Journal articles: 'Adenosine kinase'

1

Park, Jae, Bhag Singh, and Radhey S. Gupta. "Mycobacterial adenosine kinase is not a typical adenosine kinase." FEBS Letters 583, no. 13 (June 8, 2009): 2231–36. http://dx.doi.org/10.1016/j.febslet.2009.06.002.

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Kowaluk, Elizabeth A., Shripad S. Bhagwatt, and Michael F. Jarvis. "Adenosine Kinase Inhibitors." Current Pharmaceutical Design 4, no. 5 (October 1998): 403–16. http://dx.doi.org/10.2174/138161280405221010163056.

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Abstract: Adenosine (ADO) is an endogenous modulator of intercellular signaling that provides homeostatic reductions in cell excitability during tissue stress and trauma. The inhibitory actions of ADO are mediated by interactions with specific cell-surface G protein coupled receptors regulating membrane cation flux, polarization, and the release of excitatory neurotransmitters. ADO kinase (AK; EC 2.7.1.20) is the key intracellular enzyme regulating intra- and extracellular ADO concentrations. Inhibition of AK produces marked increases in extracellular ADO levels that are localized to cells and tissues undergoing accelerated ADO release. Thus AK inhibiton represents a mechanism to selectively enhance the protective actions of ADO during tissue trauma without producing the nonspecific effects associated with the systemic administration of ADO receptor agonists. During the last 10 years, specific inhibitors of AK based on the endogenous purine nucleoside substrate, ADO, have been developed. Potent AK inhibitors have recently been synthesized that demonstrate high specificity for this enzyme as compared to other ADO metabolic enzymes, transporters, and receptors. In both in vitro and in vivo models, AK inhibitors have been shown to potently increase ADO concentrations in a tissue and event specific fashion and to demonstrate potential clinical utility in animal models of epilepsy, ischemia, pain, and inflammation. AK inhibitors have demonstrated superior efficacy in these models as compared to other mechanisms of modulating ADO availability, and these agents exhibit reduced side-effect liabilities compared to direct acting ADO receptor agonists. The preclinical profile of AK inhibitors indicate that these agents may have therapeutic utility in a variety of central and peripheral diseases associated with cellular trauma and inflammation. Clinical trials are currently underway to evaluate the efficacy of AK inhibitors in seizure disorders and pain.

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Boison, Detlev. "Adenosine Dysfunction and Adenosine Kinase in Epileptogenesis." Open Neuroscience Journal 4, no. 1 (January 1, 2010): 93–101. http://dx.doi.org/10.2174/1874082001004010093.

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Ratcliffe, Steven J., Tracey Yi, and Sanjay S. Khandekar. "Synthesis and Characterization of 5′-p-fluorosulfonylbenzoyl-2′ (or 3′)-(biotinyl)adenosine as an Activity-Based Probe for Protein Kinases." Journal of Biomolecular Screening 12, no. 1 (November 12, 2006): 126–32. http://dx.doi.org/10.1177/1087057106296685.

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Most of the kinase inhibitors that are approved for therapeutic uses or that are undergoing clinical trials are directed toward the adenosine triphosphate (ATP) binding site of protein kinases. 5'-Fluorosulfonylbenzoyl 5′-adenosine (FSBA) is an activitybased probe (ABP) that covalently modifies a conserved lysine present in the nucleotide binding site of most kinases. Here the authors describe synthesis of FSBA derivatives, 2′-biotinyl-FSBA and 3′-biotinyl-FSBA as kinase ABPs, and delineate a Western blot method to screen and validate ATP competitive protein kinase inhibitors using biotinyl-FSBA as a nonselective activity-based probe for protein kinases.

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Zhulai, Galina, Eugenia Oleinik, Mikhail Shibaev, and Kirill Ignatev. "Adenosine-Metabolizing Enzymes, Adenosine Kinase and Adenosine Deaminase, in Cancer." Biomolecules 12, no. 3 (March 8, 2022): 418. http://dx.doi.org/10.3390/biom12030418.

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The immunosuppressive effect of adenosine in the microenvironment of a tumor is well established. Presently, researchers are developing approaches in immune therapy that target inhibition of adenosine or its signaling such as CD39 or CD73 inhibiting antibodies or adenosine A2A receptor antagonists. However, numerous enzymatic pathways that control ATP-adenosine balance, as well as understudied intracellular adenosine regulation, can prevent successful immunotherapy. This review contains the latest data on two adenosine-lowering enzymes: adenosine kinase (ADK) and adenosine deaminase (ADA). ADK deletes adenosine by its phosphorylation into 5′-adenosine monophosphate. Recent studies have revealed an association between a long nuclear ADK isoform and an increase in global DNA methylation, which explains epigenetic receptor-independent role of adenosine. ADA regulates the level of adenosine by converting it to inosine. The changes in the activity of ADA are detected in patients with various cancer types. The article focuses on the biological significance of these enzymes and their roles in the development of cancer. Perspectives of future studies on these enzymes in therapy for cancer are discussed.

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Khandekar, Sanjay S., Bingbing Feng, Tracey Yi, Susan Chen, Nicholas Laping, and Neal Bramson. "A Liquid Chromatography/Mass Spectrometry-Based Method for the Selection of ATP Competitive Kinase Inhibitors." Journal of Biomolecular Screening 10, no. 5 (August 2005): 447–55. http://dx.doi.org/10.1177/1087057105274846.

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The currently approved kinase inhibitors for therapeutic uses and a number of kinase inhibitors that are undergoing clinical trials are directed toward the adenosine triphosphate (ATP) binding site of protein kinases. The 5β-fluorosulfonylbenzoyl 5'-adenosine (FSBA) is an ATP-affinity reagent that covalently modifies a conserved lysine present in the nucleotide-binding site of most kinases. The authors have developed a liquid chromatography/mass spectrometry-basedmethod tomonitor binding ofATP competitive protein kinase inhibitors using FSBAas a nonselective activity-based probe for protein kinases. Their method provides a general, rapid, and reproducible means to screen and validate selective ATP competitive inhibitors of protein kinases.

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Drabikowska, Alicja K., Lidia Halec, and David Shugar. "Purification and Properties of Adenosine Kinase from Rat Liver: Separation from Deoxyadenosine Kinase Activity." Zeitschrift für Naturforschung C 40, no. 1-2 (February 1, 1985): 34–41. http://dx.doi.org/10.1515/znc-1985-1-209.

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Ion exchange and affinity chromatography techniques, similar to those previously reported for purification of adenosine kinase from human placenta, were applied to purification of rat liver adenosine kinase. The enzyme, purified 400-fold in 41% yield, was homogeneous on SDS- polyacrylamide gel electrophoresis, with a molecular weight of 52000. It specific activity, 18 μmol/min/mg protein, is the highest hitherto reported for this enzyme from mammalian sources. Chromatography on DEAE-cellulose removed about 98% of the phosphorylating activity towards 2′-deoxyadenosine present in the initial pH-treated liver extract. The final preparation exhibited only minimal activity (~ 1.5%) under optimal conditions (pH 7.5) vs- 2′-deoxy- adenosine, the lowest yet reported for such a preparation, with a Km of 670 μᴍ, as compared to 0.3 μᴍ for adenosine. The residual activity towards deoxyadenosine is considered an intrinsic property of the purified adenosine kinase and, in fact, phosphorylation of adenosine was inhibited competitively by deoxyadenosine, with a of 70 μᴍ. Competitive inhibition was also exhibited by cordycepin (3′-deoxyadenosine) with a Ki of 150 μᴍ. A more potent competitive inhibitor was tubercidin, the Ki for which was 1.9 μᴍ.

