The study on the structure-based inhibitor mechanism for xanthine oxidoreductase: beyond a lock-key system

黄嘌呤氧化还原酶（XOR）催化次黄嘌呤氧化为黄嘌呤，然后将黄嘌呤氧化为尿酸。由于体内尿酸过多会导致一种疾病，痛风，人体XOR是治疗痛风的药物的目标。XOR存在于从细菌到人的广泛生物体中，并且哺乳动物和细菌XOR的底物结合口袋在催化重要残基和三维结构方面是非常保守的。在这项研究中，我们发现在酶的实验方面，非布司他，最近在日本开发的药物抑制哺乳动物的XOR，但不细菌的XOR。这意味着所谓的键锁系统被破坏，并且从抑制剂和酶的静态三维结构的观点难以阐明这种功能差异。然而，我们成功地再现了实验结果，使用MD计算从动力学的观点（科学。2，331; DOI：10.1038/srep00331（2012））。

Xanthine oxidoreductase (XOR) catalyzes the oxidation of hypoxanthine to xanthine followed by oxidation of xanthine to uric acid. Because having too much uric acid in the body causes a disease, gout, human XOR is a target of drugs to treat gout. XOR is found in a wide range of organisms from bacteria to man, and the substrate-binding pockets of mammalian and bacterial XOR are well-conserved as regards catalytically important residues and three-dimensional structure. In this research, we found in terms of the enzymatic experiments that febuxostat, a drug recently developed in Japan inhibits mammalian XOR, but not bacterial XOR. This means that a so-called key-lock system breaks and it is difficult to elucidate this functional differences from the view point of static three-dimensional structure of an inhibitor and an enzyme. However,we succeeded in reproducing the experimental results using MD calculations from the view point of dynamics (Sci. Rep. 2, 331; DOI:10.1038/srep00331 (2012)).