Adenosine kinase: An epigenetic modulator in development and disease

Murugan, Madhuvika; Fedele, Denise E.; Millner, David; Alharfoush, Enmar; Vegunta, Geetasravya; Boison, Detlev

doi:10.1016/j.neuint.2021.105054

Cited by 34 publications

(19 citation statements)

References 93 publications

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“…Suppression of ADA resulted in beneficial effects in a MPTP-induced Parkinsonism mouse model [ 114 ] but toxic effects on motor neurons in an ALS model established with a cocultured system of induced pluripotent stem cell (iPSC)-derived astrocytes and motor neurons [ 7 ]. Accumulating evidence suggests that ADK is an epigenetic modulator in both normal and disordered neurodevelopment [ 181 , 206 ]. Together, these studies highlight the critical roles of adenosine metabolism in maintaining appropriate brain functions in health and diseases and suggest that adenosine metabolism enzymes may serve as potential drug targets for neurodegenerative diseases.…”

Section: Introductionmentioning

confidence: 99%

Emerging roles of dysregulated adenosine homeostasis in brain disorders with a specific focus on neurodegenerative diseases

Chang

Lin

et al. 2021

J Biomed Sci

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In modern societies, with an increase in the older population, age-related neurodegenerative diseases have progressively become greater socioeconomic burdens. To date, despite the tremendous effort devoted to understanding neurodegenerative diseases in recent decades, treatment to delay disease progression is largely ineffective and is in urgent demand. The development of new strategies targeting these pathological features is a timely topic. It is important to note that most degenerative diseases are associated with the accumulation of specific misfolded proteins, which is facilitated by several common features of neurodegenerative diseases (including poor energy homeostasis and mitochondrial dysfunction). Adenosine is a purine nucleoside and neuromodulator in the brain. It is also an essential component of energy production pathways, cellular metabolism, and gene regulation in brain cells. The levels of intracellular and extracellular adenosine are thus tightly controlled by a handful of proteins (including adenosine metabolic enzymes and transporters) to maintain proper adenosine homeostasis. Notably, disruption of adenosine homeostasis in the brain under various pathophysiological conditions has been documented. In the past two decades, adenosine receptors (particularly A1 and A2A adenosine receptors) have been actively investigated as important drug targets in major degenerative diseases. Unfortunately, except for an A2A antagonist (istradefylline) administered as an adjuvant treatment with levodopa for Parkinson’s disease, no effective drug based on adenosine receptors has been developed for neurodegenerative diseases. In this review, we summarize the emerging findings on proteins involved in the control of adenosine homeostasis in the brain and discuss the challenges and future prospects for the development of new therapeutic treatments for neurodegenerative diseases and their associated disorders based on the understanding of adenosine homeostasis.

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Section: Introductionmentioning

confidence: 99%

Emerging roles of dysregulated adenosine homeostasis in brain disorders with a specific focus on neurodegenerative diseases

Chang

Lin

et al. 2021

J Biomed Sci

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“…Since there are differences in the functioning of ADK-L and ADK-S, further studies are required on the role of each isoform in the maintenance of ATP/adenosine in cases with cancer. Currently, the main obstacle to such studies is a lack of isoform-specific inhibitors, in particular, highly selective for a nuclear isoform of ADK-L [41]. Besides, the contribution of ADK-S into DNA methylation is understudied [50].…”

Section: Discussionmentioning

confidence: 99%

“…In this reaction, adenosine is a by-product. If it is not completely deleted by ADK, it leads to the accumulation of SAH, which inhibits various transmethylation reactions necessary for a wide range of cellular processes [41]. The necessity of ADK enzyme for the organism was experimentally shown by Boison et al [42].…”

