Skip to main content
Book cover

Modified Nucleic Acids in Biology and Medicine pp 207–219Cite as

Diadenosine Tetraphosphate (Ap4A) in Health and Disease

Part of the RNA Technologies book series (RNATECHN)

Abstract

Diadenosine oligophosphates (ApnAs) were initially discovered more than 50 years ago. This group of molecules form a class of compounds derived from ATP and consist of two adenosine molecules bridged by up to six phosphate groups. The first enzymatic production of these compounds was noted by Zamecnik and colleagues in their study with purified lysyl tRNA synthetase (KARS) in mammalian cells.

Multiple studies on the role of ApnAs have been published during the years following their initial discovery. However, technical difficulties hampered some of the studies, and the field has been abandoned for nearly 20 years, until the use of new molecular methods inspired new studies into the functional aspects of these nucleotides in bacterial and eukaryotic systems.

In this chapter, we will discuss the role of ApnAs in prokaryotic and eukaryotic cells and will focus on the most investigated member of the ApnAs family, namely diadenosine tetraphosphate (Ap4A), and its role in a variety of tissues such as the heart and blood vessels, neurons, spermatocytes, neutrophils, and pancreatic cells.

We conclude our chapter with a description of a putative cell signaling pathway involving KARS, whose structure can be modulated so that it is no longer involved in translation but mainly in transcription, through its ability to produce the second messenger Ap4A.

Keywords

  • ApnAs: diadenosine oligophosphates
  • Ap3A: diadenosine triphosphate
  • Ap4A: diadenosine tetraphosphate
  • KARS: lysyl-tRNA-synthetase

This is a preview of subscription content, access via your institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • DOI: 10.1007/978-3-319-34175-0_9
  • Chapter length: 13 pages
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
eBook
USD   169.00
Price excludes VAT (USA)
  • ISBN: 978-3-319-34175-0
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
Softcover Book
USD   219.99
Price excludes VAT (USA)
Hardcover Book
USD   219.99
Price excludes VAT (USA)
Learn about institutional subscriptions
Fig. 1
Fig. 2

References

  • Ahmet I, Sawa Y, Nishimura M et al (2000) Cardioprotective effect of diadenosine tetraphosphate (AP4A) preservation in hypothermic storage and its relation with mitochondrial ATP-sensitive potassium channels. Transplantation 69:16–20

    CAS  CrossRef  PubMed  Google Scholar 

  • Allegrucci C, Liguori L, Mezzasoma I et al (2000) A1 adenosine receptor in human spermatozoa: its role in the fertilization process. Mol Genet Metab 71:381–386

    CAS  CrossRef  PubMed  Google Scholar 

  • Allegrucci C, Liguori L, Minelli A (2001) Stimulation by n6-cyclopentyladenosine of A1 adenosine receptors, coupled to galphai2 protein subunit, has a capacitative effect on human spermatozoa. Biol Reprod 64:1653–1659

    CAS  CrossRef  PubMed  Google Scholar 

  • Busse R, Ogilvie A, Pohl U (1988) Vasomotor activity of diadenosine triphosphate and diadenosine tetraphosphate in isolated arteries. Am J Physiol 254:H828–H832

    CAS  PubMed  Google Scholar 

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

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  • Cartwright JL, Britton P, Minnick MF et al (1999) The IalA invasion gene of Bartonella bacilliformis encodes a (de)nucleoside polyphosphate hydrolase of the MutT motif family and has homologs in other invasive bacteria. Biochem Biophys Res Commun 256:474–479

    CAS  CrossRef  PubMed  Google Scholar 

  • Chan PJ, Su BC, Tredway DR (1991) Diadenosine tetraphosphate (Ap4A) and triphosphate (Ap3A) signaling of human sperm motility. Arch Androl 27:103–108

    CAS  CrossRef  PubMed  Google Scholar 

  • Charlier J, Sanchez R (1987) Lysyl-tRNA synthetase from Escherichia coli K12: chromatographic heterogeneity and the lysU-gene product. Biochem J 248:43–51

