Preferences help
enabled [disable] Abstract
Number of results
2006 | 53 | 2 | 269-278
Article title

Adenosine as a metabolic regulator of tissue function: production of adenosine by cytoplasmic 5'-nucleotidases

Title variants
Languages of publication
Adenosine is a product of complete dephosphorylation of adenine nucleotides which takes place in various compartments of the cell. This nucleoside is a significant signal molecule engaged in regulation of physiology and modulation of the function of numerous cell types (i.e. neurons, platelets, neutrophils, mast cells and smooth muscle cells in bronchi and vasculature, myocytes etc.). As part a of purinergic signaling system, adenosine mediates neurotransmission, conduction, secretion, vasodilation, proliferation and cell death. Most of the effects of adenosine help to protect cells and tissues during stress conditions such as ischemia or anoxia. Adenosine receptors and nucleoside transporters are targets for potential drugs in many pathophysiological situations. The adenosine-producing system in vertebrates involves a cascade dephosphorylating ATP and ending with 5'-nucleotidase (EC localized either on the membrane or inside the cell. In this paper the cytoplasmic variants of 5'-nucleotidase are broadly characterized as well as their clinical relevance. The role of AMP-selective 5'-nucleotidase (cN-I) in the heart, skeletal muscle and brain is highlighted. cN-I action is crucial during ischemia and important for the efficacy of some nucleoside-based drugs and in the regulation of the substrate pool for nucleic acids synthesis. Inhibitors used in studying the roles of cytoplasmic and membrane-bound 5'-nucleotidases are also described.
Physical description
  • Department of Molecular Enzymology, Intercollegiate Faculty of Biotechnology UG-MUG, Medical University of Gdańsk, Gdańsk, Poland
  • Department of Molecular Enzymology, Intercollegiate Faculty of Biotechnology UG-MUG, Medical University of Gdańsk, Gdańsk, Poland
  • Department of Molecular Enzymology, Intercollegiate Faculty of Biotechnology UG-MUG, Medical University of Gdańsk, Gdańsk, Poland
  • Department of Molecular Enzymology, Intercollegiate Faculty of Biotechnology UG-MUG, Medical University of Gdańsk, Gdańsk, Poland
  • Allegrini S, Scaloni A, Ferrara L, Pesi R, Pinna P, Sgarrella F, Camici M, Eriksson S, Tozzi MG (2001) Bovine cytosolic 5'-nucleotidase acts through the formation of an aspartate 52-phosphoenzyme intermediate. J Biol Chem 276: 33526-33532.
  • Amici A, Magni G (2002) Human erythrocyte pyrimidine 5'-nucleotidase, PN-I. Arch Biochem Biophys 397: 184-190.
  • Amici A, Emanuelly M, Raffaelly N, Ruggieri S, Saccucci F, Magni G (2000) Human erythrocyte pyrimidine 5'-nucleotidase, PN-I, is identical to p36, a protein associated to lupus inclusion formation in response to α-interferon. Blood 96: 1596-1598.
  • Ballard HJ (1991) The influence of lactic acid on adenosine release from skeletal muscle in anaesthetized dogs. J Physiol 433: 95-108.
  • Bellardinelli L, Linden J, Berne RM (1989) The cardiac effects of adenosine. Prog Cardiovasc Dis 32: 73-97.
  • Berne RM, Knabb RM, Ely SW, Rubio R (1983) Adenosine in the local regulation of blood flow: a brief overview. Fed Proc 42: 3136-3142.
  • Bianchi V, Spychala J (2003) Mammalian 5'-nucleotidase. J Biol Chem 278: 46195-46198.
  • Bianchi V, Pontis E, Reichard P (1986) Interrelations between substrate cycles and de novo synthesis of pyrimidine deoxyribonucleoside triphosphates in 3T6 cells. Proc Natl Acad Sci USA 83: 986-990.
  • Bolling SF, Childs KF, Ning XH (1992) Amino acid substrate preloading and postischemic myocardial recovery. J Surg Res 53: 342-348.
  • Bryan PT, Marshall JM (1999a) Adenosine receptor subtypes and vasodilatation in rat skeletal muscle during systemic hypoxia: a role of A1receptors. J Physiol 514: 151-162.
