Natural mutations of humanXDHpromote the nitrite (NO2-)-reductase capacity of xanthine oxidoreductase: a novel mechanism to promote redox health?

Abstract

AbstractSeveral rare genetic variations of humanXDHhave been shown to alter xanthine oxidoreductase (XOR) activity leading to impaired purine catabolism. However, XOR is a multi-functional enzyme that depending upon the environmental conditions also expresses oxidase activity leading to both O·-and H O and nitrite (·NO-) reductase activity leading to NO. Since these products express important, and often diametrically opposite, biological activity consideration of the impact of XOR mutations in the context of each aspect of the biochemical activity of the enzyme is needed to determine the potential full impact of these variants. Herein, we show that known naturally occurringhXDHmutations do not have a uniform impact upon the biochemical activity of the enzyme in terms of uric acid (UA), reactive oxygen species (ROS) and nitric oxide (·NO) formation. We show that the His1221Arg mutant, in the presence of xanthine, increases UA, O2·-and NO generation compared to the WT, whilst the Ile703Val increases UA and ·NO formation, but not O2·-. We speculate that this change in the balance of activity of the enzyme is likely to endow those carrying these mutations with a harmful or protective influence over health that may explain the current equipoise underlying the perceived importance ofXDHmutations. We also suggest that targeting enzyme activity to enhance the NO2--reductase profile in those carrying such mutations may provide novel therapeutic options, particularly in cardiovascular disease.HighlightsMutations of xanthine oxidoreductase modulate both its expression and activityThe His1221Arg natural mutation increases xanthine oxidoreductase activityRaised xanthine oxidoreductase activity coupled with increased availability of nitrite substrate leads to increased NO provision