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Record Information
Version3.6
Creation Date2005-11-16 15:48:42 UTC
Update Date2016-02-11 01:04:10 UTC
HMDB IDHMDB01282
Secondary Accession NumbersNone
Metabolite Identification
Common NameDiadenosine hexaphosphate
DescriptionDiadenosine hexaphosphate (AP6A) is a diadenosine polyphosphate. Diadenosine polyphosphates (APnAs, n = 3-6) are a family of endogenous vasoactive purine dinucleotides which have been isolated from thrombocytes. APnAs have been demonstrated to be involved in the control of vascular tone as well as the growth of vascular smooth muscle cells and hence, possibly, in atherogenesis. APnAs isolated substances are AP3A, AP4A, AP5A, and AP6A. APnAs are naturally occurring substances that facilitate tear secretion; they are released from the corneal epithelium, they stimulate tear production and therefore they may be considered as physiological modulators of tear secretion. The APnAs were discovered in the mid-sixties in the course of studies on aminoacyl-tRNA synthetases (aaRS). APnAs have emerged as intracellular and extracellular signalling molecules implicated in the maintenance and regulation of vital cellular functions and become considered as second messengers. Great variety of physiological and pathological effects in mammalian cells was found to be associated with alterations of APnAs. APnAs are polyphosphated nucleotidic substances which are found in the CNS and are known to be released in a calcium-dependent manner from storage vesicles in brain synaptosomes. AP6A is an avid inhibitor of eosinophil-derived neurotoxin (EDN). EDN is a catalytically proficient member of the pancreatic ribonuclease superfamily secreted along with other eosinophil granule proteins during innate host defense responses and various eosinophil-related inflammatory and allergic diseases. The ribonucleolytic activity of EDN is central to its antiviral and neurotoxic activities and possibly to other facets of its biological activity. AP6A have been demonstrated to be involved in the control of vascular tone as well as the growth of vascular smooth muscle cells and hence, possibly, in atherogenesis. AP6A have been identified in human platelets and shown to be an important modulator of cardiovascular function. (PMID: 11212966 , 12738682 , 11810214 , 9607303 , 8922753 , 16401072 , 12738682 , 10094777 ).
Structure
Thumb
Synonyms
ValueSource
Adenosine 5'-hexaphosphate 5'-ester with adenosineChEBI
Adenosine-(5')-hexaphospho-(5')-adenosineChEBI
Ap(6)aChEBI
AP6aChEBI
AppppppAChEBI
Diadenosine 5',5''''-P1,P6-hexaphosphateChEBI
Diadenosine hexaphosphateChEBI
P1,P6-Di(adenosine-5')hexaphosphateChEBI
Adenosine 5'-hexaphosphoric acid 5'-ester with adenosineGenerator
P(1),P(6)-Bis(5'-adenosyl)hexaphosphoric acidGenerator
Diadenosine 5',5''''-P1,P6-hexaphosphoric acidGenerator
Diadenosine hexaphosphoric acidGenerator
P1,P6-Di(adenosine-5')hexaphosphoric acidGenerator
Adenosine 5'-(heptahydrogen hexaphosphate) P->5'-ester with adenosineHMDB
Adenosine 5'-(heptahydrogen hexaphosphate)5'-5'-ester with adenosineHMDB
Chemical FormulaC20H30N10O25P6
Average Molecular Weight996.3468
Monoisotopic Molecular Weight995.980925632
IUPAC Name{[(2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy}({[({[({[({[(2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy}(hydroxy)phosphoryl)oxy](hydroxy)phosphoryl}oxy)(hydroxy)phosphoryl]oxy}(hydroxy)phosphoryl)oxy](hydroxy)phosphoryl}oxy)phosphinic acid
Traditional NameAppppppA
CAS Registry Number56983-23-4
SMILES
NC1=C2N=CN([C@@H]3O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]4O[C@H]([C@H](O)[C@@H]4O)N4C=NC5=C(N)N=CN=C45)[C@@H](O)[C@H]3O)C2=NC=N1
InChI Identifier
InChI=1S/C20H30N10O25P6/c21-15-9-17(25-3-23-15)29(5-27-9)19-13(33)11(31)7(49-19)1-47-56(35,36)51-58(39,40)53-60(43,44)55-61(45,46)54-59(41,42)52-57(37,38)48-2-8-12(32)14(34)20(50-8)30-6-28-10-16(22)24-4-26-18(10)30/h3-8,11-14,19-20,31-34H,1-2H2,(H,35,36)(H,37,38)(H,39,40)(H,41,42)(H,43,44)(H,45,46)(H2,21,23,25)(H2,22,24,26)/t7-,8-,11-,12-,13-,14-,19-,20-/m1/s1
InChI KeyInChIKey=PZCFFCOJNXGTIM-XPWFQUROSA-N
Chemical Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as (5'->5')-dinucleotides. These are dinucleotides where the two bases are connected via a (5'->5')-phosphodiester linkage.
