华中科技大学于洪军等研究人员合作揭示真菌β-1,3-葡聚糖合成酶FKS1的结构和机制。2023年3月22日，《自然》杂志在线发表了这项成果。

研究人员展示了酿酒酵母菌FKS1和耐棘白菌素突变体FKS1(S643P)的冷冻电镜结构。这些结构揭示了该酶在膜-细胞质界面上的活性位点和一个跨越膜双层的葡聚糖转运路径。在FKS1的结构中观察到多种结合的脂质和明显的膜扭曲，表明FKS1与膜之间有活跃的相互作用。抗棘白菌素的突变集中在FKS1的TM5-6和TM8附近的一个区域。FKS1(S643P)的结构揭示了该区域脂质排列的改变，表明该突变体酶的耐药机制。这项研究揭示的FKS1结构、催化机制和对FKS1耐药性突变的分子见解，推进了对真菌β-1,3-葡聚糖生物合成的机理认识，并为通过靶向FKS开发新的抗真菌药物奠定了基础。

据介绍，膜整合合成酶FKS参与β-1,3-葡聚糖的生物合成，是真菌细胞壁的核心成分。FKS是广泛使用的抗真菌药物靶标，包括棘白菌素和ibrexafungerp。不幸的是，FKS的作用机制仍然是个谜，这阻碍了针对该酶的更有效药物的开发。

附：英文原文

Title: Structural and mechanistic insights into fungal β-1,3-glucan synthase FKS1

Author: Hu, Xinlin, Yang, Ping, Chai, Changdong, Liu, Jia, Sun, Huanhuan, Wu, Yanan, Zhang, Mingjie, Zhang, Min, Liu, Xiaotian, Yu, Hongjun

Issue&Volume: 2023-03-22

Abstract: The membrane-integrated synthase FKS is involved in the biosynthesis of β-1,3-glucan, the core component of the fungal cell wall1,2. FKS is the target of widely prescribed antifungal drugs, including echinocandin and ibrexafungerp3,4. Unfortunately, the mechanism of action of FKS remains enigmatic and this has hampered development of more effective medicines targeting the enzyme. Here we present the cryo-electron microscopy structures of Saccharomyces cerevisiae FKS1 and the echinocandin-resistant mutant FKS1(S643P). These structures reveal the active site of the enzyme at the membrane–cytoplasm interface and a glucan translocation path spanning the membrane bilayer. Multiple bound lipids and notable membrane distortions are observed in the FKS1 structures, suggesting active FKS1–membrane interactions. Echinocandin-resistant mutations are clustered at a region near TM5–6 and TM8 of FKS1. The structure of FKS1(S643P) reveals altered lipid arrangements in this region, suggesting a drug-resistant mechanism of the mutant enzyme. The structures, the catalytic mechanism and the molecular insights into drug-resistant mutations of FKS1 revealed in this study advance the mechanistic understanding of fungal β-1,3-glucan biosynthesis and establish a foundation for developing new antifungal drugs by targeting FKS.

DOI: 10.1038/s41586-023-05856-5

Source: https://www.nature.com/articles/s41586-023-05856-5