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8

Fassett, John T., Xinli Hu, Xin Xu, Zhongbing Lu, Ping Zhang, Yingjie Chen, and Robert J. Bache. "Adenosine kinase regulation of cardiomyocyte hypertrophy." American Journal of Physiology-Heart and Circulatory Physiology 300, no. 5 (May 2011): H1722—H1732. http://dx.doi.org/10.1152/ajpheart.00684.2010.

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There is evidence that extracellular adenosine can attenuate cardiac hypertrophy, but the mechanism by which this occurs is not clear. Here we investigated the role of adenosine receptors and adenosine metabolism in attenuation of cardiomyocyte hypertrophy. Phenylephrine (PE) caused hypertrophy of neonatal rat cardiomyocytes with increases of cell surface area, protein synthesis, and atrial natriuretic peptide (ANP) expression. These responses were attenuated by 5 μM 2-chloroadenosine (CADO; adenosine deaminase resistant adenosine analog) or 10 μM adenosine. While antagonism of adenosine receptors partially blocked the reduction of ANP expression produced by CADO, it did not restore cell size or protein synthesis. In support of a role for intracellular adenosine metabolism in regulating hypertrophy, the adenosine kinase (AK) inhibitors iodotubercidin and ABT-702 completely reversed the attenuation of cell size, protein synthesis, and expression of ANP by CADO or ADO. Examination of PE-induced phosphosignaling pathways revealed that CADO treatment did not reduce AKTSer473 phosphorylation but did attenuate sustained phosphorylation of RafSer338 (24–48 h), mTORSer2448 (24–48 h), p70S6kThr389 (2.5–48 h), and ERKThr202/Tyr204 (48 h). Inhibition of AK restored activation of these enzymes in the presence of CADO. Using dominant negative and constitutively active Raf adenoviruses, we found that Raf activation is necessary and sufficient for PE-induced mTORC1 signaling and cardiomyocyte hypertrophy. CADO treatment still blocked p70S6kThr389 phosphorylation and hypertrophy downstream of constitutively active Raf, however, despite a high level phosphorylation of ERKThr202/Tyr204 and AKTSer473. Reduction of Raf-induced p70S6kThr389 phosphorylation and hypertrophy by CADO was reversed by inhibiting AK. Together, these results identify AK as an important mediator of adenosine attenuation of cardiomyocyte hypertrophy, which acts, at least in part, through inhibition of Raf signaling to mTOR/p70S6k.

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9

Gomtsyan, Arthur, and Chih-Hung Lee. "Nonnucleoside Inhibitors of Adenosine Kinase." Current Pharmaceutical Design 10, no. 10 (April 1, 2004): 1093–103. http://dx.doi.org/10.2174/1381612043452703.

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10

Galazka, Jon, Boris Striepen, and Buddy Ullman. "Adenosine kinase from Cryptosporidium parvum." Molecular and Biochemical Parasitology 149, no. 2 (October 2006): 223–30. http://dx.doi.org/10.1016/j.molbiopara.2006.06.001.

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11

KOWALUK, E. A., S. S. BHAGWAT, and M. F. JARVIS. "ChemInform Abstract: Adenosine Kinase Inhibitors." ChemInform 30, no. 1 (June 18, 2010): no. http://dx.doi.org/10.1002/chin.199901275.

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12

Newby, A. C. "The role of adenosine kinase in regulating adenosine concentration." Biochemical Journal 226, no. 1 (February 15, 1985): 343–44. http://dx.doi.org/10.1042/bj2260343.

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13

Vodnala, Munender, Artur Fijolek, Reza Rofougaran, Marc Mosimann, Pascal Mäser, and Anders Hofer. "Adenosine Kinase Mediates High Affinity Adenosine Salvage inTrypanosoma brucei." Journal of Biological Chemistry 283, no. 9 (December 31, 2007): 5380–88. http://dx.doi.org/10.1074/jbc.m705603200.

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14

Rex, Christopher S., Lulu Y. Chen, Anupam Sharma, Jihua Liu, Alex H. Babayan, Christine M. Gall, and Gary Lynch. "Different Rho GTPase–dependent signaling pathways initiate sequential steps in the consolidation of long-term potentiation." Journal of Cell Biology 186, no. 1 (July 13, 2009): 85–97. http://dx.doi.org/10.1083/jcb.200901084.

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The releasable factor adenosine blocks the formation of long-term potentiation (LTP). These experiments used this observation to uncover the synaptic processes that stabilize the potentiation effect. Brief adenosine infusion blocked stimulation-induced actin polymerization within dendritic spines along with LTP itself in control rat hippocampal slices but not in those pretreated with the actin filament stabilizer jasplakinolide. Adenosine also blocked activity-driven phosphorylation of synaptic cofilin but not of synaptic p21-activated kinase (PAK). A search for the upstream origins of these effects showed that adenosine suppressed RhoA activity but only modestly affected Rac and Cdc42. A RhoA kinase (ROCK) inhibitor reproduced adenosine's effects on cofilin phosphorylation, spine actin polymerization, and LTP, whereas a Rac inhibitor did not. However, inhibitors of Rac or PAK did prolong LTP's vulnerability to reversal by latrunculin, a toxin which blocks actin filament assembly. Thus, LTP induction initiates two synaptic signaling cascades: one (RhoA-ROCK-cofilin) leads to actin polymerization, whereas the other (Rac-PAK) stabilizes the newly formed filaments.

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15

Qin, Qining, James M. Downey, and Michael V. Cohen. "Acetylcholine but not adenosine triggers preconditioning through PI3-kinase and a tyrosine kinase." American Journal of Physiology-Heart and Circulatory Physiology 284, no. 2 (February 1, 2003): H727—H734. http://dx.doi.org/10.1152/ajpheart.00476.2002.

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Adenosine and acetylcholine (ACh) trigger preconditioning by different signaling pathways. The involvement of phosphatidylinositol 3-kinase (PI3-kinase), a protein tyrosine kinase, and Src family tyrosine kinase in preconditioning was evaluated in isolated rabbit hearts. Either wortmannin (PI3-kinase blocker), genistein (tyrosine kinase blocker), lavendustin A (tyrosine kinase blocker), or 4-amino-5-(4-chlorophenyl)-7-( t-butyl)pyrazolol[3,4-d]pyrimidine (PP2; Src family tyrosine kinase blocker) was given for 15 min to bracket a 5-min infusion of either adenosine or ACh (trigger phase). The hearts then underwent 30 min of regional ischemia. Infarct size for ACh alone was 9.3 ± 3.5% of the risk zone versus 34.3 ± 4.1% in controls. All four inhibitors blocked ACh-induced protection. When wortmannin or PP2 was infused only during the 30-min ischemic period (mediator phase), ACh-induced protection was not affected (7.4 ± 2.1% and 9.7 ± 1.7% infarction, respectively). Adenosine-triggered protection was not blocked by any of the inhibitors. Therefore, PI3-kinase and at least one protein tyrosine kinase, probably Src kinase, are involved in the trigger phase of ACh-induced, but not adenosine-induced, preconditioning. Neither PI3-kinase nor Src kinase is a mediator of the protection of ACh.

