Skip to main content
SpringerLink
Log in

Amino-Acyl tRNA Synthetases Generate Dinucleotide Polyphosphates as Second Messengers: Functional Implications

  • Chapter
  • First Online:
Aminoacyl-tRNA Synthetases in Biology and Medicine

Part of the book series: Topics in Current Chemistry ((TOPCURRCHEM,volume 344))

Abstract

In this chapter we describe aminoacyl-tRNA synthetase (aaRS) production of dinucleotide polyphosphate in response to stimuli, their interaction with various signaling pathways, and the role of diadenosine tetraphosphate and diadenosine triphosphate as second messengers. The primary role of aaRS is to mediate aminoacylation of cognate tRNAs, thereby providing a central role for the decoding of genetic code during protein translation. However, recent studies suggest that during evolution, “moonlighting” or non-canonical roles were acquired through incorporation of additional domains, leading to regulation by aaRSs of a spectrum of important biological processes, including cell cycle control, tissue differentiation, cellular chemotaxis, and inflammation. In addition to aminoacylation of tRNA, most aaRSs can also produce dinucleotide polyphosphates in a variety of physiological conditions. The dinucleotide polyphosphates produced by aaRS are biologically active both extra- and intra-cellularly, and seem to function as important signaling molecules. Recent findings established the role of dinucleotide polyphosphates as second messengers.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 299.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 379.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

aaRS:

Aminoacyl tRNA synthetase

Ap3A:

Di-adenosine tri-phosphate

Ap4A:

Di-adenosine tetra-phosphate

Ap n N:

Di-adenosine polynucleotide

cAMP:

Cyclic adenosine monophosphate

Fhit:

Fragile histidine triad protein

Hint-1:

Histidine triad nucleotide-binding protein 1

LysRS:

Lysyl tRNA synthetase

MITF:

Microphthalmia transcription factor

MSC:

Multisynthetase complex

Np n N:

Dinucleotides polyphosphates

TrpRS:

Tryptophenyl tRNA synthetase

References

  1. Rall TW, Sutherland EW (1958) Formation of a cyclic adenine ribonucleotide by tissue particles. J Biol Chem 232:1065–1076

    CAS  Google Scholar 

  2. Springett GM, Kawasaki H, Spriggs DR (2004) Non-kinase second-messenger signaling: new pathways with new promise. Bioessays 26:730–738

    Article  CAS  Google Scholar 

  3. Bornfeldt KE (2006) A single second messenger: several possible cellular responses depending on distinct subcellular pools. Circ Res 99:790–792

    Article  CAS  Google Scholar 

  4. Sutherland EW (1972) Studies on the mechanism of hormone action. Science 177:401–408

    Article  CAS  Google Scholar 

  5. Bolander FF (2004) Molecular endocrinology, 3rd edn. Elsevier Academic, Amsterdam

    Google Scholar 

  6. Carmi-Levy I, Yannay-Cohen N, Kay G, Razin E, Nechushtan H (2008) Diadenosine tetraphosphate hydrolase is part of the transcriptional regulation network in immunologically activated mast cells. Mol Cell Biol 28:5777–5784

    Article  CAS  Google Scholar 

  7. de Rooij J, Zwartkruis FJ, Verheijen MH, Cool RH, Nijman SM, Wittinghofer A, Bos JL (1998) Epac is a Rap1 guanine-nucleotide-exchange factor directly activated by cyclic AMP. Nature 396:474–477

    Article  CAS  Google Scholar 

  8. Zamecnik PC, Stephenson ML, Janeway CM, Randerath K (1966) Enzymatic synthesis of diadenosine tetraphosphate and diadenosine triphosphate with a purified lysyl-sRNA synthetase. Biochem Biophys Res Commun 24:91–97

    Article  CAS  Google Scholar 

  9. Lee PC, Bochner BR, Ames BN (1983) AppppA, heat-shock stress, and cell oxidation. Proc Natl Acad Sci U S A 80:7496–7500

    Article  CAS  Google Scholar 

  10. Lee PC, Bochner BR, Ames BN (1983) Diadenosine 5′,5″′-P1,P4-tetraphosphate and related adenylylated nucleotides in Salmonella typhimurium. J Biol Chem 258:6827–6834

    CAS  Google Scholar 

  11. Varshavsky A (1983) Diadenosine 5′,5″′-P1,P4-tetraphosphate: a pleiotropically acting alarmone? Cell 34:711–712

    Article  CAS  Google Scholar 

  12. Huang R, Li M, Gregory RL (2011) Bacterial interactions in dental biofilm. Virulence 2:435–444

    Article  Google Scholar 

  13. Baker JC, Jacobson MK (1986) Alteration of adenyl dinucleotide metabolism by environmental stress. Proc Natl Acad Sci U S A 83:2350–2352

