Hu Lu, Tao Zhipeng, Wu Xu
Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School 149, 13th St. Charlestown MA 02129 USA
RSC Chem Biol. 2021 Aug 25;2(6):1567-1579. doi: 10.1039/d1cb00115a. eCollection 2021 Dec 2.
Posttranslational -fatty acylation (or -palmitoylation) modulates protein localization and functions, and has been implicated in neurological, metabolic, and infectious diseases, and cancers. Auto--fatty acylation involves reactive cysteine residues in the proteins which directly react with fatty acyl-CoA through thioester transfer reactions, and is the first step in some palmitoyl acyltransferase (PAT)-mediated catalysis reactions. In addition, many structural proteins, transcription factors and adaptor proteins might possess such "enzyme-like" activities and undergo auto--fatty acylation upon fatty acyl-CoA binding. Auto--fatty acylated proteins represent a new class of potential drug targets, which often harbor lipid-binding hydrophobic pockets and reactive cysteine residues, providing potential binding sites for covalent and non-covalent modulators. Therefore, targeting auto--fatty acylation could be a promising avenue to pharmacologically intervene in important cellular signaling pathways. Here, we summarize the recent progress in understanding the regulation and functions of auto--fatty acylation in cell signaling and diseases. We highlight the druggability of auto--fatty acylated proteins, including PATs and other proteins, with potential and rationalized drug design approaches. We also highlight structural analysis and examples of currently known small molecules targeting auto--fatty acylation, to gain insights into targeting this class of proteins, and to expand the "druggable" proteome.
翻译后 - 脂肪酸酰化（或 - 棕榈酰化）调节蛋白质的定位和功能，并与神经、代谢、感染性疾病及癌症有关。自身 - 脂肪酸酰化涉及蛋白质中的反应性半胱氨酸残基，这些残基通过硫酯转移反应直接与脂肪酰辅酶A反应，是一些棕榈酰酰基转移酶（PAT）介导的催化反应的第一步。此外，许多结构蛋白、转录因子和衔接蛋白可能具有这种“酶样”活性，并在与脂肪酰辅酶A结合时发生自身 - 脂肪酸酰化。自身 - 脂肪酸酰化蛋白代表了一类新的潜在药物靶点，它们通常含有脂质结合疏水口袋和反应性半胱氨酸残基，为共价和非共价调节剂提供了潜在的结合位点。因此，靶向自身 - 脂肪酸酰化可能是在药理学上干预重要细胞信号通路的一条有前景的途径。在此，我们总结了在理解细胞信号传导和疾病中自身 - 脂肪酸酰化的调节和功能方面的最新进展。我们强调了自身 - 脂肪酸酰化蛋白（包括PAT和其他蛋白）的可药物化性，并介绍了潜在的、合理的药物设计方法。我们还强调了针对自身 - 脂肪酸酰化的当前已知小分子的结构分析和实例，以深入了解靶向这类蛋白质，并扩展“可药物化”蛋白质组。
