Adenosine kinase

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adenosine kinase
PDB 1lio EBI.jpg
Cartoon representation of the molecular structure of protein registered with 1lio code.
Identifiers
EC number 2.7.1.20
CAS number 9027-72-9
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / EGO

Adenosine kinase (AdK; EC 2.7.1.20) is an enzyme that catalyzes the transfer of gamma-phosphate from Adenosine triphosphate (ATP) to adenosine (Ado) leading to formation of Adenosine monophosphate (AMP). In addition to its well-studied role in controlling the cellular concentration of Ado, AdK also plays an important role in the maintenance of methylation reactions.[1][2][3][4][5][6][7] All S-adenosylmethionine-dependent transmethylation reactions in cells lead to production of S-adenosylhomocysteine (SAH), which is cleaved by SAH hydrolase into Ado and homocysteine. The failure to efficiently remove these end products (Ado removed by phosphorylation by AdK) can result in buildup of SAH, which is a potent inhibitor of all transmethylation reactions.[4][8][9] The disruption of AdK gene (-/-) in mice causes neonatal hepatic steatosis, a fatal condition characterized by rapid microvesicular fat infiltration, leading to early postnatal death.[6] The liver was the main organ affected in these animals and in it the levels of adenine nucleotides were decreased, while those of SAH were elevated. Recently, missense mutations in the AdK gene in humans which result in AdK deficiency have also been shown to cause hypermethioninemia, encephalopathy and abnormal liver function.[10]

Biochemical Properties[edit]

AdK is a monomeric protein (~ 38-40 kDa), which works via an ordered Bi-Bi reaction mechanism.[7][11][12][13][14][15] It belongs to the phosphofructokinase B (PfkB) family of sugar kinases. Other members of this family (also known as the RK family) include ribokinase (RK), inosine-guanosine kinase, fructokinase, and 1-phosphofructokinase.[7][16][17] The members of the PfkB/RK family are identified by the presence of three conserved sequence motifs.[7][16][18] The structures of AdK and several other PfK family of proteins have been determined from a number of organisms (see section below)[14][15] as well as that for RK protein from E. coli.[19] Despite low sequence similarity between AdK and other PfkB family of proteins, these proteins are quite similar at structural levels.[7] Compounds that are substrates for AdK include the N-nucleosides toyocamycin, tubercidin and 6-methylmecaptopurine riboside; the C-nucleosides formycin A, 9-azadenosine, and a large number of other C- and N-nucleoside analogs.[20][21][22] The AdK from mammalian sources, in addition to carrying out ATP-dependent phosphorylation of Ado, also catalyzes an Ado-AMP exchange reaction requiring ADP.[11][23][24] This activity is an integral part of AdK[24][25] and it presumably allows a rapid and precise control of Ado concentration in cells.[25][26] The enzymatic activity of AdK from different sources show a marked dependence on phosphate (Pi) and/or pentavalent ions and it is a conserved property of the PfkB family of proteins.[18][27][28] The conserved NXXE motif, which is a distinctive property of the PfkB family of proteins, is involved in Pi (PVI) dependency.[18]

Evolution and Relationship to the PfkB Family of Proteins[edit]

The AdK gene/protein is mainly found in eukaryotic organisms[7] and its primary sequence shows a high degree of conservation (>55% aa similarity). However, AdK sequences exhibit low (~ 20-25%), but significant similarity to other PfkB family of proteins such as RK and phosphofructokinases, which are also found in prokaryotic organisms.[17][29][30] Although a protein exhibiting AdK activity has been reported in Mycobacterium tuberculosis,[31] sequence and biochemical characteristics of this enzyme reveal it to be an atypical enzyme that is more closely related to ribokinase and fructokinase (35%) than to other ADKs (less than 24%).

