Crystal structures of the active and alloxanthine-inhibited forms of xanthine dehydrogenase from Rhodobacter capsulatus
Crystal structures of the active and alloxanthine-inhibited forms of xanthine dehydrogenase from Rhodobacter capsulatus
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DOI：
10.1016/s0969-2126(01)00697-9
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发表时间：
2002-01-01
期刊：
影响因子：
5.7
通讯作者：
Kisker, C
中科院分区：
文献类型：
--
作者：
Truglio, JJ;Theis, K;Kisker, C
黄嘌呤脱氢酶（XDH）是一种复杂的铁-硫-黄素蛋白，催化次黄嘌呤氧化为黄嘌呤，黄嘌呤氧化为尿酸，同时还原NAD（+）。荚膜红杆菌XDH的2.7埃分辨率结构揭示，尽管亚基组成不同，但细菌和牛XDH具有高度相似的折叠。细菌XDH的NAD（+）结合口袋类似于牛酶的脱氢酶形式，而不是氧化酶形式，其还原O-2而不是NAD（+）。药物别嘌呤醇用于治疗痛风或癌症化疗期间发生的XDH催化尿酸积聚。作为次黄嘌呤类似物，它被氧化为别黄嘌呤，别黄嘌呤不能被进一步氧化，但作为XDH的紧密结合抑制剂。XDH-别黄嘌呤络合物的3.0埃分辨率结构显示别黄嘌呤通过氮原子与钼直接配位。这些结果为合理设计新的XDH抑制剂提供了起点。
Xanthine dehydrogenase (XDH), a complex molybdo/iron-sulfur/flavoprotein, catalyzes the oxidation of hypoxanthine to xanthine followed by oxidation of xanthine to uric acid with concomitant reduction of NAD(+). The 2.7 Angstrom resolution structure of Rhodobacter capsulatus XDH reveals that the bacterial and bovine XDH have highly similar folds despite differences in subunit composition. The NAD(+) binding pocket of the bacterial XDH resembles that of the dehydrogenase form of the bovine enzyme rather than that of the oxidase form, which reduces O-2 instead of NAD(+). The drug allopurinol is used to treat XDH-catalyzed uric acid build-up occurring in gout or during cancer chemotherapy. As a hypoxanthine analog, it is oxidized to alloxanthine, which cannot be further oxidized but acts as a tight binding inhibitor of XDH. The 3.0 Angstrom resolution structure of the XDH-alloxanthine complex shows direct coordination of alloxanthine to the molybdenum via a nitrogen atom. These results provide a starting point for the rational design of new XDH inhibitors.