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Krieg, Thomas, Qining Qin, Elizabeth C. McIntosh, Michael V. Cohen, and James M. Downey. "ACh and adenosine activate PI3-kinase in rabbit hearts through transactivation of receptor tyrosine kinases." American Journal of Physiology-Heart and Circulatory Physiology 283, no. 6 (December 1, 2002): H2322—H2330. http://dx.doi.org/10.1152/ajpheart.00474.2002.

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Adenosine and acetylcholine (ACh) trigger preconditioning through different signaling pathways. We tested whether either could activate myocardial phosphatidylinositol 3-kinase (PI3-kinase), a putative signaling protein in ischemic preconditioning. We used phosphorylation of Akt, a downstream target of PI3-kinase, as a reporter. Exposure of isolated rabbit hearts to ACh increased Akt phosphorylation 2.62 ± 0.33 fold ( P = 0.001), whereas adenosine caused a significantly smaller increase (1.52 ± 0.08 fold). ACh-induced activation of Akt was abolished by the tyrosine kinase blocker genistein indicating at least one tyrosine kinase between the muscarinic receptor and Akt. ACh-induced Akt activation was blocked by the Src tyrosine kinase inhibitor 4-amino-5-(4-chlorophenyl)-7-( t-butyl)pyrazolo[3,4- d]pyrimidine (PP2) and by 4-(3-chloroanilino)-6,7-dimethoxyquinazoline (AG-1478), an epidermal growth factor receptor (EGFR) inhibitor, suggesting phosphorylation of a receptor tyrosine kinase in an Src tyrosine kinase-dependent manner. ACh caused tyrosine phosphorylation of the EGFR, which could be blocked by PP2, thus supporting this receptor hypothesis. AG-1478 failed to block the cardioprotection of ACh, however, suggesting that other receptor tyrosine kinases might be involved. Therefore, Gi protein-coupled receptors can activate PI3-kinase/Akt through transactivation of receptor tyrosine kinases in an Src tyrosine kinase-dependent manner.

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Cao, Wei, Yanggang Yuan, Xi Liu, Qing Li, Xiaofei An, Zhimin Huang, Lin Wu, Bo Zhang, Aihua Zhang, and Changying Xing. "Adenosine kinase inhibition protects against cisplatin-induced nephrotoxicity." American Journal of Physiology-Renal Physiology 317, no. 1 (July 1, 2019): F107—F115. http://dx.doi.org/10.1152/ajprenal.00385.2018.

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Numerous studies have demonstrated that several mechanisms, including oxidative stress, DNA damage, and inflammatory responses, are closely linked to cisplatin-induced nephrotoxicity. Adenosine, emerging as a key regulatory molecule, is mostly protective in the pathophysiology of inflammatory diseases. A previous study showed that some of the adenosine receptors led to renal protection against ischemia-reperfusion injury. However, these adenosine receptor agonists lack a useful therapeutic index due to cardiovascular side effects. We hypothesized that inhibition of adenosine kinase (ADK) might exacerbate extracellular adenosine levels to reduce cisplatin-induced renal injury. In the present study, pretreatment with the ADK inhibitor ABT-702 could markedly attenuate cisplatin-induced acute kidney injury, tubular cell apoptosis, oxidative stress, and inflammation in the kidneys. Consistent with in vivo results, inhibition of ADK suppressed cisplatin-induced apoptosis, reactive oxygen species production, and inflammation in HK2 cells. Additionally, the protective effect of ADK inhibition was abolished by A1 or A2B adenosine receptor antagonist and enhanced by A2A or A3 adenosine receptor antagonist. Collectively, the results suggest that inhibition of ADK might increase extracellular adenosine levels, which inhibited cisplatin-induced oxidative stress and inflammation via A1 and A2B adenosine receptors, finally suppressing cisplatin-induced cell apoptosis. Pharmacological therapies based on ADK will be of potential use in therapy of cisplatin-induced nephrotoxicity.

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Charter, Neil W., Lindy Kauffman, Raj Singh, and Richard M. Eglen. "A Generic, Homogenous Method for Measuring Kinase and Inhibitor Activity via Adenosine 5′-Diphosphate Accumulation." Journal of Biomolecular Screening 11, no. 4 (April 28, 2006): 390–99. http://dx.doi.org/10.1177/1087057106286829.

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The authors describe an assay to measure the generation of adenosine 5′-diphosphate (ADP) resulting from phosphorylation of a substrate by a kinase. ADP accumulation is detected by conversion to a fluorescent signal via a coupled enzyme system. The technology has potential applications for the assessment of inhibitor potency and mode of action as well as kinetic analysis of enzyme activity. The assay has a wide dynamic range (0.25-75 μM) and has been validated with several kinases including the highly active cyclic adenosine monophosphate-dependent protein kinase (PKAα), casein kinase 1 (CK1), and the weakly active kinase Jun N-terminal kinase 2 (Jnk2α2). Kinase activity can be measured either in an end point or continuous mode. Assay performance in end point mode was compared with an adenosine 5′-triphosphate (ATP) depletion assay and in continuous mode with a pyruvate kinase/lactate dehydrogenase coupled assay. The ability to characterize kinase kinetics was demonstrated by deriving ATP/substrate affinity (Michaelis-Menten constant; Km) values for PKAα, CK1, and Jnk2α2. The assay readily measured activity with kinase reactions using protein substrates, indicating the suitability for use with large macromolecules. A wide range of inhibitor activities could be determined even in the presence of high ATP concentrations, making the assay highly suitable to characterize the mode of action of the inhibitor in question. Collectively, this assay provides a homogenous, generic method for a number of applications in kinase drug discovery.

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19

Sciotti, Veronica M., and David G. L. Van Wylen. "Increases in Interstitial Adenosine and Cerebral Blood Flow with Inhibition of Adenosine Kinase and Adenosine Deaminase." Journal of Cerebral Blood Flow & Metabolism 13, no. 2 (March 1993): 201–7. http://dx.doi.org/10.1038/jcbfm.1993.24.

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The purpose of this study was to determine the changes in interstitial fluid (ISF) adenosine and cerebral blood flow (CBF) during inhibition of adenosine kinase or adenosine deaminase. Brain microdialysis was used to (a) measure CBF (H2 clearance), (b) sample cerebral ISF, and (c) deliver drugs locally to the brain. Microdialysis probes were implanted bilaterally in the caudate nucleus of halothane-anesthetized rats ( n = 11). One probe was perfused with artificial cerebrospinal fluid (CSF) containing iodotubercidin (IODO), an adenosine kinase inhibitor, while the other probe was perfused with erythro-2-(2-hydroxy-3-nonyl)adenine (EHNA), an adenosine deaminase inhibitor. Both probes were subsequently perfused with EHNA + IODO. Finally, 8-( p-sulfophenyl)theophylline (SPT), an adenosine receptor antagonist, was added to EHNA + IODO in one probe, while the other probe continued to receive only EHNA + IODO. CBF and dialysate adenosine levels increased with either EHNA or IODO; however, the increases were greater with IODO. EHNA + IODO further increased CBF and dialysate adenosine. The hyperemia observed with EHNA + IODO was abolished by adenosine receptor blockade. These data suggest that basal adenosine levels are influenced to a greater extent by adenosine kinase than by adenosine deaminase. In addition, the increased CBF observed with inhibition of adenosine metabolism and the attenuation of this vasodilatory response with adenosine receptor blockade support a role for adenosine in CBF regulation.

