Abstract

Adenylate kinase (AK, EC 2.7.4.3) is a ubiquitous phosphotransferase which catalyzes the reversible transfer of high-energy β – and γ-phosphate groups between nucleotides. All classified AKs show a similar structure: they contain a large central CORE region, nucleoside monophosphate and triphosphate binding domains (NMPbd and NTPbd) and the LID domain. Analysis of amino acid sequence similarity revealed the presence of as many as nine human AK isoenzymes, which demonstrate different organ-tissue and intercellular localization. Among these kinases, only two, AK1 and AK2, fulfill the structural and functional criterion by the highest affinity for adenine nucleotides and the utilization of only AMP or dAMP as phosphate acceptors. Human AK isoenzymes are involved in nucleotide homeostasis and monitor disturbances of cell energy charge. Participating in large regulatory protein complexes, AK supplies high energy substrates for controlling the functions of channels and transporters as well as ligands for extracellular P2 nucleotide receptors. In pathological conditions AK can take over the function of other kinases, such as creatine kinase in oxygen-depleted myocardium. Directed mutagenesis and genetic studies of diseases (such as aleukocytosis, hemolytic anemia, primary ciliary dyskinesia (PCD)) link the presence and activity of AK with etiology of these disturbances. Moreover, AK participates in regulation of differentiation and maturation of cells as well as in apoptosis and oncogenesis. Involvement of AK in a wide range of processes and the correlation between AK and etiology of diseases support the medical potential for the use of adenylate kinases in the diagnosis and treatment of certain diseases. This paper summarizes the current knowledge on the structure, properties and functions of human adenylate kinase.

References

• 1. Abrusci P., Chiarelli L.R., Galizzi A., Fermo E., Bianchi P., ZanellaA., Valentini G.: Erythrocyte adenylate kinase deficiency: characterizationof recombinant mutant forms and relationship with nonspherocytichemolytic anemia. Exp. Hematol., 2007; 35: 1182-1189 2 Amiri M., Conserva F., Panayiotou C., Karlsson A., Solaroli N.: Thehuman adenylate kinase 9 is a nucleoside mono – and diphosphatekinase. Int. J. Biochem. Cell Biol., 2013; 45: 925-931
  Google Scholar
• 2. are N-acetylated. Biochim. Biophys. Acta, 1996; 1280: 251-256
  Google Scholar
• 3. Arora K., Brooks C.L. 3rd: Large-scale allosteric conformationaltransitions of adenylate kinase appear to involve a population-shiftmechanism. Proc. Natl. Acad. Sci. USA, 2007; 104: 18496-18501
  Google Scholar
• 4. Baranowska M., Kozłowska H., Korbut A., Malinowska B.: Kanałypotasowe w naczyniach krwionośnych: ich znaczenie w fizjologiii patologii. Postępy Hig. Med. Dośw., 2007; 61: 596-605
  Google Scholar
• 5. Beckstein O., Denning E.J., Perilla J.R., Woolf T.B.: Zipping and unzippingof adenylate kinase: atomistic insights into the ensemble ofopen<–>closed transitions. J. Mol. Biol., 2009; 394: 160-176
  Google Scholar
• 6. Bennett K., James C., Hussain K.: Pancreatic β-cell KATP channels:Hypoglycaemia and hyperglycaemia. Rev. Endocr. Metab. Disord.,2010; 11: 157-163
  Google Scholar
• 7. Bianchi P., Zappa M., Bredi E., Vercellati C., Pelissero G., BarracoF., Zanella A.: A case of complete adenylate kinase deficiency dueto a nonsense mutation in AK-1 gene (Arg 107 – -> Stop, CGA – ->TGA) associated with chronic haemolytic anaemia. Br. J. Haematol.,1999; 105: 75-79
