The Heart Research Institute , Newtown , New South Wales 2042 , Australia.
Sydney Medical School , University of Sydney , Sydney , New South Wales 2006 , Australia.
Chem Res Toxicol. 2019 Mar 18;32(3):513-525. doi: 10.1021/acs.chemrestox.8b00363. Epub 2019 Feb 15.
Hypochlorous acid (HOCl) is a highly reactive, toxic species generated by neutrophils via the action of myeloperoxidase in order to destroy invading pathogens. However, when HOCl is produced inappropriately, it can damage host tissue and proteins and plays a role in the initiation and progression of disease. Carnosine, a peptide of β-alanine and histidine, has been shown to react rapidly with HOCl yielding monochloramines and can undergo intramolecular transchlorination. The current study examines the kinetics and pH dependence of the reactions of carnosine and novel structural derivatives with HOCl and the occurrence of intra- and intermolecular transchlorination processes. We demonstrate that the transchlorination reactions of carnosine are pH dependent, with intramolecular transfer favored at higher pH. Carcinine, having a structure identical to carnosine though lacking the carboxylic acid group of the histidine residue, reacts with HOCl and forms monochloramines though intramolecular transfer reactions are not observed, and this is supported by computational modeling. Novel analogues with one (carnosine+1) and two (carnosine+2) methylene groups in the alkyl chain of the β-alanine react with HOCl to yield monochloramines that undergo transchlorinations to yield a mixture of mono- and dichloramines. The latter are stable over 24 h. The ability of carnosine and derivatives to react rapidly with HOCl to give long-lived, poorly reactive, species may prevent damage to proteins and other targets at sites of inflammation.
次氯酸（HOCl）是一种高度反应性、有毒的物质，由中性粒细胞通过髓过氧化物酶的作用产生，以破坏入侵的病原体。然而，当 HOCl 不适当地产生时，它会损害宿主组织和蛋白质，并在疾病的发生和发展中发挥作用。肌肽，一种β-丙氨酸和组氨酸的肽，已被证明可以与 HOCl 迅速反应生成单氯胺，并可以进行分子内转氯反应。本研究考察了肌肽和新型结构衍生物与 HOCl 的反应动力学和 pH 依赖性，以及分子内和分子间转氯过程的发生。我们证明了肌肽的转氯反应是 pH 依赖性的，在较高的 pH 值下有利于分子内转移。卡诺精，其结构与肌肽相同，但缺乏组氨酸残基的羧酸基团，与 HOCl 反应形成单氯胺，但没有观察到分子内转移反应，这得到了计算建模的支持。在β-丙氨酸的烷基链中具有一个（肌肽+1）和两个（肌肽+2）亚甲基的新型类似物与 HOCl 反应生成单氯胺，这些单氯胺发生转氯反应生成一氯胺和二氯胺的混合物。后者在 24 小时内稳定。肌肽及其衍生物与 HOCl 迅速反应生成长寿命、低反应性物质的能力可能会防止在炎症部位对蛋白质和其他靶标造成损害。
