Purine nucleoside phosphorylase: A new pharmacological target in sickle cell disease and hemolytic vasculopathy. (April 2023)

• Record Type: Journal Article
• Authors: Tofovic, Stevan P.
• Is Part Of: Medical hypotheses. Volume 173(2023)
• Publication Date: 2023-04
• Subjects: Purine nucleoside phosphorylase -- Purine metabolism -- Sickle cell disease -- Hemolytic vasculopathy; Medicine -- Periodicals; Medicine -- Periodicals; Médecine -- Périodiques; Medicine; Periodicals; 610
• DOI: 10.1016/j.mehy.2023.111045
• Languages: English
• ISSNs: 0306-9877

Abstract

Abstract: Under hemolytic conditions, there is a significant interaction among red blood cells (RBCs), endothelial cells (ECs), and platelets in the injured vasculature. In sickle cell disease (SCD), this interaction leads to painful vaso-occlusive crisis and end organ damage, results in poor quality of life, and unacceptably short life expectancy. We propose that these cells share two biochemical properties that are highly relevant to SCD. First, per cell volume, RBCs have the highest level of purine nucleoside phosphorylase (PNP, a key enzyme in purine metabolism), and ECs and platelets are very rich in PNP. Second, RBCs have to, ECs choose to, and platelets, when activated, switch to using glycolysis as a major pathway for intermediate phosphates and ATP production. We propose that these similarities are highly relevant to sickle cell disease (SCD) and hemolytic vascular injury. Human PNP catalyzes the phosphorolysis of guanosine/ deoxyguanosine and inosine /deoxyinosine into guanine and hypoxanthine, respectively, and generates ribose-1-phosphate and deoxyribose-1-phosphate. This results in forming a large amount of downstream pro-oxidant and vasculotoxic xanthines. Recently, we have detected that in SCD, hemolysis is associated with increased activity of extracellular PNP, accelerated guanosine and inosine metabolism, and augmented extracellular production of vasculotoxic hypoxanthine and xanthine. We identify PNP as a critical pathogenic mechanism in SCD and have proposed a link between PNP activity and the glycolytic production of intermediate phosphates and ATP. This link promotes (i) RBC sickling/hemolysis, (ii.) hemolytic angioproliferation, (iii.) oxidative vascular injury, and (iv.) platelets activation/aggregation. Furthermore, PNP accelerates guanosine/inosine metabolism and may diminish their well-documented anti-inflammatory, anti-ischemic, anti-thrombotic, and anti-nociceptive effects. We hypothesize that inhibition of PNP may lessen those four (i.to iv.) deleterious events and may potentiate the beneficial effects of guanosine/inosine, reducing the risk of vaso-occlusion and organ damage in SCD patients. Thereby, the PNP inhibitors may serve as a multipronged treatment approach for SCD.