Lomonte Bruno
Instituto Clodomiro Picado, Facultad de Microbiología, Universidad de Costa Rica, San José, 11501, Costa Rica.
Toxicon. 2023 Mar 1;224:107024. doi: 10.1016/j.toxicon.2023.107024. Epub 2023 Jan 9.
Muscle necrosis is a potential clinical complication of snakebite envenomings, which in severe cases can lead to functional or physical sequelae such as disability or amputation. Snake venom proteins with the ability to directly damage skeletal muscle fibers are collectively referred to as myotoxins, and include three main types: cytolysins of the "three-finger toxin" protein family expressed in many elapid venoms, the so-called "small" myotoxins found in a number of rattlesnake venoms, and the widespread secreted phospholipase A (sPLA) molecules. Among the latter, protein variants that conserve the sPLA structure, but lack such enzymatic activity, have been increasingly found in the venoms of many viperid species. Intriguingly, these sPLA-like proteins are able to induce muscle necrosis by a mechanism independent of phospholipid hydrolysis. They are commonly referred to as "Lys49 myotoxins" since they most often present, among other substitutions, the replacement of the otherwise invariant residue Asp49 of sPLAs by Lys. This work comprehensively reviews the historical developments and current knowledge towards deciphering the mechanism of action of Lys49 sPLA-like myotoxins, and points out main gaps to be filled for a better understanding of these multifaceted snake venom proteins, to hopefully lead to improved treatments for snakebites.
肌肉坏死是蛇咬伤中毒潜在的临床并发症，在严重情况下可导致功能或身体后遗症，如残疾或截肢。具有直接损伤骨骼肌纤维能力的蛇毒蛋白统称为肌毒素，主要包括三种类型：许多眼镜蛇科蛇毒中表达的“三指毒素”蛋白家族的细胞溶素、一些响尾蛇蛇毒中发现的所谓“小”肌毒素，以及广泛存在的分泌型磷脂酶A（sPLA）分子。在后者中，许多蝰蛇科物种的蛇毒中越来越多地发现了保留sPLA结构但缺乏这种酶活性的蛋白质变体。有趣的是，这些类sPLA蛋白能够通过一种独立于磷脂水解的机制诱导肌肉坏死。它们通常被称为“Lys49肌毒素”，因为在其他取代中，它们最常出现的是将sPLA原本不变的Asp49残基替换为Lys。这项工作全面回顾了在破译Lys49类sPLA肌毒素作用机制方面的历史发展和当前知识，并指出了为更好地理解这些多面性蛇毒蛋白而有待填补的主要空白，有望改进蛇咬伤的治疗方法。