KingdomOrganic compounds
Super ClassNucleosides, nucleotides, and analogues
Class(5'->5')-dinucleotides
Sub ClassNot Available
Direct Parent(5'->5')-dinucleotides
Alternative Parents
Substituents
  • (5'->5')-dinucleotide
  • Purine nucleotide sugar
  • Purine ribonucleoside
  • N-glycosyl compound
  • Glycosyl compound
  • Organic pyrophosphate
  • Monosaccharide phosphate
  • 6-aminopurine
  • Purine
  • Imidazopyrimidine
  • Monoalkyl phosphate
  • Aminopyrimidine
  • Imidolactam
  • Alkyl phosphate
  • Pyrimidine
  • Primary aromatic amine
  • Phosphoric acid ester
  • Organic phosphoric acid derivative
  • Organic phosphate
  • N-substituted imidazole
  • Monosaccharide
  • Heteroaromatic compound
  • Oxolane
  • Imidazole
  • Azole
  • Secondary alcohol
  • 1,2-diol
  • Oxacycle
  • Azacycle
  • Organoheterocyclic compound
  • Hydrocarbon derivative
  • Primary amine
  • Organooxygen compound
  • Organonitrogen compound
  • Amine
  • Alcohol
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
Ontology
StatusDetected and Quantified
Origin
  • Endogenous
BiofunctionNot Available
ApplicationNot Available
Cellular locationsNot Available
Physical Properties
StateSolid
Experimental Properties
PropertyValueReference
Melting PointNot AvailableNot Available
Boiling PointNot AvailableNot Available
Water SolubilityNot AvailableNot Available
LogPNot AvailableNot Available
Predicted Properties
PropertyValueSource
Water Solubility6.99 mg/mLALOGPS
logP0.26ALOGPS
logP-10ChemAxon
logS-2.1ALOGPS
pKa (Strongest Acidic)0.28ChemAxon
pKa (Strongest Basic)5.3ChemAxon
Physiological Charge-6ChemAxon
Hydrogen Acceptor Count26ChemAxon
Hydrogen Donor Count12ChemAxon
Polar Surface Area527.03 Å2ChemAxon
Rotatable Bond Count18ChemAxon
Refractivity187.85 m3·mol-1ChemAxon
Polarizability76.38 Å3ChemAxon
Number of Rings6ChemAxon
Bioavailability0ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash Key
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-000i-0910110002-59d115c90a4481a6b007View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-000i-0900000000-d3bcef479d59e691d5b8View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-000i-0900000000-8dec47b8f02e8a6ac5a7View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-000x-0700000209-de23da8b809775f36d57View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-001i-0900000200-eec87d1063e1b19d703aView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-003r-1902401000-c06f9d4097503496c4b3View in MoNA
Biological Properties
Cellular LocationsNot Available
Biofluid Locations
  • Blood
Tissue LocationNot Available
PathwaysNot Available
Normal Concentrations
Not Available
Abnormal Concentrations
BiofluidStatusValueAgeSexConditionReferenceDetails
BloodDetected and Quantified0.10 +/- 0.10 uMAdult (>18 years old)BothHemodialysis details
Associated Disorders and Diseases
Disease References
Hemodialysis
  1. Jankowski J, Jankowski V, Laufer U, van der Giet M, Henning L, Tepel M, Zidek W, Schluter H: Identification and quantification of diadenosine polyphosphate concentrations in human plasma. Arterioscler Thromb Vasc Biol. 2003 Jul 1;23(7):1231-8. Epub 2003 May 8. [12738682 ]
Associated OMIM IDsNone
DrugBank IDNot Available
DrugBank Metabolite IDNot Available
Phenol Explorer Compound IDNot Available
Phenol Explorer Metabolite IDNot Available
FoodDB IDFDB022533
KNApSAcK IDNot Available
Chemspider ID110267
KEGG Compound IDC20190
BioCyc IDNot Available
BiGG IDNot Available
Wikipedia LinkNot Available
NuGOwiki LinkHMDB01282
Metagene LinkHMDB01282
METLIN IDNot Available
PubChem Compound123694
PDB IDB6P
ChEBI ID63689
References
Synthesis ReferenceSawai, Hiroaki; Inaba, Toshiko; Hirano, Atsushi; Wakai, Hiromichi; Shimazu, Masamitsu. Magnesium(II) ion-mediated conversion of mono- and oligonucleotides to 5'-polyphosphates in aqueous solution. Tetrahedron Letters (1993), 34(30), 4801-4.
