Shi Yunlong, Carroll Kate S
Department of Chemistry, Scripps Research, Jupiter, FL 33458, USA.
Department of Chemistry, Scripps Research, Jupiter, FL 33458, USA.
Redox Biol. 2021 Oct;46:102072. doi: 10.1016/j.redox.2021.102072. Epub 2021 Jul 16.
Cysteine sulfenic acids (Cys-SOH) are pivotal modifications in thiol-based redox signaling and central intermediates en route to disulfide and sulfinic acid states. A core mission in our lab is to develop bioorthogonal chemical tools with the potential to answer mechanistic questions involving cysteine oxidation. Our group, among others, has contributed to the development of nucleophilic chemical probes for detecting sulfenic acids in living cells. Recently, another class of Cys-SOH probes based on strained alkene and alkyne electrophiles has emerged. However, the use of different models of sulfenic acid and methodologies, has confounded clear comparison of these probes with respect to chemical reactivity, kinetics, and selectivity. Here, we perform a parallel evaluation of nucleophilic and electrophilic chemical probes for Cys-SOH. Among the key findings, we demonstrate that a probe for Cys-SOH based on the norbornene scaffold does not react with any of the validated sulfenic acid models in this study. Furthermore, we show that purported cross-reactivity of dimedone-like probes with electrophiles, like aldehydes and cyclic sulfenamides, is a not meaningful in a biological setting. In summary, nucleophilic probes remain the most viable tools for bioorthogonal detection of Cys-SOH.
半胱氨酸亚磺酸（Cys-SOH）是基于硫醇的氧化还原信号传导中的关键修饰，也是通往二硫键和亚磺酸状态的核心中间体。我们实验室的一项核心任务是开发具有回答涉及半胱氨酸氧化的机制问题潜力的生物正交化学工具。我们小组以及其他团队为开发用于检测活细胞中亚磺酸的亲核化学探针做出了贡献。最近，另一类基于张力烯烃和炔烃亲电试剂的Cys-SOH探针出现了。然而，由于使用了不同的亚磺酸模型和方法，这些探针在化学反应性、动力学和选择性方面的清晰比较变得复杂。在这里，我们对用于Cys-SOH的亲核和亲电化学探针进行了平行评估。在主要发现中，我们证明基于降冰片烯支架的Cys-SOH探针在本研究中不与任何经过验证的亚磺酸模型反应。此外，我们表明，二甲苯酮样探针与醛和环状亚磺酰胺等亲电试剂的所谓交叉反应性在生物学环境中并无意义。总之，亲核探针仍然是用于生物正交检测Cys-SOH的最可行工具。
