Strained cycloalkynes as new protein sulfenic acid traps.
Strained cycloalkynes as new protein sulfenic acid traps.
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DOI：
10.1021/ja500364r
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发表时间：
2014-04-30
影响因子：
15
通讯作者：
King, S. Bruce
中科院分区：
文献类型：
--
作者：
Poole, Thomas H.;Reisz, Julie A.;Zhao, Weiling;Poole, Leslie B.;Furdui, Cristina M.;King, S. Bruce
蛋白质亚磺酸是由与生物相关的活性氧与蛋白质硫醇反应形成的。亚硫酸的形成直接或通过随后形成的蛋白质二硫键调节酶和转录因子的功能。确定蛋白质亚磺酸形成的位点、时间和条件对于理解细胞氧化还原调控仍然至关重要。目前捕获和分析亚磺酸的方法包括使用二美酮和其他亲核的1,3-二羰基探针，它们与半胱氨酸衍生的蛋白质亚磺酸形成共价加合物。作为一种机制选择，本研究将高度应变的双环[6.1.0]壬炔（BCN）衍生物描述为亚磺酸的协同陷阱。这些张力环炔与蛋白质和小分子中的亚磺酸有效反应，生成稳定的烯基亚砜产物，速率比1,3-二羰基试剂高100倍以上，从而与生理硫化学进行动力学竞争。与1,3-二羰基试剂类似，BCN化合物将亚磺酸氧仿与巯基、二硫、亚磺酸和s -亚硝化形式的半胱氨酸区分开来，同时显示出可接受的细胞毒性谱。这些应变炔所表现出的增强速率表明它们是一种新的生物正交探针，可以促进发现以前未知的亚磺酸位点及其亲本蛋白。
Protein sulfenic acids are formed by the reaction of biologically relevant reactive oxygen species with protein thiols. Sulfenic acid formation modulates the function of enzymes and transcription factors either directly or through the subsequent formation of protein disulfide bonds. Identifying the site, timing, and conditions of protein sulfenic acid formation remains crucial to understanding cellular redox regulation. Current methods for trapping and analyzing sulfenic acids involve the use of dimedone and other nucleophilic 1,3-dicarbonyl probes that form covalent adducts with cysteine-derived protein sulfenic acids. As a mechanistic alternative, the present study describes highly strained bicyclo[6.1.0]nonyne (BCN) derivatives as concerted traps of sulfenic acids. These strained cycloalkynes react efficiently with sulfenic acids in proteins and small molecules yielding stable alkenyl sulfoxide products at rates more than 100× greater than 1,3-dicarbonyl reagents enabling kinetic competition with physiological sulfur chemistry. Similar to the 1,3-dicarbonyl reagents, the BCN compounds distinguish the sulfenic acid oxoform from the thiol, disulfide, sulfinic acid, and S-nitrosated forms of cysteine while displaying an acceptable cell toxicity profile. The enhanced rates demonstrated by these strained alkynes identify them as new bioorthogonal probes that should facilitate the discovery of previously unknown sulfenic acid sites and their parent proteins.
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影响因子：
46.2
作者：
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通讯作者：
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作者：
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通讯作者：
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影响因子：
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通讯作者：
van Delft, Floris L.