Biology:Adenosine kinase

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Short description: Enzyme
adenosine kinase
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Adenosine kinase dimer, Mycobacterium tuberculosis
Identifiers
EC number2.7.1.20
CAS number9027-72-9
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO

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

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

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%).

Gene and isoforms

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]

Cardio- and neuro-protective roles

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 by 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

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][34][49][50] 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]

References

  1. ↑ "Some properties of partially purified mammalian adenosine kinase". The Journal of Biological Chemistry 242 (3): 350–6. February 1967. doi:10.1016/S0021-9258(18)96277-0. PMID 4290214. 
  2. ↑ "The enzymatic synthesis of adenylic acid; adenosinekinase". The Journal of Biological Chemistry 189 (2): 801–14. April 1951. doi:10.1016/S0021-9258(18)44897-1. PMID 14832298. 
  3. ↑ "Enzymatic phosphorylation of adenosine and 2,6-diaminopurine riboside". The Journal of Biological Chemistry 193 (2): 481–95. December 1951. doi:10.1016/S0021-9258(18)50904-2. PMID 14907737. 
  4. ↑ 4.0 4.1 "The role of adenosine and 2'-deoxyadenosine in mammalian cells". Annual Review of Biochemistry 47: 655–86. 1978. doi:10.1146/annurev.bi.47.070178.003255. PMID 209731. 
  5. ↑ "Role of S-adenosylhomocysteine in adenosinemediated toxicity in cultured mouse T lymphoma cells". Cell 12 (4): 931–8. December 1977. doi:10.1016/0092-8674(77)90157-X. PMID 597863. 
  6. ↑ 6.0 6.1 "Neonatal hepatic steatosis by disruption of the adenosine kinase gene". Proceedings of the National Academy of Sciences of the United States of America 99 (10): 6985–90. May 2002. doi:10.1073/pnas.092642899. PMID 11997462. Bibcode: 2002PNAS...99.6985B. 
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 "Adenosine kinase and ribokinase--the RK family of proteins". Cellular and Molecular Life Sciences 65 (18): 2875–96. September 2008. doi:10.1007/s00018-008-8123-1. PMID 18560757. 
  8. ↑ Lawrence De Koning, A. B.; Werstuck, G. H.; Zhou, J.; Austin, R. C. (2003). "Hyperhomocysteinemia and its role in the development of atherosclerosis". Clinical Biochemistry 36 (6): 431–41. doi:10.1016/S0009-9120(03)00062-6. PMID 12951169. 
  9. ↑ "S-adenosylhomocysteine toxicity in normal and adenosine kinase-deficient lymphoblasts of human origin". Proceedings of the National Academy of Sciences of the United States of America 76 (5): 2450–4. May 1979. doi:10.1073/pnas.76.5.2450. PMID 221926. Bibcode: 1979PNAS...76.2450K. 
  10. ↑ "Adenosine kinase deficiency disrupts the methionine cycle and causes hypermethioninemia, encephalopathy, and abnormal liver function". American Journal of Human Genetics 89 (4): 507–15. October 2011. doi:10.1016/j.ajhg.2011.09.004. PMID 21963049. 
  11. ↑ 11.0 11.1 "Kinetic studies of rat liver adenosine kinase. Explanation of exchange reaction between adenosine and AMP". The Journal of Biological Chemistry 269 (27): 17820–5. July 1994. doi:10.1016/S0021-9258(17)32382-7. PMID 8027035. 
  12. ↑ "Kinetic studies of adenosine kinase from Ehrlich ascites tumor cells". The Journal of Biological Chemistry 247 (7): 1972–5. April 1972. doi:10.1016/S0021-9258(19)45478-1. PMID 5062817. 
  13. ↑ "Adenosine kinase from human erythrocytes: kinetic studies and characterization of adenosine binding sites". Biochemistry 26 (7): 1982–7. April 1987. doi:10.1021/bi00381a030. PMID 3036217. 
  14. ↑ 14.0 14.1 "Crystal structures of Toxoplasma gondii adenosine kinase reveal a novel catalytic mechanism and prodrug binding". Journal of Molecular Biology 298 (5): 875–93. May 2000. doi:10.1006/jmbi.2000.3753. PMID 10801355. 
