Association of Mutations Identified in Xanthinuria with the Function and Inhibition Mechanism of Xanthine Oxidoreductase

Abstract

Xanthine oxidoreductase (XOR) is an enzyme that catalyzes the two-step reaction from hypoxanthine to xanthine and from xanthine to uric acid in purine metabolism. XOR generally carries dehydrogenase activity (XDH) but is converted into an oxidase (XO) under various pathophysiologic conditions. The complex structure and enzymatic function of XOR have been well investigated by mutagenesis studies of mammalian XOR and structural analysis of XOR–inhibitor interactions. Three XOR inhibitors are currently used as hyperuricemia and gout therapeutics but are also expected to have potential effects other than uric acid reduction, such as suppressing XO–generating reactive oxygen species. Isolated XOR deficiency, xanthinuria type I, is a good model of the metabolic effects of XOR inhibitors. It is characterized by hypouricemia, markedly decreased uric acid excretion, and increased serum and urinary xanthine concentrations, with no clinically significant symptoms. The pathogenesis and relationship between mutations and XOR activity in xanthinuria are useful for elucidating the biological role of XOR and the details of the XOR reaction process. In this review, we aim to contribute to the basic science and clinical aspects of XOR by linking the mutations in xanthinuria to structural studies, in order to understand the function and reaction mechanism of XOR in vivo.

Correlation between gout and dry eye disease

“…Xanthine oxidase is an important enzyme in purine metabolism and is a form of xanthine oxidoreductase [ 49 ]. The role of xanthine oxidase in the development of gout is well established, as it plays an important role in catalyzing the oxidative hydroxylation of hypoxanthine to xanthine and further catalyzing the production of uric acid (UA) from xanthine [ 50 ].…”

Allopurinol and oxypurinol differ in their strength and mechanisms of inhibition of xanthine oxidoreductase

“…As an example of the complete inhibition of XOR, consider the metabolism in the case of XOR deficiency, in which the patient has significantly reduced serum uric acid levels and urinary uric acid excretion accompanied by increased urinary xanthine levels ( 40 ). This results in xanthinuria and xanthine stones but no other severe symptoms ( 41 , 42 , 43 ). Plasma hypoxanthine levels, on the other hand, are not significantly increased, due to salvage by HGPRT ( Fig.…”

Candidate causative variant for xanthinuria in a Domestic Shorthair cat

“…We identified two missense variants in XDH (XDH:c.2042C>T, XDH:c.3367G>A) and both are located in the highly conserved aldehyde oxidase/XDH, a/b hammerhead domain of MOCO (Sekine et al, 2021). The MOCO domain catalyses the hydroxylation of hypoxanthine to xanthine to uric acid (Okamoto et al, 2004), and functional studies have demonstrated that variants in this domain affect XDH/xanthine oxidase activity (Kudo et al, 2008; Peretz et al, 2021).…”