Todorinova Magdalena, Beld Joris, Jaremko Kara L
Department of Chemistry, Hofstra University, Hempstead, NY, 11549, USA.
Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA, 19102, USA.
Biochem Biophys Rep. 2023 Sep 23;35:101549. doi: 10.1016/j.bbrep.2023.101549. eCollection 2023 Sep.
The acyl-acyl carrier protein synthetase enzyme enables some bacteria to scavenge free fatty acids from the environment for direct use in lipids. This fatty acid recycling pathway can help pathogens circumvent fatty acid synthase (FAS) inhibition with established antibiotics and those in clinical development. AasS enzymes are surprisingly hard to identify as they show high sequence similarity to other adenylate forming enzymes, and only a handful have been correctly annotated to date. Four recently discovered AasS enzymes from Gram negative bacteria, and , form distinct clusters in protein sequence similarity networks and have varying substrate preferences. We previously synthesized C10-AMS, an inhibitor of AasS that mimics the acyl-AMP reaction intermediate. Here we tested its ability to be broadly applicable to enzymes in this class, and found it inhibits all four newly annotated AasS enzymes. C10-AMS therefore provides a tool to study the role of AasS in fatty acid recycling in pathogenic bacteria as well as offers a platform for antibiotic development.
酰基-酰基载体蛋白合成酶使一些细菌能够从环境中清除游离脂肪酸，以供直接用于脂质合成。这种脂肪酸循环途径可帮助病原体规避已有的抗生素以及正在临床开发中的抗生素对脂肪酸合酶（FAS）的抑制作用。AasS酶令人惊讶地难以识别，因为它们与其他形成腺苷酸的酶具有高度的序列相似性，而且迄今为止只有少数几种被正确注释。最近从革兰氏阴性细菌中发现的四种AasS酶，即[具体酶名1]、[具体酶名2]、[具体酶名3]和[具体酶名4]，在蛋白质序列相似性网络中形成了不同的簇，并且具有不同的底物偏好。我们之前合成了C10-AMS，一种模拟酰基-AMP反应中间体的AasS抑制剂。在此，我们测试了它广泛适用于此类酶的能力，发现它能抑制所有四种新注释的AasS酶。因此，C10-AMS为研究AasS在病原菌脂肪酸循环中的作用提供了一种工具，同时也为抗生素开发提供了一个平台。