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  • Chen X, Boonyalai N, Lau C et al (2013) Multiple catalytic activities of Escherichia coli lysyl-tRNA synthetase (LysU) are dissected by site-directed mutagenesis. FEBS J 280:102–114

    CAS  CrossRef  PubMed  Google Scholar 

  • Coiffard B, Soubeyran P, Ghigo E (2015) Editorial: Manipulation of the cellular microbicidal response and endocytic dynamic by pathogens membrane factors. Front Cell Infect Microbiol 5:42

    CrossRef  PubMed  PubMed Central  Google Scholar 

  • Communi D, Motte S, Boeynaems JM et al (1996) Pharmacological characterization of the human P2Y4 receptor. Eur J Pharmacol 317:383–389

    CAS  CrossRef  PubMed  Google Scholar 

  • Coste H, Brevet A, Plateau P et al (1987) Non-adenylylated bis(5′-nucleosidyl) tetraphosphates occur in Saccharomyces cerevisiae and in Escherichia coli and accumulate upon temperature shift or exposure to cadmium. J Biol Chem 262:12096–12103

    CAS  PubMed  Google Scholar 

  • Diaz-Hernandez M, Pereira MF, Pintor J et al (2002) Modulation of the rat hippocampal dinucleotide receptor by adenosine receptor activation. J Pharmacol Exp Ther 301:441–450

    CAS  CrossRef  PubMed  Google Scholar 

  • Farr SB, Arnosti DN, Chamberlin MJ et al (1989) An apaH mutation causes AppppA to accumulate and affects motility and catabolite repression in Escherichia coli. Proc Natl Acad Sci USA 86:5010–5014

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  • Gasmi L, McLennan AG, Edwards SW (1996a) The diadenosine polyphosphates Ap3A and Ap4A and adenosine triphosphate interact with granulocyte-macrophage colony-stimulating factor to delay neutrophil apoptosis: implications for neutrophil: platelet interactions during inflammation. Blood 87:3442–3449

    CAS  PubMed  Google Scholar 

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

    CAS  CrossRef  PubMed  Google Scholar 

  • Gaywee J, Radulovic S, Higgins JA et al (2002) Transcriptional analysis of Rickettsia prowazekii invasion gene homolog (invA) during host cell infection. Infect Immun 70:6346–6354

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  • Genovese G, Ghosh P, Li H et al (2012) The tumor suppressor HINT1 regulates MITF and beta-catenin transcriptional activity in melanoma cells. Cell Cycle 11:2206–2215

    CAS  CrossRef  PubMed  Google Scholar 

  • Han JM, Kim JY, Kim S (2003) Molecular network and functional implications of macromolecular tRNA synthetase complex. Biochem Biophys Res Commun 303:985–993

    CAS  CrossRef  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Ismail TM, Hart CA, McLennan AG (2003) Regulation of dinucleoside polyphosphate pools by the YgdP and ApaH hydrolases is essential for the ability of Salmonella enterica serovar typhimurium to invade cultured mammalian cells. J Biol Chem 278:32602–32607

    CAS  CrossRef  PubMed  Google Scholar 

  • Jo YH, Schlichter R (1999) Synaptic corelease of ATP and GABA in cultured spinal neurons. Nat Neurosci 2:241–245

    CAS  CrossRef  PubMed  Google Scholar 

  • 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  PubMed  PubMed Central  Google Scholar 

  • Jovanovic S, Jovanovic A (2001) Diadenosine tetraphosphate-gating of recombinant pancreatic ATP-sensitive K(+) channels. Biosci Rep 21:93–99

    CAS  CrossRef  PubMed  Google Scholar 

  • Kawamoto J, Kurihara T, Kitagawa M et al (2007) Proteomic studies of an Antarctic cold-adapted bacterium, Shewanella livingstonensis Ac10, for global identification of cold-inducible proteins. Extremophiles 11:819–826