  Google Scholar
• 8. Burnstock G.: Introduction and perspective, historical note. Front.Cell. Neurosci., 2013; 7: 227
  Google Scholar
• 9. Carrasco A.J., Dzeja P.P., Alekseev A.E., Pucar D., Zingman L.V.,Abraham M.R., Hodgson D., Bienengraeber M., Puceat M., JanssenE., Wieringa B., Terzic A.: Adenylate kinase phosphotransfer communicatescellular energetic signals to ATP-sensitive potassiumchannels. Proc. Natl. Acad. Sci. USA, 2001; 98: 7623-7628
  Google Scholar
• 10. Clark R., Proks P.: ATP-sensitive potassium channels in healthand disease. Adv. Exp. Med. Biol., 2010; 654: 165-192
  Google Scholar
• 11. Collavin L., Lazarevic D., Utrera R., Marzinotto S., Monte M.,Schneider C.: wt p53 dependent expression of a membrane-associatedisoform of adenylate kinase. Oncogene, 1999; 18: 5879-5888
  Google Scholar
• 12. Dahnke T., Tsai M.D.: Mechanism of adenylate kinase. The conservedaspartates 140 and 141 are important for transition statestabilization instead of substrate-induced conformational changes.J. Biol. Chem., 1994; 269: 8075-8081
  Google Scholar
• 13. Daily M.D., Phillips G.N. Jr., Cui Q.: Many local motions cooperateto produce the adenylate kinase conformational transition. J.Mol. Biol., 2010; 400: 618-631
  Google Scholar
• 14. Donaldson S.H., Picher M., Boucher R.C.: Secreted and cell-associatedadenylate kinase and nucleoside diphosphokinase contributeto extracellular nucleotide metabolism on human airway surfaces.Am. J. Respir. Cell Mol. Biol., 2002; 26: 209-215
  Google Scholar
• 15. Dzeja P.P., Bortolon R., Perez-Terzic C., Holmuhamedov E.L., TerzicA.: Energetic communication between mitochondria and nucleusdirected by catalyzed phosphotransfer. Proc. Natl. Acad. Sci. USA,2002; 99: 10156-10161
  Google Scholar
• 16. Dzeja P.P., Chung S., Faustino R.S., Behfar A., Terzic A.: Developmentalenhancement of adenylate kinase-AMPK metabolic signalingaxis supports stem cell cardiac differentiation. PLoS One,2011; 6: e19300
  Google Scholar
• 17. Dzeja P.P., Hoyer K., Tian R., Zhang S., Nemutlu E., Spindler M.,Ingwall J.S.: Rearrangement of energetic and substrate utilizationnetworks compensate for chronic myocardial creatine kinase deficiency.J. Physiol., 2011; 589: 5193-5211
  Google Scholar
• 18. Dzeja P., Terzic A.: Adenylate kinase and AMP signaling networks:metabolic monitoring, signal communication and body energysensing. Int. J. Mol. Sci., 2009; 10: 1729-1772
  Google Scholar
• 19. Dzeja P.P., Vitkevicius K.T., Redfield M.M., Burnett J.C., TerzicA.: Adenylate kinase-catalyzed phosphotransfer in the myocardium:increased contribution in heart failure. Circ. Res., 1999; 84: 1137-1143
  Google Scholar
• 20. Fabre A.C., Vantourout P., Champagne E., Tercé F., Rolland C.,Perret B., Collet X., Barbaras R., Martinez L.O.: Cell surface adenylatekinase activity regulates the F(1)-ATPase/P2Y(13)-mediated HDLendocytosis pathway on human hepatocytes. Cell. Mol. Life Sci.,2006; 63: 2829-2837
  Google Scholar
• 21. Fermo E., Bianchi P., Vercellati C., Micheli S., Marcello A.P., PortaleoneD., Zanella A.: A new variant of adenylate kinase (delG138) associatedwith severe hemolytic anemia. Blood Cells Mol. Dis., 2004; 33: 146-149
  Google Scholar
• 22. Fernandez-Gonzalez A., Kourembanas S., Wyatt T.A., MitsialisS.A.: Mutation of murine adenylate kinase 7 underlies a primaryciliary dyskinesia phenotype. Am. J. Respir. Cell Mol. Biol.; 2009;40: 305-315