Material Safety Data Sheet (MSDS)Not Available
General References
  1. Yang X, Safrany ST, Shears SB: Site-directed mutagenesis of diphosphoinositol polyphosphate phosphohydrolase, a dual specificity NUDT enzyme that attacks diadenosine polyphosphates and diphosphoinositol polyphosphates. J Biol Chem. 1999 Dec 10;274(50):35434-40. [10585413 ]
  2. Jankowski J, Potthoff W, van der Giet M, Tepel M, Zidek W, Schluter H: High-performance liquid chromatographic assay of the diadenosine polyphosphates in human platelets. Anal Biochem. 1999 Apr 10;269(1):72-8. [10094777 ]
  3. Flores NA, Stavrou BM, Sheridan DJ: The effects of diadenosine polyphosphates on the cardiovascular system. Cardiovasc Res. 1999 Apr;42(1):15-26. [10434992 ]
  4. Jankowski J, Tepel M, van der Giet M, Tente IM, Henning L, Junker R, Zidek W, Schluter H: Identification and characterization of P(1), P(7)-Di(adenosine-5')-heptaphosphate from human platelets. J Biol Chem. 1999 Aug 20;274(34):23926-31. [10446159 ]
  5. Luo J, Jankowski J, Tepel M, von Der Giet M, Zidek W, Schluter H: Identification of diadenosine hexaphosphate in human erythrocytes. Hypertension. 1999 Oct;34(4 Pt 2):872-5. [10523376 ]
  6. Conant AR, Fisher MJ, McLennan AG, Simpson AW: Diadenosine polyphosphates are largely ineffective as agonists at natively expressed P2Y(1) and P2Y(2) receptors on cultured human saphenous vein endothelial cells. J Vasc Res. 2000 Nov-Dec;37(6):548-55. [11146409 ]
  7. Hollah P, Hausberg M, Kosch M, Barenbrock M, Letzel M, Schlatter E, Rahn KH: A novel assay for determination of diadenosine polyphosphates in human platelets: studies in normotensive subjects and in patients with essential hypertension. J Hypertens. 2001 Feb;19(2):237-45. [11212966 ]
  8. Patel K, Barnes A, Camacho J, Paterson C, Boughtflower R, Cousens D, Marshall F: Activity of diadenosine polyphosphates at P2Y receptors stably expressed in 1321N1 cells. Eur J Pharmacol. 2001 Nov 2;430(2-3):203-10. [11711032 ]
  9. Steinmetz M, Janssen AK, Pelster F, Rahn KH, Schlatter E: Vasoactivity of diadenosine polyphosphates in human small mesenteric resistance arteries. J Pharmacol Exp Ther. 2002 Aug;302(2):787-94. [12130745 ]
  10. Miras-Portugal MT, Pintor J, Gualix J: Ca2+ signalling in brain synaptosomes activated by dinucleotides. J Membr Biol. 2003 Jul 1;194(1):1-10. [14502438 ]
  11. Luo J, Jankowski V, Gungar N, Neumann J, Schmitz W, Zidek W, Schluter H, Jankowski J: Endogenous diadenosine tetraphosphate, diadenosine pentaphosphate, and diadenosine hexaphosphate in human myocardial tissue. Hypertension. 2004 May;43(5):1055-9. Epub 2004 Apr 5. [15066958 ]
  12. Stavrou BM: Diadenosine polyphosphates: postulated mechanisms mediating the cardiac effects. Curr Med Chem Cardiovasc Hematol Agents. 2003 Jun;1(2):151-69. [15320695 ]
  13. Davies G, MacAllister RJ, Bogle RG, Vallance P: Effect of diadenosine phosphates on human umbilical vessels: novel platelet-derived vasoconstrictors. Br J Clin Pharmacol. 1995 Aug;40(2):170-2. [8562302 ]
  14. Tepel M, Lowe S, Nofer JR, Assmann G, Schluter H, Zidek W: Diadenosine polyphosphates regulate cytosolic calcium in human fibroblast cells by interaction with P2x purinoceptors coupled to phospholipase C. Biochim Biophys Acta. 1996 Jun 13;1312(2):145-50. [8672537 ]
  15. Vahlensieck U, Boknik P, Knapp J, Linck B, Muller FU, Neumann J, Herzig S, Schluter H, Zidek W, Deng MC, Scheld HH, Schmitz W: Negative chronotropic and inotropic effects exerted by diadenosine hexaphosphate (AP6A) via A1-adenosine receptors. Br J Pharmacol. 1996 Nov;119(5):835-44. [8922729 ]
  16. Gasmi L, McLennan AG, Edwards SW: Neutrophil apoptosis is delayed by the diadenosine polyphosphates, Ap5A and Ap6A: synergism with granulocyte-macrophage colony-stimulating factor. Br J Haematol. 1996 Dec;95(4):637-9. [8982038 ]
