Adenosine kinase: A key regulator of purinergic physiology

Abstract

Adenosine (ADO) is an essential biomolecule for life that provides critical regulation of energy utilization and homeostasis. Adenosine kinase (ADK) is an evolutionary ancient ribokinase derived from bacterial sugar kinases that is widely expressed in all forms of life, tissues and organ systems that tightly regulates intracellular and extracellular ADO concentrations. The facile ability of ADK to alter ADO availability provides a "site and event" specificity to the endogenous protective effects of ADO in situations of cellular stress. In addition to modulating the ability of ADO to activate its cognate receptors (P1 receptors), nuclear ADK isoform activity has been linked to epigenetic mechanisms based on transmethylation pathways. Previous drug discovery research has targeted ADK inhibition as a therapeutic approach to manage epilepsy, pain, and inflammation. These efforts generated multiple classes of highly potent and selective inhibitors. However, clinical development of early ADK inhibitors was stopped due to apparent mechanistic toxicity and the lack of suitable translational markers. New insights regarding the potential role of the nuclear ADK isoform (ADK-Long) in the epigenetic modulation of maladaptive DNA methylation offers the possibility of identifying novel ADK-isoform selective inhibitors and new interventional strategies that are independent of ADO receptor activation.

Keywords: Adenosine; Adenosine Kinase; Analgesia; Inflammation; Motor activity; Seizures.

Figure 1:. Biochemical pathways controlled by ADK

Simplified scheme showing compartmentalization of the ADO system and major pathways controlled by ADK (for a comprehensive description of ADO metabolizing pathways, please see [7]). The main route for the extracellular production of ADO is degradation of ATP through a system of ectonucleotidases, with CD39 and CD73 shown here. Extra- and intracellular levels of ADO are equilibrated through equilibrative nucleoside transporters (ENT). Therefore, intracellular ADO metabolism through ADK can control adenosine receptor (AR) activation. In the intracellular compartment the ADO-ADK system is linked to S-adenosylmethionine (SAM) dependent methyltransferase (MT) reactions, which yield S-adenosylhomocysteine (SAH), which is a substrate for S-adenosylhomocysteine hydrolase (SAHH). By removing adenosine ADK-S in the cytoplasm and ADK-L in the nucleus drives the flux of methyl groups through the transmethylation pathway. In the intranuclear compartment ADK-L activity is needed to maintain DNA methyltransferase (DNMT) activity and DNA methylation.

Figure 2:. Chemical structures of adenosine and potent nucleoside and non-nucleoside adenosine kinase inhibitors.

Early ADK inhibitors include NH2-dADO, 5-IT and 5’d-5IT [48]. Detailed structure-activity studies based on these molecules and optimization of novel chemotypes identified from high-throughput screening campaigns have led to the generation of the diverse array of ADK inhibitors shown here [–55].