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20

Fassett, John T. "Adenosine kinase mediates adenosine attenuation of cardiomyocyte microtubule cytoskeletal densification." Intrinsic Activity 3, Suppl. 2 (September 9, 2015): A1.14. http://dx.doi.org/10.25006/ia.3.s2-a1.14.

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21

Kaplan, Gary B., and Tara Sharon Coyle. "Adenosine kinase inhibitors attenuate opiate withdrawal via adenosine receptor activation." European Journal of Pharmacology 362, no. 1 (November 1998): 1–8. http://dx.doi.org/10.1016/s0014-2999(98)00724-9.

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22

Tomoike, Fumiaki, Akiko Tsunetou, Kwang Kim, Noriko Nakagawa, Seiki Kuramitsu, and Ryoji Masui. "A putative adenosine kinase family protein possesses adenosine diphosphatase activity." Bioscience, Biotechnology, and Biochemistry 80, no. 11 (August 2, 2016): 2138–43. http://dx.doi.org/10.1080/09168451.2016.1214532.

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23

Decking, Ulrich K. M., Georg Schlieper, Keith Kroll, and Jürgen Schrader. "Hypoxia-Induced Inhibition of Adenosine Kinase Potentiates Cardiac Adenosine Release." Circulation Research 81, no. 2 (August 1997): 154–64. http://dx.doi.org/10.1161/01.res.81.2.154.

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Harrington, Elizabeth O., Anthony Smeglin, Nancy Parks, Julie Newton, and Sharon Rounds. "Adenosine induces endothelial apoptosis by activating protein tyrosine phosphatase: a possible role of p38α." American Journal of Physiology-Lung Cellular and Molecular Physiology 279, no. 4 (October 1, 2000): L733—L742. http://dx.doi.org/10.1152/ajplung.2000.279.4.l733.

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Endothelial cell (EC) apoptosis is important in vascular injury, repair, and angiogenesis. Homocysteine and/or adenosine exposure of ECs causes apoptosis. Elevated homocysteine or adenosine occurs in disease states such as homocysteinuria and tissue necrosis, respectively. We examined the intracellular signaling mechanisms involved in this pathway of EC apoptosis. Inhibition of protein tyrosine phosphatase (PTPase) attenuated homocysteine- and/or adenosine-induced apoptosis and completely blocked apoptosis induced by the inhibition of S-adenosylhomocysteine hydrolase with MDL-28842. Consistent with this finding, the tyrosine kinase inhibitor genistein enhanced apoptosis in adenosine-treated ECs. Adenosine significantly elevated the PTPase activity in the ECs. Mitogen-activated protein kinase activities were examined to identify possible downstream targets for the upregulated PTPase(s). Extracellular signal-regulated kinase (ERK) 1 activity was slightly elevated in adenosine-treated ECs, whereas ERK2, c-Jun NH2-terminal kinase-1, or p38β activities differed little. The mitogen-activated protein kinase-1 inhibitor PD-98059 enhanced DNA fragmentation, suggesting that increased ERK1 activity is a result but not a cause of apoptosis in adenosine-treated ECs. Adenosine-treated ECs had diminished p38α activity compared with control cells; this effect was blunted on PTPase inhibition. These results indicate that PTPase(s) plays an integral role in the induction of EC apoptosis upon exposure to homocysteine and/or adenosine, possibly by the attenuation of p38α activity.

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Lüscher, Alexandra, Pinar Önal, Anne-Marie Schweingruber, and Pascal Mäser. "Adenosine Kinase of Trypanosoma brucei and Its Role in Susceptibility to Adenosine Antimetabolites." Antimicrobial Agents and Chemotherapy 51, no. 11 (August 13, 2007): 3895–901. http://dx.doi.org/10.1128/aac.00458-07.

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ABSTRACT Trypanosoma brucei cannot synthesize purines de novo and relies on purine salvage from its hosts to build nucleic acids. With adenosine being a preferred purine source of bloodstream-form trypanosomes, adenosine kinase (AK; EC 2.7.1.20) is likely to be a key player in purine salvage. Adenosine kinase is also of high pharmacological interest, since for many adenosine antimetabolites, phosphorylation is a prerequisite for activity. Here, we cloned and functionally characterized adenosine kinase from T. brucei (TbAK). TbAK is a tandem gene, expressed in both procyclic- and bloodstream-form trypanosomes, whose product localized to the cytosol of the parasites. The RNA interference-mediated silencing of TbAK suggested that the gene is nonessential under standard growth conditions. Inhibition or downregulation of TbAK rendered the trypanosomes resistant to cordycepin (3′-deoxyadenosine), demonstrating a role for TbAK in the activation of adenosine antimetabolites. The expression of TbAK in Saccharomyces cerevisiae complemented a null mutation in the adenosine kinase gene ado1. The concomitant expression of TbAK with the T. brucei adenosine transporter gene TbAT1 allowed S. cerevisiae ado1 ade2 double mutants to grow on adenosine as the sole purine source and, at the same time, sensitized them to adenosine antimetabolites. The coexpression of TbAK and TbAT1 in S. cerevisiae ado1 ade2 double mutants proved to be a convenient tool for testing nucleoside analogues for uptake and activation by T. brucei adenosine salvage enzymes.

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Okada, Takayuki, Hajime Otani, Yue Wu, Takamichi Uchiyama, Shiori Kyoi, Reiji Hattori, Tomohiko Sumida, Hiroyoshi Fujiwara, and Hiroji Imamura. "Integrated pharmacological preconditioning and memory of cardioprotection: role of protein kinase C and phosphatidylinositol 3-kinase." American Journal of Physiology-Heart and Circulatory Physiology 289, no. 2 (August 2005): H761—H767. http://dx.doi.org/10.1152/ajpheart.00012.2005.

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Although protein kinase C (PKC) and phosphatidylinositol 3 (PI3)-kinase are implicated in cardioprotective signal transduction mediated by ischemic preconditioning, their role in pharmacological preconditioning (PPC) has not been determined. Cultured neonatal rat cardiomyocytes (CMCs) were subjected to simulated ischemia for 2 h followed by 15 min of reoxygenation. PPC of CMCs consisted of administration of 50 μM adenosine, 50 μM diazoxide, and 50 μM S-nitroso- N-acetylpenicillamine (SNAP), each alone or in combination, for 15 min followed by 30 min of washout before simulated ischemia. Although PKC-ε and PI3-kinase were significantly activated during treatment with adenosine, activation of these kinases dissipated after washout. In contrast, PPC combined with adenosine, diazoxide, and SNAP elicited sustained activation of PKC-ε and PI-3 kinase after washout. The combined-PPC, but not the single-PPC, protocol conferred antiapoptotic and antinecrotic effects after reoxygenation. The PKC inhibitor chelerythrine (5 μM) or the PI3-kinase inhibitor LY-294002 (10 μM) given during the washout period partially blocked the activation of PKC-ε and PI3-kinase mediated by the combined-PPC protocol, whereas combined addition of chelerythrine and LY-294002 completely inhibited activation of PKC-ε and PI3-kinase. Chelerythrine or LY-294002 partially blocked antiapoptotic and antinecrotic effects mediated by the combined-PPC protocol, whereas combined addition of chelerythrine and LY-294002 completely abrogated antiapoptotic and antinecrotic effects. These results suggest that the combined-PPC protocol confers cardioprotective memory through sustained and interdependent activation of PKC and PI3-kinase.