Characteristics of the AdK Gene and Its Isoforms[edit]

The AdK gene in humans is located on chromosome 10 in the 10q11-10q24 region.[32] In contrast to its coding sequence (about 1 Kb), the AdK gene in mammalian species is unusually large (~546 Kb in humans) and it consists of 11 exons (36 to 173 bp in length) and 10 introns whose lengths vary from 4.2 Kb to 128.6 Kb (average ~50Kb). The ratio of the non-coding to coding sequence for human ADK (>550) is the highest known for any gene. The AdK gene in mammalian organisms is also linked in a head to head manner to the gene for the long isoform of AdK to the gene for μ3A adaptor protein,[33][34] and both these genes are transcribed from a single bi-directional promoter. The large size of the AdK gene and its linkage to the gene for μ3A adaptor protein are apparently unique characteristic of the amniotes (e.g. various mammals, birds, and reptiles). In contrast, the AdK genes in other eukaryotic organisms are much smaller in lengths (1.3 – 20 Kb long). In mammals, two isoforms of Adk are present.[17][35][36] These two isoforms show no difference in their biological activity and they differ only at the N-terminus where the long isoform (AdK-long) contains extra 21 amino acids that replace the first 4 amino acids of the short isoform (AdK-short).[17][35][36] These two isoforms are independently regulated at the transcriptional level and the promoter for the short isoform is located within the first large AdK intron.[37] It was recently shown that of the two AdK isoforms, the AdK-long isoform is localized in the nucleus, whereas AdK-short is found in the cytoplasm.[38]

Cardioprotective and Neuroprotective Roles of AdK[edit]

AdK plays a central role in controlling the cellular levels of Ado, which via its interaction with adenosine receptors in mammalian tissues produces a broad range of physiological responses including potent cardioprotective and neuroprotective activities.[39][40][41] The overexpression of AdK in the brain, which leads to decreased Ado levels and loss of inhibition of neuronal excitability in astrocytes, has been proposed as the main underlying cause of progression of epilepsy.[42][43] Hence, the modulation of AdK by external means provides an important strategy for harnessing its potential therapeutic benefits. As such, there is much interest in developing specific inhibitors of AdK.[44][45] Many AdK inhibitors, some of which show useful analgesic, anti-seizure, and anti-inflammatory properties in animal models have been described.[44][46][47]

Studies with Mutant Mammalian Cells[edit]

In cultured mammalian cells, mainly Chinese hamster ovary (CHO) cells, many kinds of mutants that are affected in AdK and show interesting differences in their genetic and biochemical properties have been isolated;[48][49][50][51] One kind of mutant that is obtained at unusually high spontaneous mutant frequency (10−3-10−4) contain large deletions within the AdK gene that leads to the loss of several introns and exons.[33][34] Many mutants that are affected in the expression of either the expressions of the two AdK isoforms have also been isolated.[41]

Structural studies[edit]

As of late 2007, 16 structures have been solved for this class of enzymes, with PDB accession codes 1BX4​, 1DGM​, 1LII​, 1LIJ​, 1LIK​, 1LIO​, 2A9Y​, 2A9Z​, 2AA0​, 2AB8​, 2ABS​, 2GL0​, 2PKF​, 2PKK​, 2PKM​, and 2PKN​.

References[edit]