Section: Biological Significance Of Adkmentioning

confidence: 99%

“…Presently, the role of ADK in the methylation of DNA is not determined. According to the studies performed on experimental models, there is an association between the alterations in the expression of ADK and changes in DNA methylation in patients with epilepsy, brain lesion, vascular inflammation, angiogenesis, atherosclerosis, and cancer, as well as the influence of pharmacological blockade of ADK on the level of global hypermethylation [41].…”

Section: Biological Significance Of Adkmentioning

confidence: 99%

“…ADK-L participates in the reaction of SAM-dependent transmethylation, which induces DNA and histone methylation. This is contributed by the presence of ADK-L, methyltransferase, and SAH in the cellular nucleus [41]. A high level and activity of ADK-L are associated with high global methylation of DNA [50].…”

Section: Biological Significance Of Adkmentioning

confidence: 99%

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Adenosine-Metabolizing Enzymes, Adenosine Kinase and Adenosine Deaminase, in Cancer

et al. 2022

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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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N₁‐Benzoylated 5‐(4‐pyridinyl)indazole‐based kinase inhibitors: Attaining haspin and Clk4 selectivity via modulation of the benzoyl substituents

Aboelfotouh,

Abdallah,

Khalifa

et al. 2024

Archiv der Pharmazie

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Haspin and Clk4 are both understudied protein kinases (PKs), offering potential targets for the development of new anticancer agents. Thus, the identification of new inhibitors targeting these PKs is of high interest. However, the inhibitors targeting haspin or Clk4 developed to date show a poor selectivity profile over other closely related PKs, increasing the risk of side effects. Herein, we present two newly developed N1‐benzyolated 5‐(4‐pyridinyl)indazole‐based inhibitors (18 and 19), derived from a newly identified indazole hit. These inhibitors exhibit an exceptional inhibitory profile toward haspin and/or Clk4. Compound 18 (2‐acetyl benzoyl) showed a preference to inhibit Clk4 and haspin over a panel of closely related kinases, with sixfold selectivity for Clk4 (IC50 = 0.088 and 0.542 μM, respectively). Compound 19 (4‐acetyl benzoyl) showed high selectivity against haspin over the common off‐target kinases (Dyrks and Clks) with an IC50 of 0.155 μM for haspin. Molecular docking studies explained the remarkable selectivity of 18 and 19, elucidating how the new scaffold can be modified to toggle between inhibition of haspin or Clk4, despite the high homology of the ATP‐binding sites. Their distinguished profile allows these compounds to be marked as interesting chemical probes to assess the selective inhibition of haspin and/or Clk4.

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Adenosine kinase: An epigenetic modulator in development and disease

Cited by 34 publications

References 93 publications

Emerging roles of dysregulated adenosine homeostasis in brain disorders with a specific focus on neurodegenerative diseases

Emerging roles of dysregulated adenosine homeostasis in brain disorders with a specific focus on neurodegenerative diseases

Adenosine-Metabolizing Enzymes, Adenosine Kinase and Adenosine Deaminase, in Cancer

N₁‐Benzoylated 5‐(4‐pyridinyl)indazole‐based kinase inhibitors: Attaining haspin and Clk4 selectivity via modulation of the benzoyl substituents

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Adenosine kinase: An epigenetic modulator in development and disease

Cited by 34 publications

References 93 publications

Emerging roles of dysregulated adenosine homeostasis in brain disorders with a specific focus on neurodegenerative diseases

Emerging roles of dysregulated adenosine homeostasis in brain disorders with a specific focus on neurodegenerative diseases

Adenosine-Metabolizing Enzymes, Adenosine Kinase and Adenosine Deaminase, in Cancer

N1‐Benzoylated 5‐(4‐pyridinyl)indazole‐based kinase inhibitors: Attaining haspin and Clk4 selectivity via modulation of the benzoyl substituents

Contact Info

Product

Resources

About

N₁‐Benzoylated 5‐(4‐pyridinyl)indazole‐based kinase inhibitors: Attaining haspin and Clk4 selectivity via modulation of the benzoyl substituents