (IC(50) < 50 μM) (Bitterman et al. 2002; Jackson et al. 2003), suggesting that we are most likely to observe NAM-mediated inhibition on Hst1 activity under standard growth conditions in yeast. The Since Sir2 family proteins (sirtuins) are highly conserved across species (Brachmann et al. 1995; Frye 2000), it will be informative to determine whether de novo NAD+ biosynthesis activity is repressed by NAD+ (and specific NAD+ precursors) and de-repressed by NAM in a sirtuin-dependent manner in higher eukaryotes. Future studies to understand the multiple roles of NAD+ intermediates, as well as novel factors regulating NAD+ homeostasis are also highly anticipated

Recent studies have demonstrated NAD+ metabolism is a therapeutic target for several human diseases (Poyan Mehr et al. 2018; Williams et al. 2017). NAD+ preservation may also help ameliorate age-associated metabolic disorders (Katsyuba et al. 2018; Verdin 2015; Yoshino et al. 2018; Zhang et al. 2016). Understanding the molecular basis and inter-connection of multiple NAD+ metabolic pathways is important for the development of disease-specific therapeutic strategies. These strategies are more effective if associated defects in specific NAD+ biosynthesis pathways/steps are characterized in the disease models or in patients (Liu et al. 2018; Poyan Mehr et al. 2018). In addition, supplementation of specific NAD+ precursors is often combined with the use of genetic modifications and inhibitors of specific NAD+ biosynthesis steps to help channel the precursors flow through a more efficient NAD+ synthesis route (Braidy and Grant 2017; Katsyuba et al. 2018; Liu et al. 2018). It is therefore important to understand all possible interconnections and cross-regulation of NAD+ precursors and associated pathways in specific cell and tissue types.

Specific NAD+ metabolites and NAD+ biosynthesis enzymes have also been reported to have additional function (Kato and Lin 2014a; Tsang and Lin 2015). Moreover, metabolites of the de novo pathway (KYN pathway) have been linked to several brain disorders (Amaral et al. 2013; Schwarcz et al. 2012). For example, QA (QUIN) is considered neurotoxic because excess QA can induce toxicity in the central nervous system (CNS) via the glutamatergic NMDA (N-methyl-d-aspartate) receptors. It was also suggested that QA inhibits the uptake of extracellular glutamate by astrocytes, which is an important mechanism to maintain extracellular glutamate at non-toxic levels (Tavares et al. 2002). On the other hand, kynurenic acid (KA) is considered neuroprotective (Amaral et al. 2013; Chang et al. 2018; Schwarcz et al. 2012). KA is produced from KYN by the KYN aminotransferase (KAT). Yeast cells also produce KA from KYN by the Aro8/9 aminotransferases (Ohashi et al. 2017), however the function of KA in yeast remains unclear. Lower KA and KA/KYN ratio as well as higher QA and QA/KA ratio were observed in Parkinson’s diseases patients (Chang et al. 2018). Recent studies have shown that inhibiting the activities of de novo pathway enzymes such as tryptophan-2,3-dioxygenase (TDO; Bna2 in yeast) (Breda et al. 2016) and kynurenine-3-monooxygen (KMO; Bna4 in yeast) (Mole et al. 2016) via chemical inhibitors and/or genetic modifications may help alleviate specific neurological disorders. These strategies mostly center on increasing the ratio of neuroprotective KA over neurotoxic QA or 3-HK (Breda et al. 2016; Chang et al. 2018). Recent studies in yeast have expanded our understanding of the molecular basis and regulation of NAD+ metabolism. Future studies to understand the multiple roles of NAD+ intermediates, as well as novel factors regulating NAD+ homeostasis are highly anticipated.

Acknowledgment

This work is supported by NIGMS, National institute of Health, Grant GM102297. The authors declare that they have no conflicts of interest with the contents of the article.

Footnotes

Publisher's Disclaimer: This Author Accepted Manuscript is a PDF file of an unedited peer-reviewed manuscript that has been accepted for publication but has not been copyedited or corrected. The official version of record that is published in the journal is kept up to date and so may therefore differ from this version.

