Adenosine turnover C
Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
Overview
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A multifunctional, ubiquitous molecule, adenosine acts at cell-surface G protein-coupled receptors, as well as numerous enzymes, including protein kinases and adenylyl cyclase. Extracellular adenosine is thought to be produced either by export or by metabolism, predominantly through ecto-5’-nucleotidase activity (also producing inorganic phosphate). It is inactivated either by extracellular metabolism via adenosine deaminase (also producing ammonia) or, following uptake by nucleoside transporters, via adenosine deaminase or adenosine kinase (requiring ATP as co-substrate). Intracellular adenosine may be produced by cytosolic 5’-nucleotidases or through S-adenosylhomocysteine hydrolase (also producing L-homocysteine).
Enzymes
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ADA (Adenosine deaminase)
C
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ADK (Adenosine kinase) C Show summary »« Hide summary
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NT5E (Ecto-5'-Nucleotidase / CD73)
C
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SAHH (S-Adenosylhomocysteine hydrolase) C Show summary »« Hide summary
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5'-nucleotidase IA Show summary »« Hide summary
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5'-nucleotidase IB Show summary »« Hide summary
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5'-nucleotidase II Show summary »« Hide summary
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5'-nucleotidase III Show summary »« Hide summary
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5'(3')-nucleotidase Show summary »« Hide summary
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Mitochondrial 5'-nucleotidase Show summary »« Hide summary
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Further reading
* Key recommended reading is highlighted with an asterisk
al-Rashida M, Iqbal J. (2014) Therapeutic potentials of ecto-nucleoside triphosphate diphosphohydrolase, ecto-nucleotide pyrophosphatase/phosphodiesterase, ecto-5'-nucleotidase, and alkaline phosphatase inhibitors. Med Res Rev, 34 (4): 703-43. [PMID:24115166]
Antonioli L, Pacher P, Vizi ES, Haskó G. (2013) CD39 and CD73 in immunity and inflammation. Trends Mol Med, 19 (6): 355-67. [PMID:23601906]
Boison D. (2013) Adenosine kinase: exploitation for therapeutic gain. Pharmacol Rev, 65 (3): 906-43. [PMID:23592612]
Boison D. (2016) Adenosinergic signaling in epilepsy. Neuropharmacology, 104: 131-9. [PMID:26341819]
* Boison D, Jarvis MF. (2021) Adenosine kinase: A key regulator of purinergic physiology. Biochem Pharmacol, 187: 114321. [PMID:33161022]
Cortés A, Gracia E, Moreno E, Mallol J, Lluís C, Canela EI, Casadó V. (2015) Moonlighting adenosine deaminase: a target protein for drug development. Med Res Rev, 35 (1): 85-125. [PMID:24933472]
Gao ZW, Wang X, Zhang HZ, Lin F, Liu C, Dong K. (2021) The roles of adenosine deaminase in autoimmune diseases. Autoimmun Rev, 20 (1): 102709. [PMID:33197575]
* Giuliani AL, Sarti AC, Di Virgilio F. (2020) Ectonucleotidases in Acute and Chronic Inflammation. Front Pharmacol, 11: 619458. [PMID:33613285]
* Jeffrey JL, Lawson KV, Powers JP. (2020) Targeting Metabolism of Extracellular Nucleotides via Inhibition of Ectonucleotidases CD73 and CD39. J Med Chem, 63 (22): 13444-13465. [PMID:32786396]
Kloor D, Osswald H. (2004) S-Adenosylhomocysteine hydrolase as a target for intracellular adenosine action. Trends Pharmacol Sci, 25 (6): 294-7. [PMID:15165742]
Nishikura K. (2016) A-to-I editing of coding and non-coding RNAs by ADARs. Nat Rev Mol Cell Biol, 17 (2): 83-96. [PMID:26648264]
Orlandi C, Barbon A, Barlati S. (2012) Activity regulation of adenosine deaminases acting on RNA (ADARs). Mol Neurobiol, 45 (1): 61-75. [PMID:22113393]
Sawynok J. (2016) Adenosine receptor targets for pain. Neuroscience, 338: 1-18. [PMID:26500181]
Tomaselli S, Locatelli F, Gallo A. (2014) The RNA editing enzymes ADARs: mechanism of action and human disease. Cell Tissue Res, 356 (3): 527-32. [PMID:24770896]
* Vizán P, Di Croce L, Aranda S. (2021) Functional and Pathological Roles of AHCY. Front Cell Dev Biol, 9: 654344. [PMID:33869213]
Xiao Y, Su X, Huang W, Zhang J, Peng C, Huang H, Wu X, Huang H, Xia M, Ling W. (2015) Role of S-adenosylhomocysteine in cardiovascular disease and its potential epigenetic mechanism. Int J Biochem Cell Biol, 67: 158-66. [PMID:26117455]
* Yegutkin GG. (2021) Adenosine metabolism in the vascular system. Biochem Pharmacol, 187: 114373. [PMID:33340515]
