Fungal Chitin Synthases: Structure, Function, and Regulation
Linda M Brain, Mark R. Bleackley, Monika S. Doblin, Marilyn A. Anderson
Abstract
Chitin is an essential polysaccharide of the fungal cell wall, critical for structural integrity, cell division and, in pathogenic fungi, virulence. As chitin is absent in both plant and mammalian systems, chitin synthases are considered attractive targets for the specific control of fungal pathogens. Yet despite decades of research, structural information on chitin synthases was lacking and inhibitors have failed to gain approval in the clinic. Current inhibitors are also ineffective against major agricultural pathogens such as Aspergillus and Fusarium species, largely due to the presence of multiple chitin synthase isoforms in filamentous fungi and the cell wall compensatory response induced under stress. However, recent cryo-electron microscopy structures of Class I chitin synthases from yeasts Saccharomyces cerevisiae and Candida albicans and an oomycete chitin synthase have provided unprecedented insights into the structural and mechanistic properties of these large, transmembrane proteins. These studies revealed conserved, domain-swapped homodimer architectures, distinct substrate binding and catalytic pockets, and sophisticated intrinsic regulatory mechanisms. With these breakthroughs, this review summarises our current understanding of fungal chitin biosynthesis, the challenges that remain to fully biochemically characterise these enzymes, and considers how the new structural insights may guide the development of broad-spectrum antifungals.