Fungal β-1,3-glucan synthase: a review of structure, mechanism, and regulation

Fungal β-1,3-glucan synthase (Fks) plays a central role in synthesizing β-1,3-glucan, the main structural polysaccharide of fungal cell walls, and serves as a key target for antifungal drugs, such as echinocandins and ibrexafungerp. Recent cryo-electron microscopy (cryo-EM) studies have revealed the architecture of the Fks1 and Fks1-Rho1 complex and provided new insights into its catalytic and regulatory mechanisms. This review summarizes current understanding of Fks, including its domain organization, transmembrane topology, conformational dynamics, and evolutionary comparison with structurally resolved glycosyltransferases (GTs), including bacterial cellulose synthase (BcsA), plant cellulose synthase (CesA), and other eukaryotic GTs. Through comparison of publicly available cryo-EM structures of Fks in both the apo-state and Rho1-bound state, a working mechanism of the activated Fks has been discussed. In addition, we present a potential gating model of β-glucan translocation and drug-inhibition by integrating literature with structure-based analyses. This review provides a structure-based functional model of fungal β-1,3-glucan synthase and the putative binding mechanism of its inhibitor, aiming to support future antifungal drug discovery.