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Yang, Ke-Ke, Yi Sui, Hui-Rong Zhou, and Hai-Lu Zhao. "Interaction of renin–angiotensin system and adenosine monophosphate–activated protein kinase signaling pathway in renal carcinogenesis of uninephrectomized rats." Tumor Biology 39, no. 5 (May 2017): 101042831769911. http://dx.doi.org/10.1177/1010428317699116.

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Renin–angiotensin system and adenosine monophosphate–activated protein kinase signaling pathway both play important roles in carcinogenesis, but the interplay of renin–angiotensin system and adenosine monophosphate–activated protein kinase in carcinogenesis is not clear. In this study, we researched the interaction of renin–angiotensin system and adenosine monophosphate–activated protein kinase in renal carcinogenesis of uninephrectomized rats. A total of 96 rats were stratified into four groups: sham, uninephrectomized, and uninephrectomized treated with angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. Renal adenosine monophosphate–activated protein kinase and its downstream molecule acetyl coenzyme A carboxylase were detected by immunohistochemistry and western blot at 10 months after uninephrectomy. Meanwhile, we examined renal carcinogenesis by histological transformation and expressions of Ki67 and mutant p53. During the study, fasting lipid profiles were detected dynamically at 3, 6, 8, and 10 months. The results indicated that adenosine monophosphate–activated protein kinase expression in uninephrectomized rats showed 36.8% reduction by immunohistochemistry and 89.73% reduction by western blot. Inversely, acetyl coenzyme A carboxylase expression increased 83.3% and 19.07% in parallel to hyperlipidemia at 6, 8, and 10 months. The histopathology of carcinogenesis in remnant kidneys was manifested by atypical proliferation and carcinoma in situ, as well as increased expressions of Ki67 and mutant p53. Intervention with angiotensin-converting enzyme inhibitor or angiotensin receptor blocker significantly prevented the inhibition of adenosine monophosphate–activated protein kinase signaling pathway and renal carcinogenesis in uninephrectomized rats. In conclusion, the novel findings suggest that uninephrectomy-induced disturbance in adenosine monophosphate–activated protein kinase signaling pathway resulted in hyperlipidemia and carcinogenesis in tubular epithelial cells, which may be largely attenuated by renin–angiotensin system blockade, implying the interaction of renin–angiotensin system and adenosine monophosphate–activated protein kinase signaling pathway in renal carcinogenesis of uninephrectomized rats.

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Jenuth, Jack P., Ellen R. Mably, and Floyd F. Snyder. "Modelling of purine nucleoside metabolism during mouse embryonic development. Relative routes of adenosine, deoxyadenosine, and deoxyguanosine metabolism." Biochemistry and Cell Biology 74, no. 2 (March 1, 1996): 219–25. http://dx.doi.org/10.1139/o96-022.

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The individual activities for adenosine kinase, deoxyadenosine kinase, adenosine deaminase, deoxyguanosine kinase, and purine nucleoside phosphorylase were determined during days 7 to 13 of mouse embryonic development. Adenosine deaminase increased 74-fold between days 7 and 9; deoxyadenosine kinase increased 5.4-fold during the same interval. Adenosine kinase, deoxyguanosine kinase, and purine nucleoside phosphorylase exhibited less than 2-fold changes in activity between days 7 and 13. Using Michaelis constants for each enzyme and the maximal velocities determined from enzyme assay, the relative routes of adenosine and deoxyadenosine metabolism via phosphorylation or deamination were modeled as a function of nucleoside concentration for days 7 through 13. For days 7 and 8, phosphorylation of adenosine is the principle route of metabolism at physiological concentrations. A switch occurred at day 9 and following where deamination is at least 5-fold greater than phosphorylation at all substrate concentrations. Deoxyadenosine phosphorylation was at most 10% of deamination at day 7 and then declined to less than 1% for days 9 to 13. Phosphorolysis was the principle route of deoxyguanosine metabolism through the 7 to 13 day period. Thus catabolism rather than phosphorylation was the principle pathway for purine deoxynucleoside metabolism during this period.Key words: mouse embryo, purine nucleoside metabolism.

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Firestein, G. S., D. Boyle, D. A. Bullough, H. E. Gruber, F. G. Sajjadi, A. Montag, B. Sambol, and K. M. Mullane. "Protective effect of an adenosine kinase inhibitor in septic shock." Journal of Immunology 152, no. 12 (June 15, 1994): 5853–59. http://dx.doi.org/10.4049/jimmunol.152.12.5853.

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Abstract Adenosine exhibits potent anti-inflammatory activities but its therapeutic use is limited by cardiovascular side effects. Inhibitors of an enzyme involved in adenosine metabolism, adenosine kinase (EC 2.7.1.20), were evaluated for their ability to enhance endogenous adenosine production. One novel adenosine kinase inhibitor, GP-1-515, was studied in two models of septic shock to assess its protective effects. GP-1-515 significantly decreased mortality in mice that received a lethal i.v. injection of endotoxin. The beneficial effect was accompanied by decreased neutrophil accumulation in the lungs and was reversed by an adenosine receptor antagonist, implying that the effects were mediated by endogenous adenosine. Plasma levels of TNF-alpha, but not IL-1 alpha or IL-6, were lower in the GP-1-515-treated animals. In a second model of sepsis, GP-1-515 increased survival in bacterial peritonitis in rats. The mechanism of action in both models was likely multifactorial, including adenosine-mediated inhibition of neutrophil adhesion, cytokine production, and oxygen radical generation. Adenosine kinase inhibitors have potent anti-inflammatory effects in vitro and in vivo and represent a novel therapeutic approach to the treatment of inflammatory diseases.

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30

Alhusani, Alhanouf, Abdulrahman Obaid, Henk Blom, Anna Wedell, and Majid Alfadhel. "Adenosine Kinase Deficiency: Report and Review." Neuropediatrics 50, no. 01 (November 26, 2018): 046–50. http://dx.doi.org/10.1055/s-0038-1676053.

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AbstractAdenosine kinase (ADK) deficiency (OMIM [online mendelian inheritance in man]: 614300) is an autosomal recessive disorder of adenosine and methionine metabolism, with a unique clinical phenotype, mainly involving the central nervous system and dysmorphic features. Patients usually present early in life with sepsis-like symptoms, respiratory difficulties, and neonatal jaundice. Subsequently, patients demonstrate hypotonia and global developmental delay. Biochemically, methionine is elevated with normal homocysteine levels and the diagnosis is confirmed through molecular analysis of the ADK gene. There is no curative treatment; however, a methionine-restricted diet has been tried with variable outcomes. Herein, we report a 4-year-old Saudi female with global developmental delay, hypotonia, and dysmorphic features. Interestingly, she has a tall stature, developmental dysplasia of the hip, optic nerve gliosis, and tigroid fundus. We found a mutation not reported previously and we compared the current case with previously reported cases. We alert clinicians to consider ADK deficiency in any neonate presenting with global developmental delay, hypotonia, dysmorphic features, and high methionine levels.