    CAS  CrossRef  PubMed  Google Scholar 

  • Lazarowski ER, Watt WC, Stutts MJ et al (1995) Pharmacological selectivity of the cloned human P2U-purinoceptor: potent activation by diadenosine tetraphosphate. Br J Pharmacol 116:1619–1627

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

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

    CAS  CrossRef  PubMed  Google Scholar 

  • Leveque F, Plateau P, Dessen P et al (1990) Homology of lysS and lysU, the two Escherichia coli genes encoding distinct lysyl-tRNA synthetase species. Nucleic Acids Res 18:305–312

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  • Marriott AS, Copeland NA, Cunningham R et al (2015) Diadenosine 5′, 5‴-P(1), P(4)-tetraphosphate (Ap4A) is synthesized in response to DNA damage and inhibits the initiation of DNA replication. DNA Repair (Amst) 33:90–100

    CAS  CrossRef  Google Scholar 

  • Martin F, Pintor J, Rovira JM et al (1998) Intracellular diadenosine polyphosphates: a novel second messenger in stimulus-secretion coupling. FASEB J 12:1499–1506

    CAS  PubMed  Google Scholar 

  • Minelli A, Liguori L, Bellezza I et al (2003) Effects of diadenosine polyphosphates and seminal fluid vesicles on rabbit sperm cells. Reproduction 125:827–835

    CAS  CrossRef  PubMed  Google Scholar 

  • Miras-Portugal MT, Pintor J, Gualix J (2003) Ca2+ signalling in brain synaptosomes activated by dinucleotides. J Membr Biol 194:1–10

    CAS  CrossRef  PubMed  Google Scholar 

  • Ofir-Birin Y, Fang P, Bennett SP et al (2013) Structural switch of lysyl-tRNA synthetase between translation and transcription. Mol Cell 49:30–42

    CAS  CrossRef  PubMed  Google Scholar 

  • Ogilvie A, Blasius R, Schulze-Lohoff E et al (1996) Adenine dinucleotides: a novel class of signalling molecules. J Auton Pharmacol 16:325–328

    CAS  CrossRef  PubMed  Google Scholar 

  • Pintor J, Diaz-Rey MA, Torres M et al (1992) Presence of diadenosine polyphosphates—Ap4A and Ap5A—in rat brain synaptic terminals. Ca2+ dependent release evoked by 4-aminopyridine and veratridine. Neurosci Lett 136:141–144

    CAS  CrossRef  PubMed  Google Scholar 

  • Pintor J, Puche JA, Gualix J et al (1997) Diadenosine polyphosphates evoke Ca2+ transients in guinea-pig brain via receptors distinct from those for ATP. J Physiol 504(2):327–335

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  • Ralevic V, Burnstock G (1998) Receptors for purines and pyrimidines. Pharmacol Rev 50:413–492

    CAS  PubMed  Google Scholar 

  • Ripoll C, Martin F, Manuel Rovira J et al (1996) Diadenosine polyphosphates: a novel class of glucose-induced intracellular messengers in the pancreatic beta-cell. Diabetes 45:1431–1434

    CAS  CrossRef  PubMed  Google Scholar 

  • Robinson JC, Kerjan P, Mirande M (2000) Macromolecular assemblage of aminoacyl-tRNA synthetases: quantitative analysis of protein-protein interactions and mechanism of complex assembly. J Mol Biol 304:983–994

    CAS  CrossRef  PubMed  Google Scholar 

  • Sasaki C, Kitagawa H, Zhang WR et al (2000) Temporal profile of cytochrome c and caspase-3 immunoreactivities and TUNEL staining after permanent middle cerebral artery occlusion in rats. Neurol Res 22:223–228

    CAS  CrossRef  PubMed  Google Scholar 

  • Schachter JB, Li Q, Boyer JL et al (1996) Second messenger cascade specificity and pharmacological selectivity of the human P2Y1-purinoceptor. Br J Pharmacol 118:167–173