References

  1. Amaral M, Outeiro TF, Scrutton NS,Giorgini F (2013) The causative role and therapeutic potential of the kynurenine pathway in neurodegenerative disease Journal of molecular medicine (Berlin, Germany) 91:705–713 doi: 10.1007/s00109-013-1046-9 [DOI] [PubMed] [Google Scholar]
  2. Anderson RM et al. (2002) Manipulation of a nuclear NAD+ salvage pathway delays aging without altering steady-state NAD+ levels J Biol Chem 277:18881–18890 doi: 10.1074/jbc.M111773200 M111773200 [pii] [DOI] [PubMed] [Google Scholar]
  3. Anderson RM, Bitterman KJ, Wood JG, Medvedik O,Sinclair DA (2003) Nicotinamide and PNC1 govern lifespan extension by calorie restriction in Saccharomyces cerevisiae Nature 423:181–185 doi: 10.1038/nature01578 nature01578 [pii] [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bedalov A, Hirao M, Posakony J, Nelson M,Simon JA (2003) NAD+-dependent deacetylase Hst1p controls biosynthesis and cellular NAD+ levels in Saccharomyces cerevisiae Mol Cell Biol 23:7044–7054 [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Belenky P, Racette FG, Bogan KL, McClure JM, Smith JS,Brenner C (2007) Nicotinamide riboside promotes Sir2 silencing and extends lifespan via Nrk and Urh1/Pnp1/Meu1 pathways to NAD+ Cell 129:473–484 10.1016/j.cell.2007.03.024 [DOI] [PubMed] [Google Scholar]
  6. Belenky PA, Moga TG,Brenner C (2008) Saccharomyces cerevisiae YOR071C encodes the high affinity nicotinamide riboside transporter Nrt1 J Biol Chem 283:8075–8079 10.1074/jbc.C800021200 [DOI] [PubMed] [Google Scholar]
  7. Bieganowski P,Brenner C (2004) Discoveries of nicotinamide riboside as a nutrient and conserved NRK genes establish a Preiss-Handler independent route to NAD+ in fungi and humans Cell 117:495–502 doi:S0092867404004167 [pii] [DOI] [PubMed] [Google Scholar]
  8. Bieganowski P, Pace HC,Brenner C (2003) Eukaryotic NAD+ synthetase Qns1 contains an essential, obligate intramolecular thiol glutamine amidotransferase domain related to nitrilase J Biol Chem 278:33049–33055 doi: 10.1074/jbc.M302257200 M302257200 [pii] [DOI] [PubMed] [Google Scholar]
  9. Bitterman KJ, Anderson RM, Cohen HY, Latorre-Esteves M,Sinclair DA (2002) Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast sir2 and human SIRT1 J Biol Chem 277:45099–45107 doi: 10.1074/jbc.M205670200 M205670200 [pii] [DOI] [PubMed] [Google Scholar]
  10. Bogan KL, Evans C, Belenky P, Song P, Burant CF, Kennedy R,Brenner C (2009) Identification of Isn1 and Sdt1 as glucose- and vitamin-regulated nicotinamide mononucleotide and nicotinic acid mononucleotide [corrected] 5’-nucleotidases responsible for production of nicotinamide riboside and nicotinic acid riboside J Biol Chem 284:34861–34869 10.1074/jbc.M109.056689 [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Brachmann CB, Sherman JM, Devine SE, Cameron EE, Pillus L,Boeke JD (1995) The SIR2 gene family, conserved from bacteria to humans, functions in silencing, cell cycle progression, and chromosome stability Genes Dev 9:2888–2902 [DOI] [PubMed] [Google Scholar]
  12. Braidy N,Grant R (2017) Kynurenine pathway metabolism and neuroinflammatory disease Neural regeneration research 12:39–42 doi: 10.4103/1673-5374.198971 [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Breda C et al. (2016) Tryptophan-2,3-dioxygenase (TDO) inhibition ameliorates neurodegeneration by modulation of kynurenine pathway metabolites Proc Natl Acad Sci U S A 113:5435–5440 doi: 10.1073/pnas.1604453113 [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Brown KD et al. (2014) Activation of SIRT3 by the NAD(+) precursor nicotinamide riboside protects from noise-induced hearing loss Cell Metab 20:1059–1068 doi: 10.1016/j.cmet.2014.11.003 [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Canto C, Menzies KJ,Auwerx J (2015) NAD(+) Metabolism and the Control of Energy Homeostasis: A Balancing Act between Mitochondria and the Nucleus Cell Metab 22:31–53 doi: 10.1016/j.cmet.2015.05.023 [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Carroll AS, Bishop AC, DeRisi JL, Shokat KM,O’Shea EK (2001) Chemical inhibition of the Pho85 cyclin-dependent kinase reveals a role in the environmental stress response Proc Natl Acad Sci U S A 98:12578–12583 doi: 10.1073/pnas.211195798 98/22/12578 [pii] [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Chandler JL,Gholson RK (1972) De novo biosynthesis of nicotinamide adenine dinucleotide in Escherichia coli: excretion of quinolinic acid by mutants lacking quinolinate phosphoribosyl transferase J Bacteriol 111:98–102 [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Chang KH, Cheng ML, Tang HY, Huang CY, Wu YR,Chen CM (2018) Alternations of Metabolic Profile and Kynurenine Metabolism in the Plasma of Parkinson’s Disease Molecular neurobiology 55:6319–6328 doi: 10.1007/s12035-017-0845-3 [DOI] [PubMed] [Google Scholar]