* Yegutkin GG, Boison D. (2022) ATP and Adenosine Metabolism in Cancer: Exploitation for Therapeutic Gain. Pharmacol Rev, 74 (3): 797-822. [PMID:35738682]
* Zimmermann H. (2021) History of ectonucleotidases and their role in purinergic signaling. Biochem Pharmacol, 187: 114322. [PMID:33161020]
Zimmermann H, Zebisch M, Sträter N. (2012) Cellular function and molecular structure of ecto-nucleotidases. Purinergic Signal, 8 (3): 437-502. [PMID:22555564]
References
1. Agarwal RP, Spector T, Parks Jr RE. (1977) Tight-binding inhibitors--IV. Inhibition of adenosine deaminases by various inhibitors. Biochem Pharmacol, 26 (5): 359-67. [PMID:849330]
2. Boison D. (2013) Adenosine kinase: exploitation for therapeutic gain. Pharmacol Rev, 65 (3): 906-43. [PMID:23592612]
3. Burger RM, Lowenstein JM. (1975) 5'-Nucleotidase from smooth muscle of small intestine and from brain. Inhibition of nucleotides. Biochemistry, 14 (11): 2362-6. [PMID:1169962]
4. Cortés A, Gracia E, Moreno E, Mallol J, Lluís C, Canela EI, Casadó V. (2015) Moonlighting adenosine deaminase: a target protein for drug development. Med Res Rev, 35 (1): 85-125. [PMID:24933472]
5. Glazer RI, Hartman KD, Knode MC, Richard MM, Chiang PK, Tseng CK, Marquez VE. (1986) 3-Deazaneplanocin: a new and potent inhibitor of S-adenosylhomocysteine hydrolase and its effects on human promyelocytic leukemia cell line HL-60. Biochem Biophys Res Commun, 135 (2): 688-94. [PMID:3457563]
6. Guranowski A, Montgomery JA, Cantoni GL, Chiang PK. (1981) Adenosine analogues as substrates and inhibitors of S-adenosylhomocysteine hydrolase. Biochemistry, 20 (1): 110-5. [PMID:7470463]
7. Jarvis MF, Yu H, Kohlhaas K, Alexander K, Lee CH, Jiang M, Bhagwat SS, Williams M, Kowaluk EA. (2000) ABT-702 (4-amino-5-(3-bromophenyl)-7-(6-morpholinopyridin-3-yl)pyrido[2, 3-d]pyrimidine), a novel orally effective adenosine kinase inhibitor with analgesic and anti-inflammatory properties: I. In vitro characterization and acute antinociceptive effects in the mouse. J Pharmacol Exp Ther, 295 (3): 1156-64. [PMID:11082453]
8. Kameoka J, Tanaka T, Nojima Y, Schlossman SF, Morimoto C. (1993) Direct association of adenosine deaminase with a T cell activation antigen, CD26. Science, 261 (5120): 466-9. [PMID:8101391]
9. Maier SA, Galellis JR, McDermid HE. (2005) Phylogenetic analysis reveals a novel protein family closely related to adenosine deaminase. J Mol Evol, 61 (6): 776-94. [PMID:16245011]
10. McGaraughty S, Chu KL, Wismer CT, Mikusa J, Zhu CZ, Cowart M, Kowaluk EA, Jarvis MF. (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. J Pharmacol Exp Ther, 296 (2): 501-9. [PMID:11160637]
11. Wang L, Fan J, Thompson LF, Zhang Y, Shin T, Curiel TJ, Zhang B. (2011) CD73 has distinct roles in nonhematopoietic and hematopoietic cells to promote tumor growth in mice. J Clin Invest, 121 (6): 2371-82. [PMID:21537079]
12. Williams-Karnesky RL, Sandau US, Lusardi TA, Lytle NK, Farrell JM, Pritchard EM, Kaplan DL, Boison D. (2013) Epigenetic changes induced by adenosine augmentation therapy prevent epileptogenesis. J Clin Invest, 123 (8): 3552-63. [PMID:23863710]
13. Zavialov AV, Yu X, Spillmann D, Lauvau G, Zavialov AV. (2010) Structural basis for the growth factor activity of human adenosine deaminase ADA2. J Biol Chem, 285 (16): 12367-77. [PMID:20147294]
NC-IUPHAR subcommittee and family contributors
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Detlev Boison |
How to cite this family page
Database page citation (select format):
Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Fabbro D, Kelly E, Mathie AA, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Davies JA et al. (2023) The Concise Guide to PHARMACOLOGY 2023/24: Enzymes. Br J Pharmacol. 180 Suppl 2:S289-373.
An extracellular adenosine deaminase activity, termed ADA2 or adenosine deaminase growth factor (ADGF, CECR1, Q9NZK5) has been identified [4,9], which is insensitive to EHNA [13]. Other forms of adenosine deaminase act on ribonucleic acids and may be divided into two families: ADAT1 (Q9BUB4) deaminates transfer RNA; ADAR (EC 3.5.4.37, also known as 136 kDa double-stranded RNA-binding protein, P136, K88DSRBP, Interferon-inducible protein 4); ADARB1 (EC 3.5.-.-, , also known as dsRNA adenosine deaminase) and ADARB2 (EC 3.5.-.-, also known as dsRNA adenosine deaminase B2, RNA-dependent adenosine deaminase 3) act on double-stranded RNA. Particular polymorphisms of the ADA gene result in loss-of-function and severe combined immunodeficiency syndrome. Adenosine deaminase is able to complex with dipeptidyl peptidase IV (EC 3.4.14.5, DPP4, also known as T-cell activation antigen CD26, TP103, adenosine deaminase complexing protein 2) to form a cell-surface activity [8].