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  • Sherman MY, Goldberg AL (1993) Heat shock of Escherichia coli increases binding of dnaK (the hsp70 homolog) to polypeptides by promoting its phosphorylation. Proc Natl Acad Sci USA 90:8648–8652

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  • Silvestre RA, Rodriguez-Gallardo J, Egido EM et al (1999) Stimulatory effect of exogenous diadenosine tetraphosphate on insulin and glucagon secretion in the perfused rat pancreas. Br J Pharmacol 128:795–801

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  • Sirito M, Lin Q, Deng JM et al (1998) Overlapping roles and asymmetrical cross-regulation of the USF proteins in mice. Proc Natl Acad Sci USA 95:3758–3763

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  • Vahlensieck U, Boknik P, Gombosova I et al (1999) Inotropic effects of diadenosine tetraphosphate (AP4A) in human and animal cardiac preparations. J Pharmacol Exp Ther 288:805–813

    CAS  PubMed  Google Scholar 

  • Wang Y, Chang CF, Morales M et al (2003) Diadenosine tetraphosphate protects against injuries induced by ischemia and 6-hydroxydopamine in rat brain. J Neurosci 23:7958–7965

    CAS  PubMed  Google Scholar 

  • Wang L, Zhang Y, Li H et al (2007) Hint1 inhibits growth and activator protein-1 activity in human colon cancer cells. Cancer Res 67:4700–4708

    CAS  CrossRef  PubMed  Google Scholar 

  • Wang L, Li H, Zhang Y et al (2009) HINT1 inhibits beta-catenin/TCF4, USF2 and NFkappaB activity in human hepatoma cells. Int J Cancer 124:1526–1534

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  • Wright M, Boonyalai N, Tanner JA et al (2006) The duality of LysU, a catalyst for both Ap4A and Ap3A formation. FEBS J 273:3534–3544

    CAS  CrossRef  PubMed  Google Scholar 

  • Wright M, Azhar MA, Kamal A et al (2014) Syntheses of stable, synthetic diadenosine polyphosphate analogues using recombinant histidine-tagged lysyl tRNA synthetase (LysU). Bioorg Med Chem Lett 24:2346–2352

    CAS  CrossRef  PubMed  Google Scholar 

  • Yannay-Cohen N, Carmi-Levy I, Kay G et al (2009) LysRS serves as a key signaling molecule in the immune response by regulating gene expression. Mol Cell 34:603–611

    CAS  CrossRef  PubMed  Google Scholar 

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

    CAS  CrossRef  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, EinKerem, Jerusalem, 91120, Israel

    Suliman Boulos & Hovav Nechushtan

  2. Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada, The Hebrew University of Jerusalem, Jerusalem, 91120, Israel

    Ehud Razin

  3. Cardiovascular Division, Department of Medicine, and Brigham Regenerative Medicine Center, Brigham and Women’s Hospital, Boston, MA, 02115, USA

    Inbal Rachmin

  4. Harvard Stem Cell Institute and Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02139, USA

    Inbal Rachmin

Authors
  1. Suliman Boulos
    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

  4. Inbal Rachmin
    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. Nanobiomedical Center, Adam Mickiewicz University, Poznań, Poland

    Stefan Jurga

  2. Formerly at Institute of Chemistry and Biochemistry, Free University Berlin, Berlin, Germany

    Volker A. Erdmann (Deceased)

  3. Institute of the Bioorganic Chemistry of the Polish Academy of Sciences, Poznań, Poland

    Jan Barciszewski

Rights and permissions

Reprints and Permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Boulos, S., Razin, E., Nechushtan, H., Rachmin, I. (2016). Diadenosine Tetraphosphate (Ap4A) in Health and Disease. In: Jurga, S., Erdmann (Deceased), V., Barciszewski, J. (eds) Modified Nucleic Acids in Biology and Medicine. RNA Technologies. Springer, Cham. https://doi.org/10.1007/978-3-319-34175-0_9

Download citation