adenosine kinase
Adenosine kinase dimer, Mycobacterium tuberculosis
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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. ↑ Lindberg B, Klenow H, Hansen K (February 1967). "Some properties of partially purified mammalian adenosine kinase". The Journal of Biological Chemistry. 242 (3): 350–6. doi:10.1016/S0021-9258(18)96277-0. PMID 4290214.
  2. ↑ Caputto R (April 1951). "The enzymatic synthesis of adenylic acid; adenosinekinase". The Journal of Biological Chemistry. 189 (2): 801–14. doi:10.1016/S0021-9258(18)44897-1. PMID 14832298.
  3. ↑ Kornberg A, Pricer WE (December 1951). "Enzymatic phosphorylation of adenosine and 2,6-diaminopurine riboside". The Journal of Biological Chemistry. 193 (2): 481–95. doi:10.1016/S0021-9258(18)50904-2. PMID 14907737.
  4. 1 2 Fox IH, Kelley WN (1978). "The role of adenosine and 2'-deoxyadenosine in mammalian cells". Annual Review of Biochemistry. 47: 655–86. doi:10.1146/annurev.bi.47.070178.003255. PMID 209731.
  5. ↑ Kredich NM, Martin DV (December 1977). "Role of S-adenosylhomocysteine in adenosinemediated toxicity in cultured mouse T lymphoma cells". Cell. 12 (4): 931–8. doi:10.1016/0092-8674(77)90157-X. PMID 597863. S2CID 33818372.
  6. 1 2 Boison D, Scheurer L, Zumsteg V, Rülicke T, Litynski P, Fowler B, Brandner S, Mohler H (May 2002). "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. Bibcode:2002PNAS...99.6985B. doi:10.1073/pnas.092642899. PMC 124515. PMID 11997462.
  7. 1 2 3 4 5 6 Park J, Gupta RS (September 2008). "Adenosine kinase and ribokinase--the RK family of proteins". Cellular and Molecular Life Sciences. 65 (18): 2875–96. doi:10.1007/s00018-008-8123-1. PMID 18560757. S2CID 11439854.
  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. ↑ Kredich NM, Hershfield MS (May 1979). "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. Bibcode:1979PNAS...76.2450K. doi:10.1073/pnas.76.5.2450. PMC 383620. PMID 221926.
  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 Döbeln U, Gustafsson CM, Lundeberg J, Wedell A (October 2011). "Adenosine kinase deficiency disrupts the methionine cycle and causes hypermethioninemia, encephalopathy, and abnormal liver function". American Journal of Human Genetics. 89 (4): 507–15. doi:10.1016/j.ajhg.2011.09.004. PMC 3188832. PMID 21963049.
  11. 1 2 Mimouni M, Bontemps F, Van den Berghe G (July 1994). "Kinetic studies of rat liver adenosine kinase. Explanation of exchange reaction between adenosine and AMP". The Journal of Biological Chemistry. 269 (27): 17820–5. doi:10.1016/S0021-9258(17)32382-7. PMID 8027035.
  12. ↑ Henderson JF, Mikoshiba A, Chu SY, Caldwell IC (April 1972). "Kinetic studies of adenosine kinase from Ehrlich ascites tumor cells". The Journal of Biological Chemistry. 247 (7): 1972–5. doi:10.1016/S0021-9258(19)45478-1. PMID 5062817.
  13. ↑ Hawkins CF, Bagnara AS (April 1987). "Adenosine kinase from human erythrocytes: kinetic studies and characterization of adenosine binding sites". Biochemistry. 26 (7): 1982–7. doi:10.1021/bi00381a030. PMID 3036217.
  14. 1 2 Schumacher MA, Scott DM, Mathews II, Ealick SE, Roos DS, Ullman B, Brennan RG (May 2000). "Crystal structures of Toxoplasma gondii adenosine kinase reveal a novel catalytic mechanism and prodrug binding". Journal of Molecular Biology. 298 (5): 875–93. doi:10.1006/jmbi.2000.3753. PMID 10801355.
  15. 1 2 Mathews II, Erion MD, Ealick SE (November 1998). "Structure of human adenosine kinase at 1.5 A resolution". Biochemistry. 37 (45): 15607–20. CiteSeerX 10.1.1.499.8430. doi:10.1021/bi9815445. PMID 9843365.
