Immunoglobulin light chain amyloidosis (AL) is a plasma cell disorder characterized by overproduction and deposition of monoclonal immunoglobulin (Ig) light chains (LC) or variable region fragments as amyloid fibrils in various organs and tissues. Much clinical evidence indicates that patients with AL amyloidosis sustain cardiomyocyte impairment and suffer from oxidative stress. We seek to understand the underlying biochemical pathways whose disruption or amplification during sporadic or sustained disease states leads to harmful physiological consequences and to determine the detailed structures of intermediates and products that serve as signposts for the biochemical changes and represent potential biomarkers. In this study, matrix-assisted laser desorption/ionization mass spectrometry provided extensive evidence for oxidative post-translational modifications (PTMs) of an amyloidogenic Ig LC protein from a patient with AL amyloidosis. Some of the tyrosine residues were heavily mono- or di-chlorinated. In addition, a novel oxidative conversion to a nitrile moiety was observed for many of the terminal aminomethyl groups on lysine side chains. In vitro experiments using model peptides, in-solution oxidation, and click chemistry demonstrated that hypochlorous acid produced by the myeloperoxidase - hydrogen peroxide - chloride system could be responsible for these and other, more commonly observed modifications.

中文翻译：

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淀粉样蛋白原免疫球蛋白轻链蛋白的氧化翻译后修饰

免疫球蛋白轻链淀粉样变性 (AL) 是一种浆细胞疾病，其特征是单克隆免疫球蛋白 (Ig) 轻链 (LC) 或可变区片段作为淀粉样纤维在各种器官和组织中过度产生和沉积。许多临床证据表明，AL 淀粉样变性患者存在心肌细胞损伤和氧化应激。我们试图了解潜在的生化途径，其在散发或持续的疾病状态期间的破坏或放大会导致有害的生理后果，并确定中间体和产品的详细结构，作为生化变化的路标并代表潜在的生物标志物。在这项研究中，基质辅助激光解吸/电离质谱法为来自 AL 淀粉样变性患者的淀粉样变性 Ig LC 蛋白的氧化翻译后修饰 (PTM) 提供了广泛的证据。一些酪氨酸残基被重度单氯化或二氯化。此外，对于赖氨酸侧链上的许多末端氨基甲基，观察到新的氧化转化为腈部分。使用模型肽、溶液中氧化和点击化学进行的体外实验表明，髓过氧化物酶 - 过氧化氢 - 氯化物系统产生的次氯酸可能是造成这些和其他更常见的修饰的原因。此外，对于赖氨酸侧链上的许多末端氨基甲基，观察到新的氧化转化为腈部分。使用模型肽、溶液中氧化和点击化学进行的体外实验表明，髓过氧化物酶 - 过氧化氢 - 氯化物系统产生的次氯酸可能是造成这些和其他更常见的修饰的原因。此外，对于赖氨酸侧链上的许多末端氨基甲基，观察到新的氧化转化为腈部分。使用模型肽、溶液中氧化和点击化学进行的体外实验表明，髓过氧化物酶 - 过氧化氢 - 氯化物系统产生的次氯酸可能是造成这些和其他更常见的修饰的原因。