  • Bryan PT, Marshall JM (1999b) Cellular mechanism by which adenosine induces vasodilatation in rat skeletal muscle: significance for systemic hypoxia. J Physiol 514: 163-175.
  • Cheng B, Essackjee HC, Ballard HJ (2000) Evidence of control of adenosine metabolism in rat oxidative skeletal muscle by changes in pH. J Physiol 522: 467-477.
  • Cronstein BN (1994) Adenosine, an endogenous anti-inflammatory agent. J Appl Physiol 76: 5-13.
  • Cross HR, Murphy E, Black RG, Auchampach J, Steenbergen C (2002) Overexpression of A3adenosine receptors decreases heart rate, preserves energetics and protects ischemic hearts. Am J Physiol 283: H1562-H1568.
  • Darvish A, Metting P (1993) Purification and regulation of AMP-specific cytosolic 5'-nucleotidase from dog heart. Am J Physiol 264: H1528-H1534.
  • Darvish A, Pomerantz RW, Zografides PG, Metting PJ (1996) Contribution of cytosolic and membrane-bound 5'-nucleotidase to cardiac adenosine production. Am J Physiol 271: H2162-H2167.
  • Deussen A, Mose G, Schrader J (1986) Contribution of coronary endothelial cells to cardiac adenosine production. Pflugers Arch 406: 608-614.
  • Dobson JG, Rubio R, Berne RM (1971) Role of adenine nucleotides, adenosine and inorganic phosphate in the regulation skeletal muscle blood flow. Circ Res 29: 375-384.
  • Downey JM, Forman MB (1993) Spotlight on the cardioprotective properties of adenosine. Cardiovasc Res 27: 2-140.
  • Drury AN, Szent-Györgyi A (1929) The physiological activity of adenine compounds with especial reference to their action upon the mammalian heart. J Physiol 68: 213-237.
  • Dunwiddie TV, Haas HL (1985) Adenosine increases synaptic facilitation in the in vitro rat hippocampus: evidence for a presynaptic site of action. J Physiol 369: 365-377.
  • Ely SW, Berne RM (1992) Protective effects of adenosine in myocardial ischemia. Circulation 85: 893-904.
  • Fredholm BB (2003) Adenosine receptors as targets for drug development. Drug News Perspect 16: 283-289.
  • Fredholm BB, Arslan G, Halldner L, Schulte G, Wasserman W (2000) Structure and function of adenosine receptors and their genes. Naunyn Schmiedebergs Arch Pharmacol 362: 364-374.
  • Fredholm BB, Ijzerman AP, Jacobson KA, Klotz KN, Linden J (2001) International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol Rev 53: 527-552.
  • Galmarini CM, Graham K, Thomas X, Calvo F, Rousselot P, El Jafaari A, Cros E., Mackey JR, Dumontet C (2001). Expression of high Km-nucleotidase in leukemic blasts is an independent prognostic factor in adults with acute myeloid leukemia. Blood 98: 1922-1926.
  • Garvey EP, Prus KL (1999) A specific inhibitor of heart cytosolic 5'-nucleotidase I attenuates hydrolysis of adenosine 5'-monophosphate in primary rat myocytes. Arch Biochem Biophys 364: 235-240.
  • Garvey EP, Lowen GT, Almond MR (1998) Nucleotide and nucleoside analogues as inhibitors of cytosolic 5'-nucleotidase I. Biochemistry 37: 9043-9051.
  • Gazziola C, Ferraro P, Moras M, Reichard P, Bianchi V (2001) Cytosolic high Km5'-nucleotidase and 5'(3')-deoxyribonucleotidase in substrate cycles involved in nucleotide metabolism. J Biol Chem 276: 6185-6190.
  • Han D-H, Hansen PA, Nolte LA, Holloszy JO (1998) Removal of adenosine decreases the responsiveness of muscle glucose transport to insulin and contraction. Diabetes 47: 1671-1675.
  • Hellsten Y (1999) The effect of muscle contraction on the regulation of adenosine formation in rat skeletal muscle cells. J Physiol 518: 761-768.
  • Hellsten Y, Frandsen U (1997) Adenosine formation in contracting primary skeletal muscle cells and endothelial cells in culture. J Physiol 504: 695-704.
  • Hunsucker SA, Spychala J, Mitchell BS (2001) Human cytosolic 5'-nucleotidase: characterization and role in nucleoside analog resistance. J Biol Chem 276: 10498-10504.