  15. ↑ 15.0 15.1 "Structure of human adenosine kinase at 1.5 A resolution". Biochemistry 37 (45): 15607–20. November 1998. doi:10.1021/bi9815445. PMID 9843365. 
  16. ↑ 16.0 16.1 "Convergent evolution of similar enzymatic function on different protein folds: the hexokinase, ribokinase, and galactokinase families of sugar kinases". Protein Science 2 (1): 31–40. January 1993. doi:10.1002/pro.5560020104. PMID 8382990. 
  17. ↑ 17.0 17.1 17.2 17.3 "Cloning of human adenosine kinase cDNA: sequence similarity to microbial ribokinases and fructokinases". Proceedings of the National Academy of Sciences of the United States of America 93 (3): 1232–7. February 1996. doi:10.1073/pnas.93.3.1232. PMID 8577746. Bibcode: 1996PNAS...93.1232S. 
  18. ↑ 18.0 18.1 18.2 "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 41 (12): 4059–69. March 2002. doi:10.1021/bi0119161. PMID 11900549. 
  19. ↑ "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 6 (2): 183–93. February 1998. doi:10.1016/S0969-2126(98)00020-3. PMID 9519409. 
  20. ↑ "Adenosine kinase from rabbit liver. II. Substrate and inhibitor specificity". The Journal of Biological Chemistry 254 (7): 2346–52. April 1979. doi:10.1016/S0021-9258(17)30227-2. PMID 218934. 
  21. ↑ "Resistance to 9-beta-D-arabinofuranosyladenine in cultured leukemia L 1210 cells". Cancer Research 43 (10): 4791–8. October 1983. PMID 6603904. 
  22. ↑ "Purine nucleoside analogs". Drug Resistance in Mammalian Cells. 1. Florida: CRC Press. 1989. pp. 89–110. 
  23. ↑ "Phosphorylation of adenosine in anoxic hepatocytes by an exchange reaction catalysed by adenosine kinase". The Biochemical Journal 290 ( Pt 3) (3): 679–84. March 1993. doi:10.1042/bj2900679. PMID 8457194. 
  24. ↑ 24.0 24.1 "Adenosine-AMP exchange activity is an integral part of the mammalian adenosine kinase". Biochemistry and Molecular Biology International 39 (3): 493–502. June 1996. doi:10.1080/15216549600201541. PMID 8828800. 
  25. ↑ 25.0 25.1 "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". The Biochemical Journal 174 (3): 965–77. September 1978. doi:10.1042/bj1740965. PMID 215126. 
  26. ↑ "Production of adenosine and nucleoside analogs by the exchange reaction catalyzed by rat liver adenosine kinase". Biochemical Pharmacology 50 (10): 1587–91. November 1995. doi:10.1016/0006-2952(95)02033-0. PMID 7503760. 
  27. ↑ "Pentavalent ions dependency of mammalian adenosine kinase". Biochemistry and Molecular Biology International 38 (5): 889–99. April 1996. PMID 9132158. 
  28. ↑ "The influence of inorganic phosphate on the activity of adenosine kinase". Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology 1476 (1): 33–42. January 2000. doi:10.1016/S0167-4838(99)00220-4. PMID 10606765. 
  29. ↑ "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". European Journal of Biochemistry 241 (2): 564–71. October 1996. doi:10.1111/j.1432-1033.1995.tb20220.x_1. PMID 8917457. 
  30. ↑ "Identification and characterization of human ribokinase and comparison of its properties with E. coli ribokinase and human adenosine kinase". FEBS Letters 581 (17): 3211–6. July 2007. doi:10.1016/j.febslet.2007.06.009. PMID 17585908. 
  31. ↑ "Identification and characterization of a unique adenosine kinase from Mycobacterium tuberculosis". Journal of Bacteriology 185 (22): 6548–55. November 2003. doi:10.1128/JB.185.22.6548-6555.2003. PMID 14594827. 
  32. ↑ "Regional mapping, by exclusion, of adenosine kinase (ADK) on human chromosome 10 using the gene dosage approach". Cytogenet Cell Genet 25: 156. 1979. 
  33. ↑ 33.0 33.1 "Gene structure for adenosine kinase in Chinese hamster and human: high-frequency mutants of CHO cells involve deletions of several introns and exons". DNA and Cell Biology 20 (1): 53–65. January 2001. doi:10.1089/10445490150504693. PMID 11242543. 