  16. 1 2 Bork P, Sander C, Valencia A (January 1993). "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. doi:10.1002/pro.5560020104. PMC 2142297. PMID 8382990.
  17. 1 2 3 4 Spychala J, Datta NS, Takabayashi K, Datta M, Fox IH, Gribbin T, Mitchell BS (February 1996). "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. Bibcode:1996PNAS...93.1232S. doi:10.1073/pnas.93.3.1232. PMC 40062. PMID 8577746.
  18. 1 2 3 Maj MC, Singh B, Gupta RS (March 2002). "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. doi:10.1021/bi0119161. PMID 11900549.
  19. ↑ Sigrell JA, Cameron AD, Jones TA, Mowbray SL (February 1998). "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. doi:10.1016/S0969-2126(98)00020-3. PMID 9519409.
  20. ↑ Miller RL, Adamczyk DL, Miller WH, Koszalka GW, Rideout JL, Beacham LM, Chao EY, Haggerty JJ, Krenitsky TA, Elion GB (April 1979). "Adenosine kinase from rabbit liver. II. Substrate and inhibitor specificity". The Journal of Biological Chemistry. 254 (7): 2346–52. doi:10.1016/S0021-9258(17)30227-2. PMID 218934.
  21. ↑ Cass CE, Selner M, Phillips JR (October 1983). "Resistance to 9-beta-D-arabinofuranosyladenine in cultured leukemia L 1210 cells". Cancer Research. 43 (10): 4791–8. PMID 6603904.
  22. ↑ Gupta RS (1989). "Purine nucleoside analogs". In Gupta RS (ed.). Drug Resistance in Mammalian Cells. Vol. 1. Florida: CRC Press. pp. 89–110.
  23. ↑ Bontemps F, Mimouni M, Van den Berghe G (March 1993). "Phosphorylation of adenosine in anoxic hepatocytes by an exchange reaction catalysed by adenosine kinase". The Biochemical Journal. 290 ( Pt 3) (3): 679–84. doi:10.1042/bj2900679. PMC 1132334. PMID 8457194.
  24. 1 2 Gupta RS (June 1996). "Adenosine-AMP exchange activity is an integral part of the mammalian adenosine kinase". Biochemistry and Molecular Biology International. 39 (3): 493–502. doi:10.1080/15216549600201541. PMID 8828800. S2CID 25638668.
  25. 1 2 Arch JR, Newsholme EA (September 1978). "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. doi:10.1042/bj1740965. PMC 1186002. PMID 215126.
  26. ↑ Mimouni M, Bontemps F, Van den Berghe G (November 1995). "Production of adenosine and nucleoside analogs by the exchange reaction catalyzed by rat liver adenosine kinase". Biochemical Pharmacology. 50 (10): 1587–91. doi:10.1016/0006-2952(95)02033-0. PMID 7503760.
  27. ↑ Hao W, Gupta RS (April 1996). "Pentavalent ions dependency of mammalian adenosine kinase". Biochemistry and Molecular Biology International. 38 (5): 889–99. PMID 9132158.
  28. ↑ Maj M, Singh B, Gupta RS (January 2000). "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. doi:10.1016/S0167-4838(99)00220-4. PMID 10606765.
  29. ↑ Singh B, Hao W, Wu Z, Eigl B, Gupta RS (October 1996). "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. doi:10.1111/j.1432-1033.1995.tb20220.x_1. PMID 8917457.
  30. ↑ Park J, van Koeverden P, Singh B, Gupta RS (July 2007). "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. doi:10.1016/j.febslet.2007.06.009. PMID 17585908. S2CID 23400440.
  31. ↑ Long MC, Escuyer V, Parker WB (November 2003). "Identification and characterization of a unique adenosine kinase from Mycobacterium tuberculosis". Journal of Bacteriology. 185 (22): 6548–55. doi:10.1128/JB.185.22.6548-6555.2003. PMC 262096. PMID 14594827.
  32. ↑ Francke R, Thompson L (1979). "Regional mapping, by exclusion, of adenosine kinase (ADK) on human chromosome 10 using the gene dosage approach". Cytogenet Cell Genet. 25: 156.