    Article  CAS  Google Scholar 

  14. Johnstone DB, Farr SB (1991) AppppA binds to several proteins in Escherichia coli, including the heat shock and oxidative stress proteins DnaK, GroEL, E89, C45 and C40. EMBO J 10:3897–3904

    CAS  Google Scholar 

  15. Kisselev LL, Justesen J, Wolfson AD, Frolova LY (1998) Diadenosine oligophosphates (Ap(n)A), a novel class of signalling molecules? FEBS Lett 427:157–163

    Article  CAS  Google Scholar 

  16. Fraga H, Fontes R (2011) Enzymatic synthesis of mono and dinucleoside polyphosphates. Biochim Biophys Acta 1810:1195–1204

    Article  CAS  Google Scholar 

  17. Brevet A, Chen J, Leveque F, Plateau P, Blanquet S (1989) In vivo synthesis of adenylylated bis(5′-nucleosidyl) tetraphosphates (Ap4N) by Escherichia coli aminoacyl-tRNA synthetases. Proc Natl Acad Sci U S A 86:8275–8279

    Article  CAS  Google Scholar 

  18. Plateau P, Blanquet S (1982) Zinc-dependent synthesis of various dinucleoside 5′,5″′-P1,P3-tri- or 5″,5″′-P1,P4-tetraphosphates by Escherichia coli lysyl-tRNA synthetase. Biochemistry 21:5273–5279

    Article  CAS  Google Scholar 

  19. Monds RD, Newell PD, Wagner JC, Schwartzman JA, Lu W, Rabinowitz JD, O'Toole GA (2010) Di-adenosine tetraphosphate (Ap4A) metabolism impacts biofilm formation by Pseudomonas fluorescens via modulation of c-di-GMP-dependent pathways. J Bacteriol 192:3011–3023

    Article  CAS  Google Scholar 

  20. Guo RT, Chong YE, Guo M, Yang XL (2009) Crystal structures and biochemical analyses suggest a unique mechanism and role for human glycyl-tRNA synthetase in Ap4A homeostasis. J Biol Chem 284:28968–28976

    Article  CAS  Google Scholar 

  21. Merkulova T, Kovaleva G, Kisselev L (1994) P1,P3-bis(5′-adenosyl)triphosphate (Ap3A) as a substrate and a product of mammalian tryptophanyl-tRNA synthetase. FEBS Lett 350:287–290

    Article  CAS  Google Scholar 

  22. Vartanian A, Narovlyansky A, Amchenkova A, Turpaev K, Kisselev L (1996) Interferons induce accumulation of diadenosine triphosphate (Ap3A) in human cultured cells. FEBS Lett 381:32–34

    Article  CAS  Google Scholar 

  23. Guranowski A, Blanquet S (1985) Phosphorolytic cleavage of diadenosine 5′,5″′-P1,P4-tetraphosphate. Properties of homogeneous diadenosine 5′,5″′-P1,P4-tetraphosphate alpha, beta-phosphorylase from Saccharomyces cerevisiae. J Biol Chem 260:3542–3547

    CAS  Google Scholar 

  24. Plateau P, Fromant M, Schmitter JM, Blanquet S (1990) Catabolism of bis(5′-nucleosidyl) tetraphosphates in Saccharomyces cerevisiae. J Bacteriol 172:6892–6899

    CAS  Google Scholar 

  25. McLennan AG, Mayers E, Adams DG (1996) Anabaena flos-aquae and other cyanobacteria possess diadenosine 5′,5″′-P1,P4-tetraphosphate (Ap4A) phosphorylase activity. Biochem J 320(Pt 3):795–800

    CAS  Google Scholar 

  26. Guranowski A (2000) Specific and nonspecific enzymes involved in the catabolism of mononucleoside and dinucleoside polyphosphates. Pharmacol Ther 87:117–139

    Article  CAS  Google Scholar 

  27. Barnes LD, Garrison PN, Siprashvili Z, Guranowski A, Robinson AK, Ingram SW, Croce CM, Ohta M, Huebner K (1996) Fhit, a putative tumor suppressor in humans, is a dinucleoside 5′,5″′-P1,P3-triphosphate hydrolase. Biochemistry 35:11529–11535