  34. ↑ 34.0 34.1 34.2 "Genomic organization and linkage via a bidirectional promoter of the AP-3 (adaptor protein-3) mu3A and AK (adenosine kinase) genes: deletion mutants of AK in Chinese hamster cells extend into the AP-3 mu3A gene". The Biochemical Journal 378 (Pt 2): 519–28. March 2004. doi:10.1042/BJ20031219. PMID 14575525. 
  35. ↑ 35.0 35.1 \"Molecular characterization of recombinant mouse adenosine kinase and evaluation as a target for protein phosphorylation". European Journal of Biochemistry 271 (17): 3547–55. September 2004. doi:10.1111/j.1432-1033.2004.04291.x. PMID 15317590. 
  36. ↑ 36.0 36.1 "Structure-activity studies on mammalian adenosine kinase". Biochemical and Biophysical Research Communications 275 (2): 386–93. August 2000. doi:10.1006/bbrc.2000.3307. PMID 10964675. 
  37. ↑ "Molecular characterization of Chinese hamster cells mutants affected in adenosine kinase and showing novel genetic and biochemical characteristics". BMC Biochemistry 12: 22. May 2011. doi:10.1186/1471-2091-12-22. PMID 21586167. 
  38. ↑ "Subcellular localization of adenosine kinase in mammalian cells: The long isoform of AdK is localized in the nucleus". Biochemical and Biophysical Research Communications 388 (1): 46–50. October 2009. doi:10.1016/j.bbrc.2009.07.106. PMID 19635462. 
  39. ↑ "Adenosine--a cardioprotective and therapeutic agent". Cardiovascular Research 27 (1): 2. January 1993. doi:10.1093/cvr/27.1.2. PMID 8458026. 
  40. ↑ "The role of adenosine kinase in regulating adenosine concentration". The Biochemical Journal 226 (1): 343–4. February 1985. doi:10.1042/bj2260343. PMID 2983685. 
  41. ↑ 41.0 41.1 "Adenosine as a neuromodulator in neurological diseases". Current Opinion in Pharmacology 8 (1): 2–7. February 2008. doi:10.1016/j.coph.2007.09.002. PMID 17942368. 
  42. ↑ "The adenosine kinase hypothesis of epileptogenesis". Progress in Neurobiology 84 (3): 249–62. March 2008. doi:10.1016/j.pneurobio.2007.12.002. PMID 18249058. 
  43. ↑ "Adenosine kinase is a target for the prediction and prevention of epileptogenesis in mice". The Journal of Clinical Investigation 118 (2): 571–82. February 2008. doi:10.1172/JCI33737. PMID 18172552. 
  44. ↑ 44.0 44.1 "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". The Journal of Pharmacology and Experimental Therapeutics 296 (2): 501–9. February 2001. PMID 11160637. 
  45. ↑ "Therapeutic potential of adenosine kinase inhibitors". Expert Opinion on Investigational Drugs 9 (3): 551–64. March 2000. doi:10.1517/13543784.9.3.551. PMID 11060695. 
  46. ↑ "Pyridopyrimidine analogues as novel adenosine kinase inhibitors.". Bioorg Med Chem Lett 11 (16): 2071–2074. 2001. doi:10.1016/S0960-894X(01)00375-4. PMID 11514141. 
  47. ↑ "Discovery of 4-amino-5-(3-bromophenyl)-7-(6-morpholino-pyridin-3-yl)pyrido[2,3-d]pyrimidine, an orally active, non-nucleoside adenosine kinase inhibitor". Journal of Medicinal Chemistry 44 (13): 2133–8. June 2001. doi:10.1021/jm000314x. PMID 11405650. 
  48. ↑ "Genetic and biochemical studies with the adenosine analogs toyocamycin and tubercidin: mutation at the adenosine kinase locus in Chinese hamster cells". Somatic Cell Genetics 4 (6): 715–35. November 1978. doi:10.1007/BF01543160. PMID 217113. 
  49. ↑ "Genetic and biochemical studies on mutants of CHO cells resistant to 7-deazapurine nucleosides: differences in the mechanisms of action of toyocamycin and tubercidin". Biochemical and Biophysical Research Communications 120 (1): 88–95. April 1984. doi:10.1016/0006-291X(84)91417-7. PMID 6712702. 
  50. ↑ "Genetic and Biochemical Characteristics of Three Different Types of Mutants of Mammalian Cells Affected in Adenosine Kinase". Purine and Pyrimidine Metabolism in Man V. Advances in Experimental Medicine and Biology. 195 Pt B. 1986. pp. 595–603. doi:10.1007/978-1-4684-1248-2_93. ISBN 978-1-4684-1250-5. 

See also



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