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Iwashima, A., M. Ogata, K. Nosaka, H. Nishimura, and T. Hasegawa. "Adenosine kinase-deficient mutant ofSaccharomyces cerevisiae." FEMS Microbiology Letters 127, no. 1-2 (March 1995): 23–28. http://dx.doi.org/10.1111/j.1574-6968.1995.tb07444.x.

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Boison, Detlev. "The adenosine kinase hypothesis of epileptogenesis." Progress in Neurobiology 84, no. 3 (March 2008): 249–62. http://dx.doi.org/10.1016/j.pneurobio.2007.12.002.

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Boison, Detlev. "Adenosine Kinase: Exploitation for Therapeutic Gain." Pharmacological Reviews 65, no. 3 (April 16, 2013): 906–43. http://dx.doi.org/10.1124/pr.112.006361.

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34

Agrawal, Vijay K., Kamana Singh, and Padmakar V. Khadikar. "QSAR STUDIES ON ADENOSINE KINASE INHIBITORS." Medicinal Chemistry Research 13, no. 6-7 (July 2004): 479–96. http://dx.doi.org/10.1007/s00044-004-0048-0.

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35

MacRae, Ian J., Alan B. Rose, and Irwin H. Segel. "Adenosine 5′-Phosphosulfate Kinase fromPenicillium chrysogenum." Journal of Biological Chemistry 273, no. 44 (October 30, 1998): 28583–89. http://dx.doi.org/10.1074/jbc.273.44.28583.

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ROTLLAN, Pedro, and Maria Teresa MIRAS PORTUGAL. "Adenosine kinase from bovine adrenal medulla." European Journal of Biochemistry 151, no. 2 (September 1985): 365–71. http://dx.doi.org/10.1111/j.1432-1033.1985.tb09110.x.

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37

Kowaluk, Elizabeth A., and Michael F. Jarvis. "Therapeutic potential of adenosine kinase inhibitors." Expert Opinion on Investigational Drugs 9, no. 3 (March 2000): 551–64. http://dx.doi.org/10.1517/13543784.9.3.551.

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Tan, Ernest Y., Cynthia L. Richard, Hong Zhang, David W. Hoskin, and Jonathan Blay. "Adenosine downregulates DPPIV on HT-29 colon cancer cells by stimulating protein tyrosine phosphatase(s) and reducing ERK1/2 activity via a novel pathway." American Journal of Physiology-Cell Physiology 291, no. 3 (September 2006): C433—C444. http://dx.doi.org/10.1152/ajpcell.00238.2005.

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The multifunctional cell-surface protein dipeptidyl peptidase IV (DPPIV/CD26) is aberrantly expressed in many cancers and plays a key role in tumorigenesis and metastasis. Its diverse cellular roles include modulation of chemokine activity by cleaving dipeptides from the chemokine NH2-terminus, perturbation of extracellular nucleoside metabolism by binding the ecto-enzyme adenosine deaminase, and interaction with the extracellular matrix by binding proteins such as collagen and fibronectin. We have recently shown that DPPIV can be downregulated from the cell surface of HT-29 colorectal carcinoma cells by adenosine, which is a metabolite that becomes concentrated in the extracellular fluid of hypoxic solid tumors. Most of the known responses to adenosine are mediated through four different subtypes of G protein-coupled adenosine receptors: A1, A2A, A2B, and A3. We report here that adenosine downregulation of DPPIV from the surface of HT-29 cells occurs independently of these classic receptor subtypes, and is mediated by a novel cell-surface mechanism that induces an increase in protein tyrosine phosphatase activity. The increase in protein tyrosine phosphatase activity leads to a decrease in the tyrosine phosphorylation of ERK1/2 MAP kinase that in turn links to the decline in DPPIV mRNA and protein. The downregulation of DPPIV occurs independently of changes in the activities of protein kinases A or C, phosphatidylinositol 3-kinase, other serine/threonine phosphatases, or the p38 or JNK MAP kinases. This novel action of adenosine has implications for our ability to manipulate adenosine-dependent events within the solid tumor microenvironment.

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Xaus, Jordi, Annabel F. Valledor, Marina Cardó, Laura Marquès, Jorge Beleta, José M. Palacios, and Antonio Celada. "Adenosine Inhibits Macrophage Colony-Stimulating Factor-Dependent Proliferation of Macrophages Through the Induction of p27kip-1 Expression." Journal of Immunology 163, no. 8 (October 15, 1999): 4140–49. http://dx.doi.org/10.4049/jimmunol.163.8.4140.

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Abstract Adenosine is produced during inflammation and modulates different functional activities in macrophages. In murine bone marrow-derived macrophages, adenosine inhibits M-CSF-dependent proliferation with an IC50 of 45 μM. Only specific agonists that can activate A2B adenosine receptors such as 5′-N-ethylcarboxamidoadenosine, but not those active on A1 (N6-(R)-phenylisopropyladenosine), A2A ([p-(2-carbonylethyl)phenylethylamino]-5′-N-ethylcarboxamidoadenosine), or A3 (N6-(3-iodobenzyl)adenosine-5′-N-methyluronamide) receptors, induce the generation of cAMP and modulate macrophage proliferation. This suggests that adenosine regulates macrophage proliferation by interacting with the A2B receptor and subsequently inducing the production of cAMP. In fact, both 8-Br-cAMP (IC50 85 μM) and forskolin (IC50 7 μM) inhibit macrophage proliferation. Moreover, the inhibition of adenylyl cyclase and protein kinase A blocks the inhibitory effect of adenosine and its analogues on macrophage proliferation. Adenosine causes an arrest of macrophages at the G1 phase of the cell cycle without altering the activation of the extracellular-regulated protein kinase pathway. The treatment of macrophages with adenosine induces the expression of p27kip-1, a G1 cyclin-dependent kinase inhibitor, in a protein kinase A-dependent way. Moreover, the involvement of p27kip-1 in the adenosine inhibition of macrophage proliferation was confirmed using macrophages from mice with a disrupted p27kip-1 gene. These results demonstrate that adenosine inhibits macrophage proliferation through a mechanism that involves binding to A2B adenosine receptor, the generation of cAMP, and the induction of p27kip-1 expression.

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Bontemps, F., M. F. Vincent, and G. Van den Berghe. "Mechanisms of elevation of adenosine levels in anoxic hepatocytes." Biochemical Journal 290, no. 3 (March 15, 1993): 671–77. http://dx.doi.org/10.1042/bj2900671.

