Structures and mechanism of chitin synthase and its inhibition by antifungal drug Nikkomycin Z
Yanan Wu, Min Zhang, Yizheng Yang, Xuyang Ding, Ping Yang, Kai Huang, Xinlin Hu, Mingjie Zhang, Xiaotian Liu, Hongjun Yu
Abstract
Chitin, one of the most common polysaccharides in nature, is produced by fungi, insects, fish, etc. Chitin is a linear N-acetylglucosamine (GlcNAc) polymer with -1,4linkage and is synthesized by membrane-integrated chitin synthase (Chs). As the essential polysaccharide in cell walls of prominent fungal pathogens, chitin plays vital roles in cell wall assembly and cell integrity maintenance for fungi 1 . Chitin biosynthesis, therefore, becomes an appealing target for antifungal drug development 1,2 . One well-known example is Nikkomycin Z (NikZ), the competitive inhibitor of Chs 3,4 (Fig. NikZ is under clinical development for treating coccidioidomycosis, blastomycosis, and histoplasmosis 2,5,6 . However, the mechanism of action of Chs and its inhibition by NikZ remain enigmatic.