  17. Ogilvie A, Blasius R, Schulze-Lohoff E, Sterzel RB: Adenine dinucleotides: a novel class of signalling molecules. J Auton Pharmacol. 1996 Dec;16(6):325-8. [9131408 ]
  18. Jankowski J, Schluter H, Tepel M, Spieker C, Zidek W: Effect of diadenosine polyphosphates on Ca2+ ATPase activity. J Mol Med. 1997 Sep;75(9):674-7. [9351706 ]
  19. Stachon A, Stegemann H, Hohage H, Rahn KH, Schlatter E: Effects of diadenosine polyphosphates on the intracellular Ca2+ concentration in endothelial cells. Cell Physiol Biochem. 1998;8(4):175-84. [9694344 ]
  20. Pintor J, Carracedo G, Alonso MC, Bautista A, Peral A: Presence of diadenosine polyphosphates in human tears. Pflugers Arch. 2002 Jan;443(3):432-6. Epub 2001 Aug 23. [11810214 ]
  21. Jankowski J, Jankowski V, Laufer U, van der Giet M, Henning L, Tepel M, Zidek W, Schluter H: Identification and quantification of diadenosine polyphosphate concentrations in human plasma. Arterioscler Thromb Vasc Biol. 2003 Jul 1;23(7):1231-8. Epub 2003 May 8. [12738682 ]
  22. Kisselev LL, Justesen J, Wolfson AD, Frolova LY: Diadenosine oligophosphates (Ap(n)A), a novel class of signalling molecules? FEBS Lett. 1998 May 8;427(2):157-63. [9607303 ]
  23. Pintor J, King BF, Miras-Portugal MT, Burnstock G: Selectivity and activity of adenine dinucleotides at recombinant P2X2 and P2Y1 purinoceptors. Br J Pharmacol. 1996 Nov;119(5):1006-12. [8922753 ]
  24. Baker MD, Holloway DE, Swaminathan GJ, Acharya KR: Crystal structures of eosinophil-derived neurotoxin (EDN) in complex with the inhibitors 5'-ATP, Ap3A, Ap4A, and Ap5A. Biochemistry. 2006 Jan 17;45(2):416-26. [16401072 ]

Enzymes

General function:
Involved in hydrolase activity
Specific function:
Cleaves a beta-phosphate from the diphosphate groups in PP-InsP5 (diphosphoinositol pentakisphosphate), suggesting that it may play a role in signal transduction. Also able to catalyze the hydrolysis of dinucleoside oligophosphates, with Ap6A and Ap5A being the preferred substrates. The major reaction products are ADP and p4a from Ap6A and ADP and ATP from Ap5A. Also able to hydrolyze 5-phosphoribose 1-diphosphate.
Gene Name:
NUDT10
Uniprot ID:
Q8NFP7
Molecular weight:
18499.765
Reactions
Diadenosine hexaphosphate + Water → Adenosine 5'-pentaphosphate + Adenosine monophosphatedetails
General function:
Involved in hydrolase activity
Specific function:
Cleaves a beta-phosphate from the diphosphate groups in PP-InsP5 (diphosphoinositol pentakisphosphate), suggesting that it may play a role in signal transduction. Also able to catalyze the hydrolysis of dinucleoside oligophosphates, with Ap6A and Ap5A being the preferred substrates. The major reaction products are ADP and p4a from Ap6A and ADP and ATP from Ap5A. Also able to hydrolyze 5-phosphoribose 1-diphosphate.
Gene Name:
NUDT11
Uniprot ID:
Q96G61
Molecular weight:
18558.835
Reactions
Diadenosine hexaphosphate + Water → Adenosine 5'-pentaphosphate + Adenosine monophosphatedetails
General function:
Involved in hydrolase activity
Specific function:
Cleaves a beta-phosphate from the diphosphate groups in PP-InsP5 (diphosphoinositol pentakisphosphate) and [PP]2-InsP4 (bisdiphosphoinositol tetrakisphosphate), suggesting that it may play a role in signal transduction. InsP6 (inositol hexakisphophate) is not a substrate. Acts as a negative regulator of the ERK1/2 pathway. Also able to catalyze the hydrolysis of dinucleoside oligophosphates, with Ap6A and Ap5A being the preferred substrates. The major reaction products are ADP and p4a from Ap6A and ADP and ATP from Ap5A. Also able to hydrolyze 5-phosphoribose 1-diphosphate.
Gene Name:
NUDT3
Uniprot ID:
O95989
Molecular weight:
19470.855