  • Hunsucker SA, Mitchell BS, Spychala J (2005) The 5'-nucleotidases as regulators of nucleotide and drug metabolism. Pharmacol Ther 107: 1-30.
  • Imai S, Nakazawa M, eds (1991) Role of Adenosine and Adenine Nucleotides in the Biological System. Metabolism, Release, Transport, Receptors, Transduction Mechanism and Biological Actions, p 726, Elsevier, Amsterdam.
  • Itoh R (1993) IMP-GMP 5'-nucleotidase. Comp Biochem Physiol B 105: 13-19.
  • Jacobson KA, Hoffmann C, Cattabeni F, Abbracchio MP (1999) Adenosine-induced cell death: evidence for receptor-mediated signaling. Apoptosis 4: 197-211.
  • Kitakaze M, Hori M, Minamino T, Takashima S, Komamura K, Node K, Kurihara T, Morioka T, Sato H, Inoue M, Kamada T (1994) Evidence for deactivation of both ectosolic and cytosolic 5'-nucleotidase by adenosine A1receptor activation in the rat cardiomyocytes. J Clin Invest 94: 2451-2456.
  • Klabunde RE (1983) Dipyridamole inhibition of adenosine metabolism in human blood. Eur J Pharmacol 93: 21-26.
  • Lu Y, LI Y, Herin GA, Aizenman E, Epstein PM, Rosenberg PA (2004) Elevation of intracellular cAMP evokes activity-dependent release of adenosine in cultured rat forebrain neurons. Eur J Neurosci 19: 2669-2681.
  • Meghji P, Skladanowski AC, Newby AC, Slakey LL, Pearson JD (1993) Effect of 5‘-deoxy-5‘-isobutylthioadenosine on formation and release of adenosine from neonatal and adult rat ventricular myocytes. Biochem J 291: 833-839.
  • Newby AC (1984) Adenosine and the concept of “retaliatory metabolites”. Trends Biochem Sci 9: 42-44.
  • Newby AC (1988) The pigeon heart 5'-nucleotidase responsible for ischemia-induced adenosine formation. Biochem J 253: 123-130.
  • Obata T (2002) Adenosine production and its interaction with protection of ischemic and reperfusion injury of myocardium. Life Sci 71: 2083-2103.
  • Oka J, Matsumoto A, Hosokawa Y, Inoue S (1994) Molecular cloning of human cytosolic purine 5'-nucleotidase. Biochem Biophys Res Commun 205: 917-922.
  • Page T, Yu A, Fontanesi J, Nyhan WL (1997) Developmental disorder associated with increased cellular nucleotidase activity. Proc Natl Acad Sci USA 94: 11601-11606.
  • Paterson AR, Babb LR, Paran JH, Cass CE (1977) Inhibition by nitrobenzylthioinosine of adenosine uptake by asynchronous HeLa cells. Mol Pharmacol 13: 1147-1158.
  • Pesi R, Turriani M, Allegrini S, Scolozzi C, Camici M, Ipata PL, Tozzi MG (1994) The bifunctional cytosolic 5'-nucleotidase: regulation of the phosphotransferase and nucleotidase activities. Arch Biochem Biophys 312: 75-80.
  • Pesi R, Micheli V, Jacomelli G, Peruzzi L, Camici M, Garcia-Gil M, Allegrini S, Tozzi MG (2000) Cytosolic 5'-nucleotidase hyperactivity in erythrocytes of Lesch-Nyhan syndrome patients. Neuroreport 11: 1827-1831.
  • Podgorska M, Kocbuch K, Pawełczyk T (2005) Recent advances in studies on biochemical and structural properties of equilibrative and concentrative nucleoside transporters. Acta Biochim Polon 52: 749-758.
  • Radegran A, Hellsten Y (2000) Adenosine and nitric oxide in exercise-induced human skeletal muscle vasodilatation. Acta Physiol Scand 168: 575-579.
  • Rees DC, Duley JA, Marinaki AM (2003) Pyrimidine 5' nucleotidase deficiency. Br J Haematol 120: 375-383.
  • Relavic V, Burnstock G (1998) Receptors for purines and pyrimidines. Pharmacol Rev 50: 413-480.