  Google Scholar
• 23. Fratelli M., Demol H., Puype M., Casagrande S., Villa P., Eberini I.,Vandekerckhove J., Gianazza E., Ghezzi P.: Identification of proteinsundergoing glutathionylation in oxidatively stressed hepatocytesand hepatoma cells. Proteomics, 2003; 3: 1154-1161
  Google Scholar
• 24. Fukami-Kobayashi K., Nosaka M., Nakazawa A., Go M.: Ancientdivergence of long and short isoforms of adenylate kinase: molecularevolution of the nucleoside monophosphate kinase family. FEBSLett., 1996; 385: 214-220
  Google Scholar
• 25. Gur M., Madura J.D., Bahar I.: Global transitions of proteins exploredby a multiscale hybrid methodology: application to adenylatekinase. Biophys. J., 2013; 105: 1643-1652
  Google Scholar
• 26. Hardie D.G.: AMP-activated protein kinase: an energy sensor thatregulates all aspects of cell function. Genes Dev., 2011; 25: 1895-1908
  Google Scholar
• 27. Jacquet S., Malaval C., Martinez L.O., Sak K., Rolland C., PerezC., Nauze M., Champagne E., Tercé F., Gachet C., Perret B., Collet X.,Boeynaems J.M., Barbaras R.: The nucleotide receptor P2Y13 is a keyregulator of hepatic high-density lipoprotein (HDL) endocytosis. CellMol. Life Sci., 2005; 62: 2508-2515
  Google Scholar
• 28. Janssen E., Dzeja P.P., Oerlemans F., Simonetti A.W., Heerschap A.,de Haan A., Rush P.S., Terjung R.R., Wieringa B., Terzic A.: Adenylatekinase 1 gene deletion disrupts muscle energetic economy despitemetabolic rearrangement. EMBO J., 2000; 19: 6371-6381
  Google Scholar
• 29. Janssen E., de Groof A., Wijers M., Fransen J., Dzeja P.P., TerzicA., Wieringa B..: Adenylate kinase 1 deficiency induces molecularand structural adaptations to support muscle energy metabolism.J. Biol. Chem., 2003; 278: 12937-12945
  Google Scholar
• 30. Janssen E., Kuiper J., Hodgson D., Zingman L.V., Alekseev A.E.,Terzic A., Wieringa B.: Two structurally distinct and spatially compartmentalizedadenylate kinases are expressed from the AK1 genein mouse brain. Mol. Cell. Biochem., 2004; 256-257: 59-72
  Google Scholar
• 31. Kenyon C.P., Roth R.L.: The role of the C8 proton of ATP in thecatalysis of shikimate kinase and adenylate kinase. BMC Biochem.,2012; 13: 15
  Google Scholar
• 32. Kim H., Lee H.J., Oh Y., Choi S.G., Hong S.H., Kim H.J., Lee S.Y.,Choi J.W., Su Hwang D., Kim K.S., Kim H.J., Zhang J., Youn H.J., NohD.Y., Jung Y.K.: The DUSP26 phosphatase activator adenylate kinase 2 regulates FADD phosphorylation and cell growth. Nat. Commun.,2014; 5: 3351
  Google Scholar
• 33. Kishi F., Tanizawa Y., Nakazawa A.: Isolation and characterizationof two types of cDNA for mitochondrial adenylate kinase and theirexpression in Escherichia coli. J. Biol. Chem., 1987; 262: 11785-11789
  Google Scholar
• 34. Klier H., Magdolen V., Schricker R., Strobel G., Lottspeich F., BandlowW.: Cytoplasmic and mitochondrial forms of yeast adenylate kinase
  Google Scholar
• 35. Lachant N.A., Zerez C.R., Barredo J., Lee D.W., Savely S.M., TanakaK.R.: Hereditary erythrocyte adenylate kinase deficiency: a defect ofmultiple phosphotransferases? Blood, 1991; 77: 2774-2784
  Google Scholar
• 36. Lagresle-Peyrou C., Six E.M., Picard C., Rieux-Laucat F., MichelV., Ditadi A., Demerens-de Chappedelaine C., Morillon E., ValensiF., Simon-Stoos K.L., Mullikin J.C., Noroski L.M., Besse C., WulffraatN.M., Ferster A. i wsp.: Human adenylate kinase 2 deficiency causesa profound hematopoietic defect associated with sensorineural deafness.Nat. Genet., 2009; 41: 106-111