  1. ^ Lindberg B, Klenow H, Hansen K: Some properties of partially purified mammalian adenosine kinase. J. Biol. Chem 1967, 242: 350–356.
  2. ^ Caputto R: The enzymatic synthesis of adenylic acid; adenosinekinase. J. Biol. Chem 1951, 189: 801–814.
  3. ^ Kornberg A, Pricer WE: Enzymatic phosphorylation of adenosine and 2,6-diaminopurine riboside. J. Biol. Chem 1951, 193: 481–495.
  4. ^ a b Fox IH, Kelley WN: The role of adenosine and 2'-deoxyadenosine in mammalian cells. Annu Rev Biochem 1978, 47: 655-686.
  5. ^ Kredich NM, Martin DV, Jr.: Role of S-adenosylhomocysteine in adenosinemediated toxicity in cultured mouse T lymphoma cells. Cell 1977, 12: 931-938.
  6. ^ a b Boison D, Scheurer L, Zumsteg V, Rulicke T, Litynski P, Fowler B, Brandner S, Mohler H: Neonatal hepatic steatosis by disruption of the adenosine kinase gene. Proc Natl Acad Sci U S A 2002, 99: 6985-6990.
  7. ^ a b c d e f Park J, Gupta RS: Adenosine kinase and ribokinase--the RK family of proteins. Cell Mol Life Sci 2008, 65: 2875-2896.
  8. ^ Lawrence de Koning AB, Werstuck GH, Zhou J, Austin RC: Hyperhomocysteinemia and its role in the development of atherosclerosis. Clin Biochem 2003, 36: 431-441.
  9. ^ Kredich NM, Hershfield MS: S-adenosylhomocysteine toxicity in normal and adenosine kinase-deficient lymphoblasts of human origin. Proc Natl Acad Sci U S A 1979, 76: 2450-2454.
  10. ^ Bjursell MK, Blom HJ, Cayuela JA, Engvall ML, Lesko N, Balasubramaniam S, Brandberg G, Halldin M, Falkenberg M, Jakobs C, Smith D, Struys E, von Dobeln U, Gustafsson CM, Lundeberg J, Wedell A: Adenosine kinase deficiency disrupts the methionine cycle and causes hypermethioninemia, encephalopathy, and abnormal liver function. Am J Hum Genet 2011, 89: 507-515.
  11. ^ a b Mimouni M, Bontemps F, Van den BG: Kinetic studies of rat liver adenosine kinase. Explanation of exchange reaction between adenosine and AMP. J Biol Chem 1994, 269: 17820-17825.
  12. ^ Henderson JF, Mikoshiba A, Chu SY, Caldwell IC: Kinetic studies of adenosine kinase from Ehrlich ascites tumor cells. J Biol Chem 1972, 247: 1972-1975.
  13. ^ Hawkins CF, Bagnara AS: Adenosine kinase from human erythrocytes: kinetic studies and characterization of adenosine binding sites. Biochemistry 1987, 26: 1982-1987.
  14. ^ a b Schumacher MA, Scott DM, Mathews II, Ealick SE, Roos DS, Ullman B, Brennan RG: Crystal structures of Toxoplasma gondii adenosine kinase reveal a novel catalytic mechanism and prodrug binding. J Mol Biol 2000, 298: 875-893.
  15. ^ a b Mathews II, Erion MD, Ealick SE: Structure of human adenosine kinase at 1.5 A resolution. Biochemistry 1998, 37: 15607-15620.
  16. ^ a b Bork P, Sander C, Valencia A: Convergent evolution of similar enzymatic function on different protein folds: the hexokinase, ribokinase, and galactokinase families of sugar kinases. Protein Sci 1993, 2: 31-40.
  17. ^ a b c d Spychala J, Datta NS, Takabayashi K, Datta M, Fox IH, Gribbin T, Mitchell BS: Cloning of human adenosine kinase cDNA: sequence similarity to microbial ribokinases and fructokinases. Proc Natl Acad Sci U S A 1996, 93: 1232-1237.
  18. ^ a b c Maj MC, Singh B, Gupta RS: Pentavalent ions dependency is a conserved property of adenosine kinase from diverse sources: identification of a novel motif implicated in phosphate and magnesium ion binding and substrate inhibition. Biochemistry 2002, 41: 4059-4069.