  • Rinaldo-Matthis A, Rampazzo C, Reichard P, Bianchi V, Nordlund P (2002) Crystal structure of a human mitochondrial deoxyribonucleotidase. Nat Struct Biol 9: 779-787.
  • Rubio R, Berne RM, Dobson JG Jr (1973) Sites of adenosine production in cardiac and skeletal muscle. Am J Physiol 225: 938-953.
  • Sala-Newby GB, Newby AC (2001) Cloning of a mouse cytosolic 5'-nucleotidase-I identifies a new gene related to human autoimmune infertility-related protein. Biochem Biophys Acta 1521: 12-18.
  • Sala-Newby GB, Skladanowski AC, Newby AC (1999) The mechanism of adenosine formation in cells. Cloning of cytosolic 5'-nucleotidase I. J Biol Chem 274: 17789-17793.
  • Sala-Newby GB, Freeman NV, Skladanowski AC, Newby AC (2000) Distinct roles for recombinant cytosolic 5'-nucleotidase-I and -II in AMP and IMP catabolism in COS-7 and H9c2 rat myoblast cell lines. J Biol Chem 275: 11666-11671.
  • Sawynok J, Sweeney MJ (1989) The role of purines in nociception. Neuroscience 32: 557-569.
  • Shryock JC, Belardinelli LB (1997) Adenosine and adenosine receptors in the cardiovascular system: biochemistry, physiology and pharmacology. Am J Cardiol 79: 2-10.
  • Silinsky EM (1975) On the association between transmitter secretion and the release of adenine nucleotides from mammalian motor nerve terminals. J Physiol 247: 145-162.
  • Skladanowski AC, Newby AC (1990) Partial purification and properties of an AMP-specific soluble 5'-nucleotidase from pigeon heart. Biochem J 268: 117-122.
  • Skladanowski AC, Smolenski RT, Tavernier M, De Jong JW, Yacoub MH, Seymour AM (1996) Soluble forms of 5'-nucleotidase in rat and human heart. Am J Physiol 270: H1493-H1500.
  • Skladanowski AC, Newby AC, Makarewicz W (1998) Purification and some molecular properties of pigeon heart AMP-selective 5'-nucleotidase. Adv Exp Med Biol 431: 113-117.
  • Spychala J (2000) Tumor-promoting functions of adenosine. Pharmacol Ther 87: 161-173.
  • Spychala J, Mitchell BS, Barankiewicz J (1997) Adenosine metabolism during phorbol myristate acetate-mediated induction of HL-60 cell differentiation: changes in expression pattern of adenosine kinase, adenosine deaminase and 5'-nucleotidase. J Immunol 158: 4947-4952.
  • Thorn JA, Jarvis SM (1996) Adenosine transporters. Gen Pharmacol 27: 613-620.
  • Tkacz-Stachowska K, Lechward K, Skladanowski AC (2005) Isolation and characterization of pigeon breast muscle cytosolic 5'-nucleotidase-I (cN-I). Acta Biochim Polon 52: 789-796.
  • Truong VL, Collinson AR, Lowenstein JM (1988) 5'-Nucleotidases in rat heart. Evidence for occurrence of two soluble enzymes with different substrate specificities. Biochem J 253: 117-121.
  • Ullman B, Kaur K (1983) Biochemical effects of dipyridamole on purine overproduction and excretion by mutant murine T-lymphoblasts. J Biol Chem 258: 9620-9622.
  • Yaar R, Jones MR, Chen JF, Ravid K (2005) Animal models for the study of adenosine receptor function. J Cell Physiol 202: 9-20.
  • Yamazaki Y, Truong VL, Lowenstein JM (1991) 5'-Nucleotidase I from rabbit heart. Biochemistry 30: 1503-1509.
  • Zhang Y, Lautt WW (1991) Dilazep increases plasma adenosine levels during adenosine infusion in the anesthetized cat. Proc West Pharmacol Soc 34: 167-169.
  • Zimmermann H (1994) Signaling via ATP in the nervous system. Trends Neurosci 17: 420-426.
  • Zimmermann H, Braun N (1996) Extracellular metabolism of nucleotides in the nervous system. J Auton Pharmacol 16: 397-400.
Document Type
Publication order reference
YADDA identifier
JavaScript is turned off in your web browser. Turn it on to take full advantage of this site, then refresh the page.