  Google Scholar
• 37. Lazarowski E.R., Boucher R.C.: Purinergic receptors in airwayepithelia. Curr. Opin. Pharmacol., 2009; 9: 262-267
  Google Scholar
• 38. Lee H.J., Pyo J.O., Oh Y., Kim H.J., Hong S.H., Jeon Y.J., Kim H., ChoD.H., Woo H.N., Song S., Nam J.H., Kim H.J., Kim K.S., Jung Y.K.: AK2activates a novel apoptotic pathway through formation of a complexwith FADD and caspase-10. Nat. Cell. Biol., 2007; 9: 1303-1310
  Google Scholar
• 39. Liu R., Ström A.L., Zhai J., Gal J., Bao S., Gong W., Zhu H.: Enzymaticallyinactive adenylate kinase 4 interacts with mitochondrialADP/ATP translocase. Int. J. Biochem. Cell Biol., 2009; 41: 1371-1380
  Google Scholar
• 40. Liu R., Xu H., Wei Z., Wang Y., Lin Y., Gong W.: Crystal structureof human adenylate kinase 4 (L171P) suggests the role of hinge regionin protein domain motion. Biochem. Biophys. Res. Commun.,2009; 379: 92-97
  Google Scholar
• 41. Marcus A.J., Broekman M.J., Drosopoulos J.H., Olson K.E., IslamN., Pinsky D.J., Levi R.: Role of CD39 (NTPDase-1) in thromboregulation,cerebroprotection, andcardioprotection. Semin. Thromb.Hemost., 2005; 31: 234-346
  Google Scholar
• 42. Matsunaga Y., Fujisaki H., Terada T., Furuta T., Moritsugu K., KideraA.: Minimum free energy path of ligand-induced transition inadenylate kinase. PLoS Comput. Biol., 2012; 8: e1002555
  Google Scholar
• 43. Miki T., Nagashima K., Seino S.: The structure and function ofthe ATP-sensitive K+ channel in insulin-secreting pancreatic beta–cells. J. Mol. Endocrinol., 1999; 22: 113-123
  Google Scholar
• 44. Miwa S., Fujii H., Tani K., Takahashi K., Takizawa T., IgarashiT.: Red cell adenylate kinase deficiency associated with hereditarynonspherocytic hemolytic anemia: clinical and biochemical studies.Am. J. Hematol., 1983; 14: 325-333
  Google Scholar
• 45. Miyoshi K., Akazawa Y., Horiguchi T., Noma T.: Localization ofadenylate kinase 4 in mouse tissues. Acta Histochem. Cytochem.,2009; 42: 55-64
  Google Scholar
• 46. Müller C.W., Schlauderer G.J., Reinstein J., Schulz G.E.: Adenylatekinase motions during catalysis: an energetic counterweight balancingsubstrate binding. Structure, 1996; 4: 147-156
  Google Scholar
• 47. Noma T.: Dynamics of nucleotide metabolism as a supporter oflife phenomena. J. Med. Invest., 2005; 52: 127-136
  Google Scholar
• 48. Noma T., Fujisawa K., Yamashiro Y., Shinohara M., Nakazawa A.,Gondo T., Ishihara T., Yoshinobu K.: Structure and expression of humanmitochondrial adenylate kinase targeted to the mitochondrialmatrix. Biochem. J., 2001; 358: 225-232
  Google Scholar
• 49. Panayiotou C., Solaroli N., Karlsson A.: The many isoforms ofhuman adenylate kinases. Int. J. Biochem. Cell Biol., 2014; 49: 75-83
  Google Scholar
• 50. Panayiotou C., Solaroli N., Xu Y., Johansson M., Karlsson A.:The characterization of human adenylate kinases 7 and 8 demonstratesdifferences in kinetic parameters and structural organizationamong the family of adenylate kinase isoenzymes. Biochem.J., 2011; 433: 527-534
  Google Scholar
• 51. Pannicke U., Hönig M., Hess I., Friesen C., Holzmann K., RumpE.M., Barth T.F., Rojewski M.T., Schulz A., Boehm T., Friedrich W., Schwarz K.: Reticular dysgenesis (aleukocytosis) is caused by mutationsin the gene encoding mitochondrial adenylate kinase 2. Nat.Genet., 2009; 41: 101-105
