Advertisement

Current Genetics

, Volume 65, Issue 5, pp 1113–1119 | Cite as

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

  • Christol James Theoga Raj
  • Su-Ju LinEmail author
Mini-Review

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 

Notes

Acknowledgements

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.

References

  1. Amaral M, Outeiro TF, Scrutton NS, Giorgini F (2013) The causative role and therapeutic potential of the kynurenine pathway in neurodegenerative disease. J Mol Med (Berlin, Germany) 91:705–713.  https://doi.org/10.1007/s00109-013-1046-9 CrossRefGoogle 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.  https://doi.org/10.1074/jbc.m111773200 CrossRefGoogle 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.  https://doi.org/10.1038/nature01578 CrossRefGoogle 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 23:7044–7054CrossRefGoogle 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.  https://doi.org/10.1016/j.cell.2007.03.024 CrossRefGoogle 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.  https://doi.org/10.1074/jbc.c800021200 CrossRefGoogle 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 117:495–502CrossRefGoogle 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.  https://doi.org/10.1074/jbc.m302257200 CrossRefGoogle 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.  https://doi.org/10.1074/jbc.m205670200 CrossRefGoogle 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.  https://doi.org/10.1074/jbc.m109.056689 CrossRefGoogle 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 9:2888–2902CrossRefGoogle Scholar
  12. Braidy N, Grant R (2017) Kynurenine pathway metabolism and neuroinflammatory disease. Neural Regen Res 12:39–42.  https://doi.org/10.4103/1673-5374.198971 CrossRefGoogle 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 USA 113:5435–5440.  https://doi.org/10.1073/pnas.1604453113 CrossRefGoogle 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.  https://doi.org/10.1016/j.cmet.2014.11.003 CrossRefGoogle 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.  https://doi.org/10.1016/j.cmet.2015.05.023 CrossRefGoogle 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 USA 98:12578–12583.  https://doi.org/10.1073/pnas.211195798 CrossRefGoogle 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 111:98–102Google 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. Mol Neurobiol 55:6319–6328.  https://doi.org/10.1007/s12035-017-0845-3 CrossRefGoogle Scholar
  19. Chini CC, Tarrago MG, Chini EN (2016) NAD and the aging process: role in life, death and everything in between. Mol Cell Endocrinol.  https://doi.org/10.1016/j.mce.2016.11.003 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.  https://doi.org/10.1074/jbc.m117.807214 CrossRefGoogle 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 455:13–17CrossRefGoogle Scholar
  22. Frye RA (2000) Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins. Biochem Biophys Res Commun 273:793–798CrossRefGoogle 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.  https://doi.org/10.1038/nrendo.2015.117 CrossRefGoogle Scholar
  24. Ghislain M, Talla E, Francois JM (2002) Identification and functional analysis of the Saccharomyces cerevisiae nicotinamidase gene, PNC1. Yeast 19:215–224.  https://doi.org/10.1002/yea.810 CrossRefGoogle Scholar
  25. Graden JA, Winge DR (1997) Copper-mediated repression of the activation domain in the yeast Mac1p transcription factor. Proc Natl Acad Sci USA 94:5550–5555CrossRefGoogle 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.  https://doi.org/10.1128/JB.187.8.2774-2782.2005 CrossRefGoogle 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.  https://doi.org/10.1074/jbc.M005946200 CrossRefGoogle Scholar
  28. Grozio A et al (2019) Slc12a8 is a nitotinamide mononucleotide transporter. Nat Metab 1:47–57.  https://doi.org/10.1038/s42255-018-0009-4 CrossRefGoogle Scholar
  29. Imai S, Guarente L (2014) NAD+ and sirtuins in aging and disease. Trends Cell Biol 24:464–471.  https://doi.org/10.1016/j.tcb.2014.04.002 CrossRefGoogle 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.  https://doi.org/10.1074/jbc.m306552200 CrossRefGoogle 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.  https://doi.org/10.1074/jbc.ra118.006987 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 273:23805–23811CrossRefGoogle 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 12:5051–5056CrossRefGoogle Scholar
  34. Kato M, Lin SJ (2014a) Regulation of NAD+ metabolism, signaling and compartmentalization in the yeast Saccharomyces cerevisiae. DNA Repair 23:49–58.  https://doi.org/10.1016/j.dnarep.2014.07.009 CrossRefGoogle 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.  https://doi.org/10.1074/jbc.m114.558643 CrossRefGoogle Scholar