  19. Chini CC, Tarrago MG,Chini EN (2016) NAD and the aging process: Role in life, death and everything in between Molecular and cellular endocrinology doi: 10.1016/j.mce.2016.11.003 [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Croft T, James Theoga Raj C, Salemi M, Phinney BS,Lin SJ (2018) A functional link between NAD(+) homeostasis and N-terminal protein acetylation in Saccharomyces cerevisiae J Biol Chem 293:2927–2938 doi: 10.1074/jbc.M117.807214 [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Emanuelli M, Carnevali F, Lorenzi M, Raffaelli N, Amici A, Ruggieri S,Magni G (1999) Identification and characterization of YLR328W, the Saccharomyces cerevisiae structural gene encoding NMN adenylyltransferase. Expression and characterization of the recombinant enzyme FEBS Lett 455:13–17 doi:S0014–5793(99)00852–2 [pii] [DOI] [PubMed] [Google Scholar]
  22. Frye RA (2000) Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins Biochemical and biophysical research communications 273:793–798 [DOI] [PubMed] [Google Scholar]
  23. Garten A, Schuster S, Penke M, Gorski T, de Giorgis T,Kiess W (2015) Physiological and pathophysiological roles of NAMPT and NAD metabolism Nat Rev Endocrinol 11:535–546 doi: 10.1038/nrendo.2015.117 [DOI] [PubMed] [Google Scholar]
  24. Ghislain M, Talla E,Francois JM (2002) Identification and functional analysis of the Saccharomyces cerevisiae nicotinamidase gene, PNC1 Yeast 19:215–224 10.1002/yea.810 [DOI] [PubMed] [Google Scholar]
  25. Graden JA,Winge DR (1997) Copper-mediated repression of the activation domain in the yeast Mac1p transcription factor Proc Natl Acad Sci U S A 94:5550–5555 [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Grose JH, Bergthorsson U,Roth JR (2005) Regulation of NAD synthesis by the trifunctional NadR protein of Salmonella enterica J Bacteriol 187:2774–2782 10.1128/JB.187.8.2774-2782.2005 [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Gross C, Kelleher M, Iyer VR, Brown PO,Winge DR (2000) Identification of the copper regulon in Saccharomyces cerevisiae by DNA microarrays J Biol Chem 275:32310–32316 doi: 10.1074/jbc.M005946200 [DOI] [PubMed] [Google Scholar]
  28. Grozio A et al. (2019) Slc12a8 is a nitotinamide mononucleotide transporter Nature Metabolism 1:47–57 doi: 10.1038/s42255-018-0009-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Imai S,Guarente L (2014) NAD+ and sirtuins in aging and disease Trends Cell Biol 24:464–471 doi: 10.1016/j.tcb.2014.04.002 [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Jackson MD, Schmidt MT, Oppenheimer NJ,Denu JM (2003) Mechanism of nicotinamide inhibition and transglycosidation by Sir2 histone/protein deacetylases J Biol Chem 278:50985–50998 doi: 10.1074/jbc.M306552200 [DOI] [PubMed] [Google Scholar]
  31. James Theoga Raj C, Croft T, Venkatakrishnan P, Groth B, Dhugga G, Cater T,Lin SJ (2019) The copper-sensing transcription factor Mac1, the histone deacetylase Hst1, and nicotinic acid regulate de novo NAD(+) biosynthesis in budding yeast J Biol Chem doi: 10.1074/jbc.RA118.006987 [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Jensen LT, Posewitz MC, Srinivasan C,Winge DR (1998) Mapping of the DNA binding domain of the copper-responsive transcription factor Mac1 from Saccharomyces cerevisiae J Biol Chem 273:23805–23811 [DOI] [PubMed] [Google Scholar]