  Google Scholar
• 52. Picher M., Boucher R.C.: Human airway ecto-adenylate kinase.A mechanism to propagate ATP signaling on airway surfaces. J. Biol.Chem., 2003; 278: 11256-11264
  Google Scholar
• 53. Ping J., Hao P., Li Y.X., Wang J.F.: Molecular dynamics studies onthe conformational transitions of adenylate kinase: a computationalevidence for the conformational selection mechanism. Biomed. Res.Int., 2013; 2013: 628536
  Google Scholar
• 54. Pucar D., Janssen E., Dzeja P.P., Juranic N., Macura S., WieringaB., Terzic A.: Compromised energetics in the adenylate kinase AK1gene knockout heart under metabolic stress. J. Biol. Chem., 2000;275: 41424-41429
  Google Scholar
• 55. Quillen E.E., Haslam G.C., Samra H.S., Amani-Taleshi D., KnightJ.A., Wyatt D.E., Bishop S.C., Colvert K.K., Richter M.L., Kitos P.A.:Ectoadenylate kinase and plasma membrane ATP synthase activitiesof human vascular endothelial cells. J. Biol. Chem., 2006; 281:20728-20737
  Google Scholar
• 56. Ren H., Wang L., Bennett M., Liang Y., Zheng X., Lu F., Li L., NanJ., Luo M., Eriksson S., Zhang C., Su X.D.: The crystal structure of humanadenylate kinase 6: An adenylate kinase localized to the cellnucleus. Proc. Natl. Acad. Sci USA, 2005; 102: 303-308
  Google Scholar
• 57. Robson S.C., Sévigny J., Zimmermann H.: The E-NTPDase familyof ectonucleotidases: Structure function relationships and pathophysiologicalsignificance. Purinergic Signal., 2006; 2: 409-430
  Google Scholar
• 58. Ruan Q., Chen Y., Gratton E., Glaser M., Mantulin W.W.: Cellularcharacterization of adenylate kinase and its isoform: two-photonexcitation fluorescence imaging and fluorescence correlation spectroscopy.Biophys. J., 2002; 83: 3177-3187
  Google Scholar
• 59. Stanojevic V., Habener J.F., Holz G.G., Leech C.A.: Cytosolic adenylatekinases regulate K-ATP channel activity in human beta-cells.Biochem. Biophys. Res. Commun., 2008; 368: 614-619
  Google Scholar
• 60. Studzińska B., Seroka A., Łępicka M., Roszek K., Komoszyński M.:The increase of adenylate kinase activity in the blood can controlaggregation of platelets in coronary or peripheral arterial ischemia.Health, 2010; 2: 246-252
  Google Scholar
• 61. Tanimura A., Horiguchi T., Miyoshi K., Hagita H., Noma T.: Differentialexpression of adenine nucleotide converting enzymes in mitochondrialintermembrane space: a potential role of adenylate kinaseisozyme 2 in neutrophil differentiation. PLoS One, 2014; 9: e89916
  Google Scholar
• 62. van Rompay A.R., Johansson M., Karlsson A.: Identification ofa novel human adenylate kinase. cDNA cloning, expression analysis,chromosome localization and characterization of the recombinantprotein. Eur. J. Biochem., 1999; 261: 509-517
  Google Scholar
• 63. Walker E.J., Dow J.W.: Location and properties of two isoenzymesof cardiac adenylate kinase. Biochem. J., 1982; 203: 361-369
  Google Scholar
• 64. Yan H.G., Tsai M.D.: Mechanism of adenylate kinase. Demonstrationof a functional relationship between aspartate 93 and Mg2+ bysite-directed mutagenesis and proton, phosphorus-31, and magnesium-25NMR. Biochemistry, 1991; 30: 5539-5546
  Google Scholar
• 65. Yegutkin G.G.: Nucleotide – and nucleoside-converting ectoenzymes:Important modulators of purinergic signalling cascade.Biochim. Biophys. Acta, 2008; 1783: 673-694
  Google Scholar

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