    Article  CAS  Google Scholar 

  28. Thorne NM, Hankin S, Wilkinson MC, Nunez C, Barraclough R, McLennan AG (1995) Human diadenosine 5′,5″′-P1,P4-tetraphosphate pyrophosphohydrolase is a member of the MutT family of nucleotide pyrophosphatases. Biochem J 311(Pt 3):717–721

    CAS  Google Scholar 

  29. Safrany ST, Ingram SW, Cartwright JL, Falck JR, McLennan AG, Barnes LD, Shears SB (1999) The diadenosine hexaphosphate hydrolases from Schizosaccharomyces pombe and Saccharomyces cerevisiae are homologues of the human diphosphoinositol polyphosphate phosphohydrolase. Overlapping substrate specificities in a MutT-type protein. J Biol Chem 274:21735–21740

    Article  CAS  Google Scholar 

  30. Bessman MJ, Frick DN, O'Handley SF (1996) The MutT proteins or “Nudix” hydrolases, a family of versatile, widely distributed, “housecleaning” enzymes. J Biol Chem 271:25059–25062

    Article  CAS  Google Scholar 

  31. Pintor J, King BF, Ziganshin AU, Miras-Portugal MT, Burnstock G (1996) Diadenosine polyphosphate-activated inward and outward currents in follicular oocytes of Xenopus laevis. Life Sci 59:PL179–184

    Article  CAS  Google Scholar 

  32. Hilderman RH, Martin M, Zimmerman JK, Pivorun EB (1991) Identification of a unique membrane receptor for adenosine 5′,5″′-P1,P4-tetraphosphate. J Biol Chem 266:6915–6918

    CAS  Google Scholar 

  33. Trapasso F, Krakowiak A, Cesari R, Arkles J, Yendamuri S, Ishii H, Vecchione A, Kuroki T, Bieganowski P, Pace HC, Huebner K, Croce CM, Brenner C (2003) Designed FHIT alleles establish that Fhit-induced apoptosis in cancer cells is limited by substrate binding. Proc Natl Acad Sci U S A 100:1592–1597

    Article  CAS  Google Scholar 

  34. Feussner K, Guranowski A, Kostka S, Wasternack C (1996) Diadenosine 5′,5″′-P1,P4-tetraphosphate (Ap4A) hydrolase from tomato (Lycopersicon esculentum cv. Lukullus) – purification, biochemical properties and behaviour during stress. Z Naturforsch C 51:477–486

    CAS  Google Scholar 

  35. Zourgui L, Baltz D, Baltz T, Oukerro F, Tarrago-Litvak L (1988) Purification, immunological and biochemical characterization of Ap4A binding protein from Xenopus laevis oocytes. Nucleic Acids Res 16:2913–2929

    Article  CAS  Google Scholar 

  36. Lee YN, Nechushtan H, Figov N, Razin E (2004) The function of lysyl-tRNA synthetase and Ap4A as signaling regulators of MITF activity in FcεRI-activated mast cells. Immunity 20:145–151

    Article  CAS  Google Scholar 

  37. Jovanovic A, Zhang S, Alekseev AE, Terzic A (1996) Diadenosine polyphosphate-induced inhibition of cardiac KATP channels: operative state-dependent regulation by a nucleoside diphosphate. Pflugers Arch 431:800–802

    CAS  Google Scholar 

  38. Klishin A, Lozovaya N, Pintor J, Miras-Portugal MT, Krishtal O (1994) Possible functional role of diadenosine polyphosphates: negative feedback for excitation in hippocampus. Neuroscience 58:235–236

    Article  CAS  Google Scholar 

  39. Green AK, Cobbold PH, Dixon CJ (1995) Cytosolic free Ca2+ oscillations induced by diadenosine 5′,5″′-P1,P3-triphosphate and diadenosine 5′,5″′-P1,P4-tetraphosphate in single rat hepatocytes are indistinguishable from those induced by ADP and ATP respectively. Biochem J 310(Pt 2):629–635

    CAS  Google Scholar 

  40. Gasmi L, McLennan AG, Edwards SW (1996) Neutrophil apoptosis is delayed by the diadenosine polyphosphates, Ap5A and Ap6A: synergism with granulocyte-macrophage colony-stimulating factor. Br J Haematol 95:637–639

    Article  CAS  Google Scholar 

  41. Ripoll C, Martin F, Manuel Rovira J, Pintor J, Miras-Portugal MT, Soria B (1996) Diadenosine polyphosphates. A novel class of glucose-induced intracellular messengers in the pancreatic beta-cell. Diabetes 45:1431–1434