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Previous work has shown that normoxic isolated rat hepatocytes continuously produce adenosine from AMP and that the nucleoside is not catabolized further but immediately rephosphorylated by adenosine kinase [Bontemps, Van den Berghe and Hers (1983) Proc. Natl. Acad. Sci. U.S.A. 80, 2829-2833]. We now report the effect of anoxia on adenosine production and on the AMP/adenosine substrate cycle. In cell suspensions incubated in O2/CO2, the adenosine concentration was about 0.4 microM. It increased 30-fold in cells incubated in N2/CO2 or with 5 mM KCN, and 20-fold in cells incubated with 2 mM amytal. Adenosine production, measured in hepatocytes in which adenosine kinase and adenosine deaminase were inhibited by 5-iodotubercidin and deoxycoformycin respectively, was about 18 nmol/min per g of cells in normoxia; it increased about 2-fold in anoxia, although AMP increased 8-16-fold in this condition. From studies with inhibitors of membrane 5′-nucleotidase and of S-adenosylhomocysteine hydrolase, it was deduced that adenosine is produced by the latter enzyme and by cytosolic 5′-nucleotidase in normoxia, and by cytosolic and membrane 5′-nucleotidases in anoxia. Unlike in normoxic hepatocytes, inhibition of adenosine kinase by 5-iodotubercidin neither elevated the adenosine concentration nor enhanced total purine release from adenine nucleotides in cells treated with N2/CO2 or KCN; it had only a slight effect in cells treated with amytal. This indicates that recycling of adenosine is suppressed or profoundly inhibited in anoxia. The rate of accumulation of adenosine in anoxia was several-fold lower than the rate of its rephosphorylation upon reoxygenation. It is concluded that the elevation of adenosine in anoxic hepatocytes is much more dependent on decreased recycling of adenosine by adenosine kinase than on increased production by dephosphorylation of AMP.

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Bontemps, F., M. Mimouni, and G. Van den Berghe. "Phosphorylation of adenosine in anoxic hepatocytes by an exchange reaction catalysed by adenosine kinase." Biochemical Journal 290, no. 3 (March 15, 1993): 679–84. http://dx.doi.org/10.1042/bj2900679.

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The elevation of adenosine levels induced by anoxia in isolated rat hepatocytes has been shown to result mainly from an arrest of the recycling of the nucleoside by adenosine kinase [Bontemps, Vincent and Van den Berghe (1993) Biochem. J. 290, 671-677]. To assess the activity of the latter enzyme in intact hepatocytes, incorporation of radioactive adenosine into the cells' adenine nucleotides was measured. Unexpectedly, despite the near-absence of ATP in anoxic cells, 40% of 50 microM [8-14C]adenosine was still incorporated into adenylates over 5 min. Moreover, whereas unlabelled and labelled adenosine were utilized in parallel in normoxic cells, uptake of [8-14C]adenosine did not correspond to a net disappearance of adenosine in anoxic cells. Addition of 1 mM unlabelled adenosine to anoxic hepatocytes in which the adenine nucleotides had been prelabelled with [U-14C]adenine induced an immediate loss of their radioactivity. The latter was recovered in the form of adenosine, but the size of the adenylate pool was not modified. Taken together, these results suggest the occurrence of an exchange reaction between AMP and adenosine. Incubation of Sephadex G-25-filtered high-speed supernatants of rat liver with 20 microM [8-14C]adenosine, 10 mM MgCl2 and 1 mM AMP resulted in the labelling of AMP in the total absence of ATP. This labelling was influenced by effectors of both adenosine kinase and cytosolic IMP-GMP 5′-nucleotidase; the latter is known to catalyse an exchange reaction [Worku and Newby (1982) Biochem. J. 205, 503-510]. Chromatography of cytosolic fractions of rat liver on DEAE-Sepharose, followed by Sephacryl S-200 and AMP-Sepharose, demonstrated that the exchange reaction between adenosine and AMP co-purified with adenosine kinase. It is concluded that incorporation of labelled adenosine into adenine nucleotides should not be considered to be proof of adenosine kinase activity in anoxia.

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Jaswal, Jagdip S., Manoj Gandhi, Barry A. Finegan, Jason R. B. Dyck, and Alexander S. Clanachan. "p38 mitogen-activated protein kinase mediates adenosine-induced alterations in myocardial glucose utilization via 5′-AMP-activated protein kinase." American Journal of Physiology-Heart and Circulatory Physiology 292, no. 4 (April 2007): H1978—H1985. http://dx.doi.org/10.1152/ajpheart.01121.2006.

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Adenosine-induced acceleration of glycolysis in hearts stressed by transient ischemia is accompanied by suppression of glycogen synthesis and by increases in activity of adenosine 5′-monophosphate-activated protein kinase (AMPK). Because p38 mitogen-activated protein kinase (MAPK) may regulate glucose metabolism and may be activated downstream of AMPK, this study determined the effects of the p38 MAPK inhibitors SB202190 and SB203580 on adenosine-induced alterations in glucose utilization and AMPK activity. Studies were performed in working rat hearts perfused aerobically following stressing by transient ischemia (2 × 10-min ischemia followed by 5-min reperfusion). Phosphorylation of AMPK and p38 MAPK each were increased fourfold by adenosine, and these effects were inhibited by either SB202190 or SB203580. Neither of these inhibitors directly affected AMPK activity. Attenuation of the adenosine-induced increase in AMPK and p38 MAPK phosphorylation by SB202190 and SB203580 occurred independently of any change in tissue ATP-to-AMP ratio and did not alter glucose uptake, but it was accompanied by an increase in glycogen synthesis and glycogen content and by inhibition of glycolysis and proton production. There was a significant inverse correlation between the rate of glycogen synthesis and AMPK activity and between AMPK activity and glycogen content. These data demonstrate that AMPK is likely downstream of p38 MAPK in mediating the effects of adenosine on glucose utilization in hearts stressed by transient ischemia. The ability of p38 MAPK inhibitors to relieve the inhibition of glycogen synthesis and to inhibit glycolysis and proton production suggests that these agents may restore adenosine-induced cardioprotection in stressed hearts.

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43

Kam, Antony, Valentina Razmovski-Naumovski, Xian Zhou, John Troung, and Kelvin Chan. "Nucleoside Transport Inhibition by Dipyridamole Prevents Angiogenesis Impairment by Homocysteine and Adenosine." Journal of Pharmacy & Pharmaceutical Sciences 18, no. 5 (December 8, 2015): 871. http://dx.doi.org/10.18433/j3tg88.

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Purpose: Adenosine plays an important role in the pathogenesis of homocysteine-associated vascular complications. Methods: This study examined the effects of dipyridamole, an inhibitor for nucleoside transport, on impaired angiogenic processes caused by homocysteine and adenosine in human cardiovascular endothelial cell line (EAhy926). Results: The results showed that dipyridamole restored the extracellular adenosine and intracellular S-adenosylhomocysteine concentrations disrupted by the combination of homocysteine and adenosine. Dipyridamole also ameliorated the impaired proliferation, migration and formation of capillary-like tubes of EAhy926 cells caused by the combination of homocysteine and adenosine. Mechanism analysis revealed that dipyridamole induced the phosphorylation of mitogen-activated protein kinase kinase (MEK) and extracellular signal-regulated kinases (ERK) and its effect on cell growth was attenuated by the MEK inhibitor, U0126. Conclusion: Dipyridamole protected against impaired angiogenesis caused by homocysteine and adenosine, at least in part, by activating the MEK/ERK signalling pathway, and this could be associated with its effects in suppressing intracellular S-adenosylhomocysteine accumulation.Novelty of the Work: This is the first paper showing that nucleoside transport inhibition by dipyridamole reduced impaired angiogenic process caused by homocysteine and adenosine.This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

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Weisberg, Ellen, Hwan Geun Choi, Arghya Ray, Rosemary Barrett, Jianming Zhang, Taebo Sim, Wenjun Zhou, et al. "Discovery of a small-molecule type II inhibitor of wild-type and gatekeeper mutants of BCR-ABL, PDGFRα, Kit, and Src kinases: novel type II inhibitor of gatekeeper mutants." Blood 115, no. 21 (May 27, 2010): 4206–16. http://dx.doi.org/10.1182/blood-2009-11-251751.