  19. ^ Sigrell JA, Cameron AD, Jones TA, Mowbray SL: Structure of Escherichia coli ribokinase in complex with ribose and dinucleotide determined to 1.8 A resolution: insights into a new family of kinase structures. Structure 1998, 6: 183-193.
  20. ^ Miller RL, Adamczyk DL, Miller WH, Koszalka GW, Rideout JL, Beacham LM, III, Chao EY, Haggerty JJ, Krenitsky TA, Elion GB: Adenosine kinase from rabbit liver. II. Substrate and inhibitor specificity. J Biol Chem 1979, 254: 2346-2352.
  21. ^ Cass CE, Selner M, Phillips JR: Resistance to 9-beta-D-arabinofuranosyladenine in cultured leukemia L 1210 cells. Cancer Res 1983, 43: 4791-4798.
  22. ^ Gupta RS: Purine nucleoside analogs. In Drug Resistance in Mammalian Cells.Vol.1. Edited by Gupta RS. CRC Press, Florida; 1989:89-110.
  23. ^ Bontemps F, Mimouni M, Van den BG: Phosphorylation of adenosine in anoxic hepatocytes by an exchange reaction catalysed by adenosine kinase. Biochem J 1993, 290 ( Pt 3): 679-684.
  24. ^ a b Gupta RS: Adenosine-AMP exchange activity is an integral part of the mammalian adenosine kinase. Biochem Mol Biol Int 1996, 39: 493-502.
  25. ^ a b Arch JR, Newsholme EA: Activities and some properties of 5'-nucleotidase, adenosine kinase and adenosine deaminase in tissues from vertebrates and invertebrates in relation to the control of the concentration and the physiological role of adenosine. Biochem J 1978, 174: 965-977.
  26. ^ Mimouni M, Bontemps F, Van den BG: Production of adenosine and nucleoside analogs by the exchange reaction catalyzed by rat liver adenosine kinase. Biochem Pharmacol 1995, 50: 1587-1591.
  27. ^ Hao W, Gupta RS: Pentavalent ions dependency of mammalian adenosine kinase. Biochem Mol Biol Int 1996, 38: 889-899.
  28. ^ Maj M, Singh B, Gupta RS: The influence of inorganic phosphate on the activity of adenosine kinase. Biochim Biophys Acta 2000, 1476: 33-42.
  29. ^ Singh B, Hao W, Wu Z, Eigl B, Gupta RS: Cloning and characterization of cDNA for adenosine kinase from mammalian (Chinese hamster, mouse, human and rat) species. High frequency mutants of Chinese hamster ovary cells involve structural alterations in the gene. Eur J Biochem 1996, 241: 564-571.
  30. ^ Park J, van Koeverden P, Singh B, Gupta RS: Identification and characterization of human ribokinase and comparison of its properties with E. coli ribokinase and human adenosine kinase. FEBS Lett 2007, 581: 3211-3216.
  31. ^ Long MC, Escuyer V, Parker WB: Identification and characterization of a unique adenosine kinase from Mycobacterium tuberculosis. J Bacteriol 2003, 185: 6548-6555.
  32. ^ Francke R, Thompson L: Regional mapping, by exclusion, of adenosine kinase (ADK) on human chromosome 10 using the gene dosage approach (Abstract). Cytogenet Cell Genet 1979, 25: 156.
  33. ^ a b Singh B, Lin A, Wu ZC, Gupta RS: Gene structure for adenosine kinase in Chinese hamster and human: high-frequency mutants of CHO cells involve deletions of several introns and exons. DNA Cell Biol 2001, 20: 53-65.
  34. ^ a b Singh B, Gupta RS: Genomic organization and linkage via a bidirectional promoter of the AP-3 (adaptor protein-3) mu3A and AdK (adenosine kinase) genes: deletion mutants of AdK in Chinese hamster cells extend into the AP-3 mu3A gene. Biochem J 2004, 378: 519-528.
