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Review
. 2013 Apr 16;65(3):906-43.
doi: 10.1124/pr.112.006361. Print 2013 Jul.

Adenosine kinase: exploitation for therapeutic gain

Detlev Boison  1
Affiliations
Review

Adenosine kinase: exploitation for therapeutic gain

Detlev Boison. Pharmacol Rev. .

Abstract

Adenosine kinase (ADK; EC 2.7.1.20) is an evolutionarily conserved phosphotransferase that converts the purine ribonucleoside adenosine into 5'-adenosine-monophosphate. This enzymatic reaction plays a fundamental role in determining the tone of adenosine, which fulfills essential functions as a homeostatic and metabolic regulator in all living systems. Adenosine not only activates specific signaling pathways by activation of four types of adenosine receptors but it is also a primordial metabolite and regulator of biochemical enzyme reactions that couple to bioenergetic and epigenetic functions. By regulating adenosine, ADK can thus be identified as an upstream regulator of complex homeostatic and metabolic networks. Not surprisingly, ADK dysfunction is involved in several pathologies, including diabetes, epilepsy, and cancer. Consequently, ADK emerges as a rational therapeutic target, and adenosine-regulating drugs have been tested extensively. In recent attempts to improve specificity of treatment, localized therapies have been developed to augment adenosine signaling at sites of injury or pathology; those approaches include transplantation of stem cells with deletions of ADK or the use of gene therapy vectors to downregulate ADK expression. More recently, the first human mutations in ADK have been described, and novel findings suggest an unexpected role of ADK in a wider range of pathologies. ADK-regulating strategies thus represent innovative therapeutic opportunities to reconstruct network homeostasis in a multitude of conditions. This review will provide a comprehensive overview of the genetics, biochemistry, and pharmacology of ADK and will then focus on pathologies and therapeutic interventions. Challenges to translate ADK-based therapies into clinical use will be discussed critically.

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Figures

Fig. 1.
Fig. 1.
Adenosine acts as a homeostatic network regulator via multiple adenosine receptor-dependent and -independent pathways.
Fig. 2.
Fig. 2.
Transmethylation pathway. Adenosine is an obligatory end product of transmethylation reactions, including those catalyzed by DNA methyltransferases. If adenosine is not constantly removed by adenosine kinase, increased levels of adenosine drive the S-adenosylhomocysteine hydrolase reaction toward . SAH synthesis. SAH is a potent inhibitor of methyltransferases, which use SAM as methyl group (−CH3) donor.
Fig. 3.
Fig. 3.
Chemical structures of ADK’s endogenous substrate adenosine and of selected nucleoside and nonnucleoside ADK inhibitors. Numbers in black refer to the IC50 of the inhibitor in nanomolars for rat cytosolic ADK. For details and references, please refer to main text.
Fig. 4.
Fig. 4.
Genetic disruption of ADK leads to hepatic steatosis. Wild-type mouse (left) and Adk−/− mouse (right) prepared at postnatal day 7. Note the reduced body size of the mutant and the yellow discoloration of the liver. Scale bar: 1 cm.
Fig. 5.
Fig. 5.
ADK expression changes during early postnatal brain development of the mouse. Top, first row: ADK immunohistochemistry (brown) shows strong ADK labeling in cell bodies of CA1 pyramidal cells at P4 and P8 but not at P14. Arrow pairs denote outer and inner boundaries of stratum pyramidale. Top, second row: Confocal imaging of immunofluorescence for ADK (red) and the neuronal marker NeuN (green) shows colocalization of ADK and NeuN in CA1 pyramidal cell bodies at P4 and P8 (yellow). Black scale bar: 75 µm; white scale bar: 12 µm. Bottom: Corresponding immunohistochemical characterization of the CA3 area, which loses neuronal ADK expression earlier than CA1.
Fig. 6.
Fig. 6.
Astrocytes constitute a sink for the metabolic clearance of adenosine in the brain. Whereas neurons are capable of releasing adenosine directly, astrocytes can release ATP via vesicular release and/or by direct release through hemichannels (h-ch). Extracellular ATP is rapidly degraded into adenosine (ADO) by a series of ectonucleotidases. Adenosine can also be released directly via equilibrative nucleoside transporters (nt). Intracellular adenosine levels are largely controlled by adenosine kinase, which phosphorylates adenosine into AMP. Small changes in adenosine kinase activity rapidly translate into major changes in adenosine. Intracellular astrocytic adenosine kinase is considered to be a metabolic reuptake system for adenosine. Only selected mechanisms and pathways are shown; for details please refer to main text.
Fig. 7.
Fig. 7.
Astrogliosis and overexpression of ADK in a mouse model of temporal lobe epilepsy. (A and B) Brains from kainic acid (KA)-treated mice were taken at 4 weeks after either intrahippocampal KA or saline injection. Transverse brain sections of the KA-injected brain hemisphere were stained for ADK-immunoreactivity. Note prominent overexpression of astrogliosis in association with spontaneous seizures activity in B. (C and D) Colocalization of ADK and GFAP immunofluorescence, as seen by confocal laser scanning microscopy. Transverse brain sections of a KA-injected animal taken 4 weeks after the injection and those from a naive control animal were double stained for ADK (red) and the astrocyte marker GFAP (green). Optical sections were digitized at high magnification and superimposed for display. (C) Dentate gyrus of a control animal. Note that the cell bodies of individual astrocytes (green processes) are stained for ADK (red). (D) Dentate gyrus of a KA-injected animal. Note the massive gliosis characterized by the swelling of cell bodies, the enlargement of astrocytic processes, and the expansion of ADK-immunoreactivity into the processes (colocalization of ADK and GFAP, yellow). sp, Stratum pyramidale; sml, stratum moleculare; sg, stratum granulosum.
Fig. 8.
Fig. 8.
Downregulation of ADK in a mouse model of cerebral stroke. Brains from mice were taken 3 hours after 60 minutes of middle cerebral artery occlusion (right) or a sham surgery and stained for ADK immunoreactivity. Images show part of the striatum ipsilateral to the stroke.
Fig. 9.
Fig. 9.
Emerging new roles of adenosine kinase. Summary of key findings; for details please refer to main text.
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