Insights into auto-S-fatty acylation: targets, druggability, and inhibitors,RSC Chemical Biology

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Insights into auto-S-fatty acylation: targets, druggability, and inhibitors
RSC Chemical Biology ( IF 4.2 ) Pub Date : 2021-08-25 , DOI: 10.1039/d1cb00115a
Lu Hu ₁ , Zhipeng Tao ₁ , Xu Wu ₁

Affiliation

Posttranslational S-fatty acylation (or S-palmitoylation) modulates protein localization and functions, and has been implicated in neurological, metabolic, and infectious diseases, and cancers. Auto-S-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-S-fatty acylation upon fatty acyl-CoA binding. Auto-S-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-S-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-S-fatty acylation in cell signaling and diseases. We highlight the druggability of auto-S-fatty acylated proteins, including PATs and other proteins, with potential in silico and rationalized drug design approaches. We also highlight structural analysis and examples of currently known small molecules targeting auto-S-fatty acylation, to gain insights into targeting this class of proteins, and to expand the “druggable” proteome.

中文翻译：

深入了解自体 S-脂肪酰化：靶点、成药性和抑制剂

翻译后S-脂肪酰化（或S-棕榈酰化）调节蛋白质定位和功能，并与神经、代谢、传染病和癌症有关。自体-S-脂肪酰化涉及蛋白质中的反应性半胱氨酸残基，通过硫酯转移反应直接与脂肪酰辅酶A反应，并且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、转录因子和接头蛋白可能具有这种“酶样”活性，并在脂肪酰辅酶A结合后发生自S-脂肪酰化。自体-S-脂肪酰化蛋白代表了一类新的潜在药物靶标，其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潜在的结合位点。因此，靶向自体S-脂肪酰化可能是药理学干预重要细胞信号传导途径的一个有前途的途径。在这里，我们总结了了解自体S-脂肪酰化在细胞信号传导和疾病中的调节和功能的最新进展。我们强调自体S-脂肪酰化蛋白（包括 PAT 和其他蛋白）的成药性，在计算机模拟和合理化药物设计方法中具有潜力。我们还重点介绍了目前已知的针对自体S-脂肪酰化的小分子的结构分析和示例，以深入了解针对此类蛋白质的情况，并扩展“可成药”蛋白质组。

更新日期：2021-09-24

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