  33. Jungmann J, Reins HA, Lee J, Romeo A, Hassett R, Kosman D,Jentsch S (1993) MAC1, a nuclear regulatory protein related to Cu-dependent transcription factors is involved in Cu/Fe utilization and stress resistance in yeast EMBO J 12:5051–5056 [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Kato M,Lin SJ (2014a) Regulation of NAD+ metabolism, signaling and compartmentalization in the yeast Saccharomyces cerevisiae DNA Repair 23:49–58 10.1016/j.dnarep.2014.07.009 [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Kato M,Lin SJ (2014b) YCL047C/POF1 is a novel nicotinamide mononucleotide adenylyltransferase (NMNAT) in Saccharomyces cerevisiae J Biol Chem 289:15577–15587 10.1074/jbc.M114.558643 [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Katsyuba E et al. (2018) De novo NAD(+) synthesis enhances mitochondrial function and improves health Nature 563:354–359 doi: 10.1038/s41586-018-0645-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Kulikova V et al. (2015) Generation, Release, and Uptake of the NAD Precursor Nicotinic Acid Riboside by Human Cells J Biol Chem 290:27124–27137 doi: 10.1074/jbc.M115.664458 [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Lin JB et al. (2016) NAMPT-Mediated NAD(+) Biosynthesis Is Essential for Vision In Mice Cell Rep 17:69–85 doi: 10.1016/j.celrep.2016.08.073 [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Liu HW et al. (2018) Pharmacological bypass of NAD(+) salvage pathway protects neurons from chemotherapy-induced degeneration Proc Natl Acad Sci U S A 115:10654–10659 doi: 10.1073/pnas.1809392115 [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Llorente B,Dujon B (2000) Transcriptional regulation of the Saccharomyces cerevisiae DAL5 gene family and identification of the high affinity nicotinic acid permease TNA1 (YGR260w) FEBS Lett 475:237–241 doi:S0014–5793(00)01698–7 [pii] [DOI] [PubMed] [Google Scholar]
  41. Lu SP, Kato M,Lin SJ (2009) Assimilation of endogenous nicotinamide riboside is essential for calorie restriction-mediated life span extension in Saccharomyces cerevisiae J Biol Chem 284:17110–17119 10.1074/jbc.M109.004010 [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Lu SP,Lin SJ (2010) Regulation of yeast sirtuins by NAD(+) metabolism and calorie restriction Biochim Biophys Acta 1804:1567–1575 10.1016/j.bbapap.2009.09.030 [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Lu SP,Lin SJ (2011) Phosphate-responsive signaling pathway is a novel component of NAD+ metabolism in Saccharomyces cerevisiae J Biol Chem 286:14271–14281 10.1074/jbc.M110.217885 [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Medvedik O, Lamming DW, Kim KD,Sinclair DA (2007) MSN2 and MSN4 link calorie restriction and TOR to sirtuin-mediated lifespan extension in Saccharomyces cerevisiae PLoS Biol 5:e261 10.1371/journal.pbio.0050261 [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Mole DJ et al. (2016) Kynurenine-3-monooxygenase inhibition prevents multiple organ failure in rodent models of acute pancreatitis Nat Med 22:202–209 doi: 10.1038/nm.4020 [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Nikiforov A, Dolle C, Niere M,Ziegler M (2011) Pathways and subcellular compartmentation of NAD biosynthesis in human cells: from entry of extracellular precursors to mitochondrial NAD generation J Biol Chem 286:21767–21778 10.1074/jbc.M110.213298 [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Nikiforov A, Kulikova V,Ziegler M (2015) The human NAD metabolome: Functions, metabolism and compartmentalization Crit Rev Biochem Mol Biol 50:284–297 doi: 10.3109/10409238.2015.1028612 [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Ohashi K, Chaleckis R, Takaine M, Wheelock CE,Yoshida S (2017) Kynurenine aminotransferase activity of Aro8/Aro9 engage tryptophan degradation by producing kynurenic acid in Saccharomyces cerevisiae Scientific reports 7:12180 doi: 10.1038/s41598-017-12392-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Ohashi K, Kawai S,Murata K (2013) Secretion of quinolinic acid, an intermediate in the kynurenine pathway, for utilization in NAD+ biosynthesis in the yeast Saccharomyces cerevisiae Eukaryot Cell 12:648–653 10.1128/EC.00339-12 [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Panozzo C et al. (2002) Aerobic and anaerobic NAD+ metabolism in Saccharomyces cerevisiae FEBS Lett 517:97–102 doi:S0014579302025851 [pii] [DOI] [PubMed] [Google Scholar]