  35. ^ a b Sahin B, Kansy JW, Nairn AC, Spychala J, Ealick SE, Fienberg AA, Greene RW, Bibb JA: Molecular characterization of recombinant mouse adenosine kinase and evaluation as a target for protein phosphorylation. Eur J Biochem 2004, 271: 3547-3555.
  36. ^ a b Maj MC, Singh B, Gupta RS: Structure-activity studies on mammalian adenosine kinase. Biochem Biophys Res Commun 2000, 275: 386-393.
  37. ^ Cui XA, Agarwal T, Singh B, Gupta RS: Molecular characterization of Chinese hamster cells mutants affected in adenosine kinase and showing novel genetic and biochemical characteristics. BMC Biochem 2011, 12: 22.
  38. ^ Cui XA, Singh B, Park J, Gupta RS: Subcellular localization of adenosine kinase in mammalian cells: The long isoform of AdK is localized in the nucleus. Biochem Biophys Res Commun 2009, 388: 46-50.
  39. ^ Berne RM: Adenosine--a cardioprotective and therapeutic agent. Cardiovasc Res 1993, 27: 2.
  40. ^ Newby AC: The role of adenosine kinase in regulating adenosine concentration. Biochem J 1985, 226: 343-344.
  41. ^ a b Boison D: Adenosine as a neuromodulator in neurological diseases. Curr Opin Pharmacol 2008, 8: 2-7.
  42. ^ Boison D: The adenosine kinase hypothesis of epileptogenesis. Prog Neurobiol 2008, 84: 249-262.
  43. ^ Li T, Ren G, Lusardi T, Wilz A, Lan JQ, Iwasato T, Itohara S, Simon RP, Boison D: Adenosine kinase is a target for the prediction and prevention of epileptogenesis in mice. J Clin Invest 2008, 118: 571-582.
  44. ^ a b McGaraughty S, Chu KL, Wismer CT, Mikusa J, Zhu CZ, Cowart M, Kowaluk EA, Jarvis MF: Effects of A-134974, a novel adenosine kinase inhibitor, on carrageenan-induced inflammatory hyperalgesia and locomotor activity in rats: evaluation of the sites of action. J Pharmacol Exp Ther 2001, 296: 501-509.
  45. ^ Kowaluk EA, Jarvis MF: Therapeutic potential of adenosine kinase inhibitors. Expert Opin Investig Drugs 2000, 9: 551-564.
  46. ^ Zheng GZ, Lee C, Pratt JK, Perner RJ, Jiang MQ, Gomtsyan A, Matulenko MA, Mao Y, Koenig JR, Kim KH, Muchmore S, Yu H, Kohlhaas K, Alexander KM, McGaraughty S, Chu KL, Wismer CT, Mikusa J, Jarvis MF, Marsh K, Kowaluk EA, Bhagwat SS, Stewart AO: Pyridopyrimidine analogues as novel adenosine kinase inhibitors. Bioorg Med Chem Lett 2001, 11: 2071-2074.
  47. ^ Lee CH, Jiang M, Cowart M, Gfesser G, Perner R, Kim KH, Gu YG, Williams M, Jarvis MF, Kowaluk EA, Stewart AO, Bhagwat SS: Discovery of 4-amino-5-(3-bromophenyl)-7-(6-morpholino-pyridin-3-yl)pyrido[2,3-d]pyrimi dine, an orally active, non-nucleoside adenosine kinase inhibitor. J Med Chem 2001, 44: 2133-2138.
  48. ^ Gupta RS, Siminovitch L: Genetic and biochemical studies with the adenosine analogs toyocamycin and tubercidin: mutation at the adenosine kinase locus in Chinese hamster cells. Somatic Cell Genet 1978, 4: 715-735.
  49. ^ Mehta KD, Gupta RS: Formycin B-resistant mutants of Chinese hamster ovary cells: novel genetic and biochemical phenotype affecting adenosine kinase. Mol Cell Biol 1983, 3: 1468-1477.
  50. ^ Gupta RS, Mehta KD: Genetic and biochemical studies on mutants of CHO cells resistant to 7-deazapurine nucleosides: differences in the mechanisms of action of toyocamycin and tubercidin. Biochem Biophys Res Commun 1984, 120: 88-95.
  51. ^ Gupta RS, Mehta KD: Genetic and biochemical characteristics of three different types of mutants of mammalian cells affected in adenosine kinase. Adv Exp Med Biol 1986, 195 Pt B: 595-603.

See also[edit]