    Article  CAS  Google Scholar 

  42. Weinmann-Dorsch C, Hedl A, Grummt I, Albert W, Ferdinand FJ, Friis RR, Pierron G, Moll W, Grummt F (1984) Drastic rise of intracellular adenosine(5′)tetraphospho(5′)adenosine correlates with onset of DNA synthesis in eukaryotic cells. Eur J Biochem 138:179–185

    Article  CAS  Google Scholar 

  43. Perret J, Hepburn A, Cochaux P, Van Sande J, Dumont JE (1990) Diadenosine 5′,5″′-P1,P4-tetraphosphate (AP4A) levels under various proliferative and cytotoxic conditions in several mammalian cell types. Cell Signal 2:57–65

    Article  CAS  Google Scholar 

  44. Oka K, Suzuki T, Onodera Y, Miki Y, Takagi K, Nagasaki S, Akahira J, Ishida T, Watanabe M, Hirakawa H, Ohuchi N, Sasano H (2011) Nudix-type motif 2 in human breast carcinoma: a potent prognostic factor associated with cell proliferation. Int J Cancer 128:1770–1782

    Article  CAS  Google Scholar 

  45. Rapaport E, Zamecnik PC, Baril EF (1981) HeLa cell DNA polymerase alpha is tightly associated with tryptophanyl-tRNA synthetase and diadenosine 5′,5″′-P1,P4-tetraphosphate binding activities. Proc Natl Acad Sci U S A 78:838–842

    Article  CAS  Google Scholar 

  46. Grummt F (1978) Diadenosine 5′,5″′-P1,P4-tetraphosphate triggers initiation of in vitro DNA replication in baby hamster kidney cells. Proc Natl Acad Sci U S A 75:371–375

    Article  CAS  Google Scholar 

  47. Vartanian A, Prudovsky I, Suzuki H, Dal Pra I, Kisselev L (1997) Opposite effects of cell differentiation and apoptosis on Ap3A/Ap4A ratio in human cell cultures. FEBS Lett 415:160–162

    Article  CAS  Google Scholar 

  48. Vartanian A, Alexandrov I, Prudowski I, McLennan A, Kisselev L (1999) Ap4A induces apoptosis in human cultured cells. FEBS Lett 456:175–180

    Article  CAS  Google Scholar 

  49. Carmi-Levy I, Motzik A, Ofir-Birin Y, Yagil Z, Yang CM, Kemeny DM, Han JM, Kim S, Kay G, Nechushtan H, Suzuki R, Rivera J, Razin E (2011) Importin beta plays an essential role in the regulation of the LysRS-Ap(4)A pathway in immunologically activated mast cells. Mol Cell Biol 31:2111–2121

    Article  CAS  Google Scholar 

  50. Lee YN, Razin E (2005) Nonconventional involvement of LysRS in the molecular mechanism of USF2 transcriptional activity in FcepsilonRI-activated mast cells. Mol Cell Biol 25:8904–8912

    Article  CAS  Google Scholar 

  51. Yannay-Cohen N, Carmi-Levy I, Kay G, Yang CM, Han JM, Kemeny DM, Kim S, Nechushtan H, Razin E (2009) LysRS serves as a key signaling molecule in the immune response by regulating gene expression. Mol Cell 34:603–611

    Article  CAS  Google Scholar 

  52. Lima CD, Klein MG, Hendrickson WA (1997) Structure-based analysis of catalysis and substrate definition in the HIT protein family. Science 278:286–290

    Article  CAS  Google Scholar 

  53. Brenner C, Garrison P, Gilmour J, Peisach D, Ringe D, Petsko GA, Lowenstein JM (1997) Crystal structures of HINT demonstrate that histidine triad proteins are GalT-related nucleotide-binding proteins. Nat Struct Biol 4:231–238

    Article  CAS  Google Scholar 

  54. Brenner C (2002) Hint, Fhit, and GalT: function, structure, evolution, and mechanism of three branches of the histidine triad superfamily of nucleotide hydrolases and transferases. Biochemistry 41:9003–9014

    Article  CAS  Google Scholar 

  55. Pichiorri F, Palumbo T, Suh SS, Okamura H, Trapasso F, Ishii H, Huebner K, Croce CM (2008) Fhit tumor suppressor: guardian of the preneoplastic genome. Future Oncol 4:815–824

    Article  CAS  Google Scholar 

  56. Siprashvili Z, Sozzi G, Barnes LD, McCue P, Robinson AK, Eryomin V, Sard L, Tagliabue E, Greco A, Fusetti L, Schwartz G, Pierotti MA, Croce CM, Huebner K (1997) Replacement of Fhit in cancer cells suppresses tumorigenicity. Proc Natl Acad Sci U S A 94:13771–13776