  51. Poyan Mehr A et al. (2018) De novo NAD(+) biosynthetic impairment in acute kidney injury in humans Nat Med 24:1351–1359 doi: 10.1038/s41591-018-0138-z [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Ratajczak J et al. (2016) NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells Nat Commun 7:13103 doi: 10.1038/ncomms13103 [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Revollo JR, Grimm AA,Imai S (2004) The NAD biosynthesis pathway mediated by nicotinamide phosphoribosyltransferase regulates Sir2 activity in mammalian cells J Biol Chem 279:50754–50763 doi: 10.1074/jbc.M408388200 M408388200 [pii] [DOI] [PubMed] [Google Scholar]
  54. Said HM, Nabokina SM, Balamurugan K, Mohammed ZM, Urbina C,Kashyap ML (2007) Mechanism of nicotinic acid transport in human liver cells: experiments with HepG2 cells and primary hepatocytes Am J Physiol Cell Physiol 293:C1773–1778 doi: 10.1152/ajpcell.00409.2007 [DOI] [PubMed] [Google Scholar]
  55. Schwarcz R, Bruno JP, Muchowski PJ,Wu HQ (2012) Kynurenines in the mammalian brain: when physiology meets pathology Nature reviews Neuroscience 13:465–477 doi: 10.1038/nrn3257 [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Serpe M, Joshi A,Kosman DJ (1999) Structure-function analysis of the protein-binding domains of Mac1p, a copper-dependent transcriptional activator of copper uptake in Saccharomyces cerevisiae J Biol Chem 274:29211–29219 [DOI] [PubMed] [Google Scholar]
  57. Sporty J, Lin SJ, Kato M, Ognibene T, Stewart B, Turteltaub K,Bench G (2009) Quantitation of NAD+ biosynthesis from the salvage pathway in Saccharomyces cerevisiae Yeast 26:363–369 doi: 10.1002/yea.1671 [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Swinnen E et al. (2006) Rim15 and the crossroads of nutrient signalling pathways in Saccharomyces cerevisiae Cell Div 1:3 10.1186/1747-1028-1-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Tavares RG, Tasca CI, Santos CE, Alves LB, Porciuncula LO, Emanuelli T,Souza DO (2002) Quinolinic acid stimulates synaptosomal glutamate release and inhibits glutamate uptake into astrocytes Neurochem Int 40:621–627 [DOI] [PubMed] [Google Scholar]
  60. Trammell SA et al. (2016) Nicotinamide riboside is uniquely and orally bioavailable in mice and humans Nat Commun 7:12948 doi: 10.1038/ncomms12948 [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Tsang F, James C, Kato M, Myers V, Ilyas I, Tsang M,Lin SJ (2015) Reduced Ssy1-Ptr3-Ssy5 (SPS) Signaling Extends Replicative Life Span by Enhancing NAD+ Homeostasis in Saccharomyces cerevisiae J Biol Chem 290:12753–12764 10.1074/jbc.M115.644534 [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Tsang F,Lin SJ (2015) Less is more: Nutrient limitation induces cross-talk of nutrient sensing pathways with NAD(+) homeostasis and contributes to longevity Front Biol (Beijing) 10:333–357 doi: 10.1007/s11515-015-1367-x [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Verdin E (2015) NAD(+) in aging, metabolism, and neurodegeneration Science 350:1208–1213 doi: 10.1126/science.aac4854 [DOI] [PubMed] [Google Scholar]
  64. Wei M, Fabrizio P, Hu J, Ge H, Cheng C, Li L,Longo VD (2008) Life span extension by calorie restriction depends on Rim15 and transcription factors downstream of Ras/PKA, Tor, and Sch9 PLoS Genet 4:e13 doi:07-PLGE-RA-0807 [pii] 10.1371/journal.pgen.0040013 [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Williams PA et al. (2017) Vitamin B3 modulates mitochondrial vulnerability and prevents glaucoma in aged mice Science 355:756–760 doi: 10.1126/science.aal0092 [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Yang Y,Sauve AA (2016) NAD+ metabolism: Bioenergetics, signaling and manipulation for therapy Biochim Biophys Acta 1864:1787–1800 doi: 10.1016/j.bbapap.2016.06.014 [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Yoshino J, Baur JA,Imai SI (2018) NAD(+) Intermediates: The Biology and Therapeutic Potential of NMN and NR Cell Metab 27:513–528 doi: 10.1016/j.cmet.2017.11.002 [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. Zhang H et al. (2016) NAD+ repletion improves mitochondrial and stem cell function and enhances life span in mice Science 352:1436–1443 [DOI] [PubMed] [Google Scholar]
  69. Zhu Z, Labbe S, Pena MM,Thiele DJ (1998) Copper differentially regulates the activity and degradation of yeast Mac1 transcription factor J Biol Chem 273:1277–1280 [DOI] [PubMed] [Google Scholar]

RESOURCES