Sekine Mai, Okamoto Ken, Ichida Kimiyoshi
Department of Pathophysiology, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
Biomedicines. 2021 Nov 20;9(11):1723. doi: 10.3390/biomedicines9111723.
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.
黄嘌呤氧化还原酶（XOR）是一种在嘌呤代谢中催化从次黄嘌呤到黄嘌呤以及从黄嘌呤到尿酸的两步反应的酶。XOR通常具有脱氢酶活性（XDH），但在各种病理生理条件下会转化为氧化酶（XO）。通过对哺乳动物XOR的诱变研究和XOR-抑制剂相互作用的结构分析，对XOR的复杂结构和酶功能进行了充分研究。目前有三种XOR抑制剂用作高尿酸血症和痛风的治疗药物，但预计它们除了降低尿酸外还具有其他潜在作用，例如抑制XO产生的活性氧。孤立的XOR缺乏症，即I型黄嘌呤尿症，是XOR抑制剂代谢作用的良好模型。其特征为低尿酸血症、尿酸排泄明显减少、血清和尿中黄嘌呤浓度升高，且无临床显著症状。黄嘌呤尿症的发病机制以及突变与XOR活性之间的关系，对于阐明XOR的生物学作用和XOR反应过程的细节很有用。在这篇综述中，我们旨在通过将黄嘌呤尿症中的突变与结构研究联系起来，为XOR的基础科学和临床方面做出贡献，以便了解XOR在体内的功能和反应机制。