  36. Katsyuba E et al (2018) De novo NAD(+) synthesis enhances mitochondrial function and improves health. Nature 563:354–359.  https://doi.org/10.1038/s41586-018-0645-6 CrossRefGoogle 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.  https://doi.org/10.1074/jbc.M115.664458 CrossRefGoogle Scholar
  38. Lin JB et al (2016) NAMPT-mediated NAD(+) biosynthesis is essential for vision in mice. Cell Rep 17:69–85.  https://doi.org/10.1016/j.celrep.2016.08.073 CrossRefGoogle Scholar
  39. Liu HW et al (2018) Pharmacological bypass of NAD(+) salvage pathway protects neurons from chemotherapy-induced degeneration. Proc Natl Acad Sci USA 115:10654–10659.  https://doi.org/10.1073/pnas.1809392115 CrossRefGoogle 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 475:237–241CrossRefGoogle Scholar
  41. Lu SP, Lin SJ (2010) Regulation of yeast sirtuins by NAD(+) metabolism and calorie restriction. Biochim Biophys Acta 1804:1567–1575.  https://doi.org/10.1016/j.bbapap.2009.09.030 CrossRefGoogle Scholar
  42. 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.  https://doi.org/10.1074/jbc.m110.217885 CrossRefGoogle Scholar
  43. 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.  https://doi.org/10.1074/jbc.M109.004010 CrossRefGoogle 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.  https://doi.org/10.1371/journal.pbio.0050261 CrossRefGoogle 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.  https://doi.org/10.1038/nm.4020 CrossRefGoogle 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.  https://doi.org/10.1074/jbc.M110.213298 CrossRefGoogle 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.  https://doi.org/10.3109/10409238.2015.1028612 CrossRefGoogle Scholar
  48. 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.  https://doi.org/10.1128/ec.00339-12 CrossRefGoogle Scholar
  49. 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. Sci Rep 7:12180.  https://doi.org/10.1038/s41598-017-12392-6 CrossRefGoogle Scholar
  50. Panozzo C et al (2002) Aerobic and anaerobic NAD+ metabolism in Saccharomyces cerevisiae. FEBS Lett 517:97–102CrossRefGoogle Scholar
  51. Poyan Mehr A et al (2018) De novo NAD(+) biosynthetic impairment in acute kidney injury in humans. Nat Med 24:1351–1359.  https://doi.org/10.1038/s41591-018-0138-z CrossRefGoogle Scholar
  52. Ratajczak J et al (2016) NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells. Nat Commun 7:13103.  https://doi.org/10.1038/ncomms13103 CrossRefGoogle 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.  https://doi.org/10.1074/jbc.m408388200 CrossRefGoogle 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–C1778.  https://doi.org/10.1152/ajpcell.00409.2007 CrossRefGoogle Scholar
  55. Schwarcz R, Bruno JP, Muchowski PJ, Wu HQ (2012) Kynurenines in the mammalian brain: when physiology meets pathology. Nat Rev Neurosci 13:465–477.  https://doi.org/10.1038/nrn3257 CrossRefGoogle 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 274:29211–29219CrossRefGoogle 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.  https://doi.org/10.1002/yea.1671 CrossRefGoogle Scholar
  58. Swinnen E et al (2006) Rim15 and the crossroads of nutrient signalling pathways in Saccharomyces cerevisiae. Cell Div 1:3.  https://doi.org/10.1186/1747-1028-1-3 CrossRefGoogle 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 40:621–627CrossRefGoogle Scholar
  60. Trammell SA et al (2016) Nicotinamide riboside is uniquely and orally bioavailable in mice and humans. Nat Commun 7:12948.  https://doi.org/10.1038/ncomms12948 CrossRefGoogle Scholar
  61. 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.  https://doi.org/10.1007/s11515-015-1367-x CrossRefGoogle Scholar
  62. 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.  https://doi.org/10.1074/jbc.m115.644534 CrossRefGoogle Scholar
  63. Verdin E (2015) NAD(+) in aging, metabolism, and neurodegeneration. Science 350:1208–1213.  https://doi.org/10.1126/science.aac4854 CrossRefGoogle 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.  https://doi.org/10.1371/journal.pgen.0040013 CrossRefGoogle Scholar
  65. Williams PA et al (2017) Vitamin B3 modulates mitochondrial vulnerability and prevents glaucoma in aged mice. Science 355:756–760.  https://doi.org/10.1126/science.aal0092 CrossRefGoogle Scholar
  66. Yang Y, Sauve AA (2016) NAD+ metabolism: Bioenergetics, signaling and manipulation for therapy. Biochim Biophys Acta 1864:1787–1800.  https://doi.org/10.1016/j.bbapap.2016.06.014 CrossRefGoogle 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.  https://doi.org/10.1016/j.cmet.2017.11.002 CrossRefGoogle Scholar
  68. Zhang H et al (2016) NAD+ repletion improves mitochondrial and stem cell function and enhances life span in mice. Science 352:1436–1443CrossRefGoogle 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 273:1277–1280CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Microbiology and Molecular Genetics, College of Biological SciencesUniversity of CaliforniaDavisUSA

Personalised recommendations