Enzyme inactivation through sulfhydryl oxidation by physiologic NO-carriers
Enzyme inactivation through sulfhydryl oxidation by physiologic NO-carriers
复制标题
DOI：
10.1038/nsb0498-267
复制
发表时间：
1998-04-01
期刊：
影响因子：
--
通讯作者：
Karplus, PA
中科院分区：
文献类型：
--
作者：
Becker, K;Savvides, SN;Karplus, PA
一氧化氮(NO)是一种多功能的调节分子，但其发挥作用的分子机制在很大程度上尚不清楚。NO的生理学靶分子很少被识别，即使是这些，NO引起的修饰仍然不是很清楚。人谷胱甘肽还原酶(HGR)是细胞抗氧化防御的中心酶，被NO的两种体内转运形式S-亚硝基-谷胱甘肽(GSNO)和二还原型谷胱甘肽-二亚硝基-铁(DNIC-[GSH](2))抑制。在这里，被GSNO和DNIC-[GSH](2)在1.7埃分辨率下灭活的HGR的晶体结构提供了第一幅无载体使酶失活的图片：在GSNO修饰的HGR中，活性中心残基Cys 63被氧化成非常稳定的半胱氨酸磺酸(R-SOH)，而用DNIC-[GSH](2)修饰将Cys 63氧化成半胱氨酸磺酸(R-SO2H)。我们的结果表明，不同形式的NO可以介导不同的化学作用，必须认为巯基氧化是NO作用的主要机制。
Nitric oxide (NO) is a pluripotent regulatory molecule, yet the molecular mechanisms by which it exerts its effects are largely unknown. Few physiologic target molecules of NO have been identified, and even for these, the modifications caused by NO remain uncharacterized. Human glutathione reductase (hGR), a central enzyme of cellular antioxidant defense, is inhibited by S-nitrosoglutathione (GSNO) and by diglutathionyl-dinitroso-iron (DNIC-[GSH](2)), two in vivo transport forms of NO. Here, crystal structures of hGR inactivated by GSNO and DNIC-[GSH](2) at 1.7 Angstrom resolution provide the first picture of enzyme inactivation by NO-carriers: in GSNO-modified hGR, the active site residue Cys 63 is oxidized to an unusually stable cysteine sulfenic acid (R-SOH), whereas modification with DNIC-[GSH](2) oxidizes Cys 63 to a cysteine sulfinic acid (R-SO2H). Our results illustrate that various forms of NO can mediate distinct chemistry, and that sulfhydryl oxidation must be considered as a major mechanism of NO action.