Abstract
Adenosine deaminase (ADA) is an enzyme of purine metabolism that irreversibly converts adenosine to inosine or 2′deoxyadenosine to 2′deoxyinosine. ADA is active both inside the cell and on the cell surface where it was found to interact with membrane proteins, such as CD26 and adenosine receptors, forming ecto-ADA (eADA). In addition to adenosine uptake, the activity of eADA is an essential mechanism that terminates adenosine signaling. This is particularly important in cardiovascular system, where adenosine protects against endothelial dysfunction, vascular inflammation, or thrombosis. Besides enzymatic function, ADA protein mediates cell-to-cell interactions involved in lymphocyte co-stimulation or endothelial activation. Furthermore, alteration in ADA activity was demonstrated in many cardiovascular pathologies such as atherosclerosis, myocardial ischemia-reperfusion injury, hypertension, thrombosis, or diabetes. Modulation of ADA activity could be an important therapeutic target. This work provides a systematic review of ADA activity and anchoring inhibitors as well as summarizes the perspectives of their therapeutic use in cardiovascular pathologies associated with increased activity of ADA.
Highlights
Adenosine deaminase (ADA, EC 3.5.4.4), known as adenosine aminohydrolase, is a key enzyme engaged in purine metabolism that irreversibly converts adenosine to inosine or 20 deoxyadenosine to 20 deoxyinosine [1]
Vascular ecto-adenosine deaminase represents a critical checkpoint in the regulation of extracellular adenosine level in the vessel wall and, in the control of receptor stimulation, playing a pivotal role in the modulation of purinergic responses that lead to atherosclerosis development
Adenosine deaminase is an essential regulator of multiple cellular processes, including DNA synthesis, adenosine receptor-mediated pathways and cell-to-cell interactions
Summary
Adenosine deaminase (ADA, EC 3.5.4.4), known as adenosine aminohydrolase, is a key enzyme engaged in purine metabolism that irreversibly converts adenosine to inosine or 20 deoxyadenosine to 20 deoxyinosine [1]. Mounting evidence indicates that extracellular adenosine levels increase dramatically to micromolar concentrations that activate low-affinity receptors in tissues submitted to stressful conditions, such as ischemia, hypoxia, and inflammation, being a key protective and anti-inflammatory mechanism [27]. There is an evidence of the formation of trimeric complexes dipeptidyl peptidase IV (CD26)-ADA-A2A R involving two cells [6] This co-stimulatory and cell-to-cell connecting actions of eADA along with its activity regulate many cellular processes related to proliferation and differentiation, which affect pathological conditions associated with cardiovascular diseases such as endothelial activation and dysfunction, inflammation, myocardial ischemia-reperfusion injury or coagulation disorders. The lower pKa value for ADA2 in comparison with the value for ADA1 (5.6) provides the evidence for the more substantial role of above mentioned amino acids in ADA2 catalyzed reaction than in the case of ADA1 [39]
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