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Abstract Many clinically validated kinases, such as BCR-ABL, c-Kit, PDGFR, and EGFR, become resistant to adenosine triphosphate-competitive inhibitors through mutation of the so-called gatekeeper amino acid from a threonine to a large hydrophobic amino acid, such as an isoleucine or methionine. We have developed a new class of adenosine triphosphate competitive inhibitors, exemplified by HG-7-85-01, which is capable of inhibiting T315I- BCR-ABL (clinically observed in chronic myeloid leukemia), T670I-c-Kit (clinically observed in gastrointestinal stromal tumors), and T674I/M-PDGFRα (clinically observed in hypereosinophilic syndrome). HG-7-85-01 is unique among all currently reported kinase inhibitors in having the ability to accommodate either a gatekeeper threonine, present in the wild-type forms of these kinases, or a large hydrophobic amino acid without becoming a promiscuous kinase inhibitor. The distinctive ability of HG-7-85-01 to simultaneously inhibit both wild-type and mutant forms of several kinases of clinical relevance is an important step in the development of the next generation of tyrosine kinase inhibitors.

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Kim, Jaeyoon, Jae Young Shin, Yun-Ho Choi, So Young Lee, Mu Hyun Jin, Chang Deok Kim, Nae-Gyu Kang, and Sanghwa Lee. "Adenosine and Cordycepin Accelerate Tissue Remodeling Process through Adenosine Receptor Mediated Wnt/β-Catenin Pathway Stimulation by Regulating GSK3b Activity." International Journal of Molecular Sciences 22, no. 11 (May 25, 2021): 5571. http://dx.doi.org/10.3390/ijms22115571.

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Adenosine is a cellular metabolite with diverse derivatives that possesses a wide range of physiological roles. We investigated the molecular mechanisms of adenosine and cordycepin for their promoting effects in wound-healing process. The mitochondrial energy metabolism and cell proliferation markers, cAMP responsive element binding protein 1 (CREB1) and Ki67, were enhanced by adenosine and cordycepin in cultured dermal fibroblasts. Adenosine and cordycepin stimulated adenosine receptor signaling via elevated cAMP. The phosphorylation of mitogen-activated protein kinase kinase (MEK) 1/2, mammalian target of rapamycin (mTOR) and glycogen synthase kinase 3 beta (Gsk3b) and Wnt target genes such as bone morphogenetic protein (BMP) 2/4 and lymphoid enhancer binding factor (Lef) 1 were activated. The enhanced gene expression by adenosine and cordycepin was abrogated by adenosine A2A and A2B receptor inhibitors, ZM241385 and PSH603, and protein kinase A (PKA) inhibitor H89, indicating the involvement of adenosine receptor A2A, A2B and PKA. As a result of Wnt/β-catenin pathway activation, the secretion of growth factors such as insulin-like growth factor (IGF)-1 and transforming growth factor beta (TGFβ) 3 was increased, previously reported to facilitate the wound healing process. In addition, in vitro fibroblast migration was also increased, demonstrating their possible roles in facilitating the wound healing process. In conclusion, our data strongly demonstrate that adenosine and cordycepin stimulate the Wnt/β-catenin signaling through the activation of adenosine receptor, possibly promoting the tissue remodeling process and suggest their therapeutic potential for treating skin wounds.

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Feliu, Catherine, Hélène Peyret, Gael Poitevin, Yoann Cazaubon, Floriane Oszust, Philippe Nguyen, Hervé Millart, and Zoubir Djerada. "Complementary Role of P2 and Adenosine Receptors in ATP Induced-Anti-Apoptotic Effects Against Hypoxic Injury of HUVECs." International Journal of Molecular Sciences 20, no. 6 (March 22, 2019): 1446. http://dx.doi.org/10.3390/ijms20061446.

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Background: Vascular endothelial injury during ischemia generates apoptotic cell death and precedes apoptosis of underlying tissues. We aimed at studying the role of extracellular adenosine triphosphate (ATP) on endothelial cells protection against hypoxia injury. Methods: In a hypoxic model on endothelial cells, we quantified the extracellular concentration of ATP and adenosine. The expression of mRNA (ectonucleotidases, adenosine, and P2 receptors) was measured. Apoptosis was evaluated by the expression of cleaved caspase 3. The involvement of P2 and adenosine receptors and signaling pathways was investigated using selective inhibitors. Results: Hypoxic stress induced a significant increase in extracellular ATP and adenosine. After a 2-h hypoxic injury, an increase of cleaved caspase 3 was observed. ATP anti-apoptotic effect was prevented by suramin, pyridoxalphosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS), and CGS15943, as well as by selective A2A, A2B, and A3 receptor antagonists. P2 receptor-mediated anti-apoptotic effect of ATP involved phosphoinositide 3-kinase (PI3K), extracellular signal-regulated kinases (ERK1/2), mitoKATP, and nitric oxide synthase (NOS) pathways whereas adenosine receptor-mediated anti-apoptotic effect involved ERK1/2, protein kinase A (PKA), and NOS. Conclusions: These results suggest a complementary role of P2 and adenosine receptors in ATP-induced protective effects against hypoxia injury of endothelial. This could be considered therapeutic targets to limit the development of ischemic injury of organs such as heart, brain, and kidney.

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Newsholme, E. A., and M. N. Fisher. "Adenosine kinase and the control of adenosine concentration in the heart." Biochemical Journal 226, no. 1 (February 15, 1985): 344. http://dx.doi.org/10.1042/bj2260344.

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Carson, Dennis A., E. Olayi Kajander, Masaru Kubota, and Eric H. Willis. "MECHANISM OF ADENOSINE TOXICITY TO ADENOSINE KINASE DEFICIENT MAMMALIAN CELLS: 30." Pediatric Research 19, no. 7 (July 1985): 748. http://dx.doi.org/10.1203/00006450-198507000-00050.

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Cowart, Marlon, Michael J. Bennett, and James F. Kerwin. "Synthesis of Novel Carbocyclic Adenosine Analogues as Inhibitors of Adenosine Kinase." Journal of Organic Chemistry 64, no. 7 (April 1999): 2240–49. http://dx.doi.org/10.1021/jo981658m.

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Golembiowska, Krystyna, Thomas D. White, and Jana Sawynok. "Adenosine kinase inhibitors augment release of adenosine from spinal cord slices." European Journal of Pharmacology 307, no. 2 (June 1996): 157–62. http://dx.doi.org/10.1016/0014-2999(96)00248-8.

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Journal articles on the topic 'Adenosine kinase'

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