  33. 1 2 Singh B, Lin A, Wu ZC, Gupta RS (January 2001). "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. doi:10.1089/10445490150504693. PMID 11242543.
  34. 1 2 3 Singh B, Gupta RS (March 2004). "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. doi:10.1042/BJ20031219. PMC 1223951. PMID 14575525.
  35. 1 2 \Sahin B, Kansy JW, Nairn AC, Spychala J, Ealick SE, Fienberg AA, Greene RW, Bibb JA (September 2004). "Molecular characterization of recombinant mouse adenosine kinase and evaluation as a target for protein phosphorylation". European Journal of Biochemistry. 271 (17): 3547–55. doi:10.1111/j.1432-1033.2004.04291.x. PMID 15317590.
  36. 1 2 Maj MC, Singh B, Gupta RS (August 2000). "Structure-activity studies on mammalian adenosine kinase". Biochemical and Biophysical Research Communications. 275 (2): 386–93. doi:10.1006/bbrc.2000.3307. PMID 10964675.
  37. ↑ Cui XA, Agarwal T, Singh B, Gupta RS (May 2011). "Molecular characterization of Chinese hamster cells mutants affected in adenosine kinase and showing novel genetic and biochemical characteristics". BMC Biochemistry. 12: 22. doi:10.1186/1471-2091-12-22. PMC 3118340. PMID 21586167.
  38. ↑ Cui XA, Singh B, Park J, Gupta RS (October 2009). "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. doi:10.1016/j.bbrc.2009.07.106. PMID 19635462.
  39. ↑ Berne RM (January 1993). "Adenosine--a cardioprotective and therapeutic agent". Cardiovascular Research. 27 (1): 2. doi:10.1093/cvr/27.1.2. PMID 8458026.
  40. ↑ Newby AC (February 1985). "The role of adenosine kinase in regulating adenosine concentration". The Biochemical Journal. 226 (1): 343–4. doi:10.1042/bj2260343. PMC 1144713. PMID 2983685.
  41. 1 2 Boison D (February 2008). "Adenosine as a neuromodulator in neurological diseases". Current Opinion in Pharmacology. 8 (1): 2–7. doi:10.1016/j.coph.2007.09.002. PMC 2950121. PMID 17942368.
  42. ↑ Boison D (March 2008). "The adenosine kinase hypothesis of epileptogenesis". Progress in Neurobiology. 84 (3): 249–62. doi:10.1016/j.pneurobio.2007.12.002. PMC 2278041. PMID 18249058.
  43. ↑ Li T, Ren G, Lusardi T, Wilz A, Lan JQ, Iwasato T, Itohara S, Simon RP, Boison D (February 2008). "Adenosine kinase is a target for the prediction and prevention of epileptogenesis in mice". The Journal of Clinical Investigation. 118 (2): 571–82. doi:10.1172/JCI33737. PMC 2157568. PMID 18172552.
  44. 1 2 McGaraughty S, Chu KL, Wismer CT, Mikusa J, Zhu CZ, Cowart M, Kowaluk EA, Jarvis MF (February 2001). "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. PMID 11160637.
  45. ↑ Kowaluk EA, Jarvis MF (March 2000). "Therapeutic potential of adenosine kinase inhibitors". Expert Opinion on Investigational Drugs. 9 (3): 551–64. doi:10.1517/13543784.9.3.551. PMID 11060695. S2CID 41792818.
  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 (2001). "Pyridopyrimidine analogues as novel adenosine kinase inhibitors". Bioorg Med Chem Lett. 11 (16): 2071–2074. doi:10.1016/S0960-894X(01)00375-4. PMID 11514141.
  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 (June 2001). "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. doi:10.1021/jm000314x. PMID 11405650.
  48. ↑ Gupta RS, Siminovitch L (November 1978). "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. doi:10.1007/BF01543160. PMID 217113. S2CID 46508059.
  49. ↑ Gupta RS, Mehta KD (April 1984). "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. doi:10.1016/0006-291X(84)91417-7. PMID 6712702.
  50. ↑ Gupta RS, Mehta KD (1986). "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. Vol. 195 Pt B. pp. 595–603. doi:10.1007/978-1-4684-1248-2_93. ISBN 978-1-4684-1250-5. PMID 3020927.

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