Okamoto Ken, Eger Bryan T, Nishino Tomoko, Pai Emil F, Nishino Takeshi
Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, Japan.
Nucleosides Nucleotides Nucleic Acids. 2008 Jun;27(6):888-93. doi: 10.1080/15257770802146577.
Inhibitors of xanthine oxidoreductase block conversion of xanthine to uric acid and are therefore potentially useful for treatment of hyperuricemia or gout. We determined the crystal structure of reduced bovine milk xanthine oxidoreductase complexed with oxipurinol at 2.0 A resolution. Clear electron density was observed between the N2 nitrogen of oxipurinol and the molybdenum atom of the molybdopterin cofactor, indicating that oxipurinol coordinated directly to molybdenum. Oxipurinol forms hydrogen bonds with glutamate 802, arginine 880, and glutamate 1261, which have previously been shown to be essential for the enzyme reaction. We discuss possible differences in the hypouricemic effect of inhibitors, including allopurinol and newly developed inhibitors, based on their mode of binding in the crystal structures.
黄嘌呤氧化还原酶抑制剂可阻断黄嘌呤向尿酸的转化，因此可能对治疗高尿酸血症或痛风有用。我们测定了还原型牛乳黄嘌呤氧化还原酶与奥昔嘌醇复合物的晶体结构，分辨率为2.0埃。在奥昔嘌醇的N2氮原子与钼蝶呤辅因子的钼原子之间观察到清晰的电子密度，表明奥昔嘌醇直接与钼配位。奥昔嘌醇与谷氨酸802、精氨酸880和谷氨酸1261形成氢键，这些氨基酸先前已被证明对酶反应至关重要。我们根据抑制剂在晶体结构中的结合模式，讨论了包括别嘌醇和新开发的抑制剂在内的抑制剂降尿酸作用可能存在的差异。