    Article  CAS  Google Scholar 

  57. Pace HC, Garrison PN, Robinson AK, Barnes LD, Draganescu A, Rosler A, Blackburn GM, Siprashvili Z, Croce CM, Huebner K, Brenner C (1998) Genetic, biochemical, and crystallographic characterization of Fhit-substrate complexes as the active signaling form of Fhit. Proc Natl Acad Sci U S A 95:5484–5489

    Article  CAS  Google Scholar 

  58. Wali A (2010) FHIT: doubts are clear now. Sci World J 10:1142–1151

    Article  CAS  Google Scholar 

  59. Weiske J, Albring KF, Huber O (2007) The tumor suppressor Fhit acts as a repressor of beta-catenin transcriptional activity. Proc Natl Acad Sci U S A 104:20344–20349

    Article  Google Scholar 

  60. Jayachandran G, Sazaki J, Nishizaki M, Xu K, Girard L, Minna JD, Roth JA, Ji L (2007) Fragile histidine triad-mediated tumor suppression of lung cancer by targeting multiple components of the Ras/Rho GTPase molecular switch. Cancer Res 67:10379–10388

    Article  CAS  Google Scholar 

  61. Semba S, Trapasso F, Fabbri M, McCorkell KA, Volinia S, Druck T, Iliopoulos D, Pekarsky Y, Ishii H, Garrison PN, Barnes LD, Croce CM, Huebner K (2006) Fhit modulation of the Akt-survivin pathway in lung cancer cells: Fhit-tyrosine 114 (Y114) is essential. Oncogene 25:2860–2872

    Article  CAS  Google Scholar 

  62. Bange FC, Flohr T, Buwitt U, Bottger EC (1992) An interferon-induced protein with release factor activity is a tryptophanyl-tRNA synthetase. FEBS Lett 300:162–166

    Article  CAS  Google Scholar 

  63. Rubin BY, Anderson SL, Xing L, Powell RJ, Tate WP (1991) Interferon induces tryptophanyl-tRNA synthetase expression in human fibroblasts. J Biol Chem 266:24245–24248

    CAS  Google Scholar 

  64. Sajish M, Zhou Q, Kishi S, Valdez DM Jr, Kapoor M, Guo M, Lee S, Kim S, Yang XL, Schimmel P (2012) Trp-tRNA synthetase bridges DNA-PKcs to PARP-1 to link IFN-gamma and p53 signaling. Nat Chem Biol 8:547–554

    Article  CAS  Google Scholar 

  65. Wakasugi K, Schimmel P (1999) Two distinct cytokines released from a human aminoacyl-tRNA synthetase. Science 284:147–151

    Article  CAS  Google Scholar 

  66. Amsterdam A, Nissen RM, Sun Z, Swindell EC, Farrington S, Hopkins N (2004) Identification of 315 genes essential for early zebrafish development. Proc Natl Acad Sci USA 101:12792–12797

    Article  CAS  Google Scholar 

  67. Mukhopadhyay R, Jia J, Arif A, Ray PS, Fox PL (2009) The GAIT system: a gatekeeper of inflammatory gene expression. Trends Biochem Sci 34:324–331

    Article  CAS  Google Scholar 

  68. Ko YG, Kim EY, Kim T, Park H, Park HS, Choi EJ, Kim S (2001) Glutamine-dependent antiapoptotic interaction of human glutaminyl-tRNA synthetase with apoptosis signal-regulating kinase 1. J Biol Chem 276:6030–6036

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Nuclear Medicine, Hadassah Hebrew University Medical Center, Jerusalem, Israel

    Sagi Tshori

  2. Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada, Hebrew University Hadassah Medical School, Jerusalem, Israel

    Ehud Razin

  3. Department of Oncology, Hadassah Hebrew University Medical Center, Jerusalem, Israel

    Hovav Nechushtan

Authors
  1. Sagi Tshori
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ehud Razin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hovav Nechushtan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ehud Razin .

Editor information

Editors and Affiliations

  1. Department of Molecular Medicine and Biopharmaceutical Sciences, Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Korea, Republic of (South Korea)

    Sunghoon Kim

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Tshori, S., Razin, E., Nechushtan, H. (2013). Amino-Acyl tRNA Synthetases Generate Dinucleotide Polyphosphates as Second Messengers: Functional Implications. In: Kim, S. (eds) Aminoacyl-tRNA Synthetases in Biology and Medicine. Topics in Current Chemistry, vol 344. Springer, Dordrecht. https://doi.org/10.1007/128_2013_426

Download citation

Publish with us

Policies and ethics

Search

Navigation