The structure and synthesis of the fungal cell wall Shaun M. Bowman and Stephen J. Free* Summary The fungal cell wall is a dynamic structure that protects the cell from changes in osmotic pressure and other environmental stresses, while allowing the fungal cell to interact with its environment. The structure and biosynth- esis of a fungal cell wall is unique to the fungi, and is therefore an excellent target for the development of anti- fungal drugs. The structure of the fungal cell wall and the drugs that target its biosynthesis are reviewed. Based on studies in a number of fungi, the cell wall has been shown to be primarily composed of chitin, glucans, mannans and glycoproteins. The biosynthesis of the various components of the fungal cell wall and the importance of the components in the formation of a functional cell wall, as revealed through mutational analyses, are discussed. There is strong evidence that the chitin, glucans and glycoproteins are covalently cross-linked together and that the cross-linking is a dynamic process that occurs extracellularly. BioEssays 28:799–808, 2006. ß 2006 Wiley Periodicals, Inc. Introduction The fungal cell wall is a dynamic organelle that functions in a number of important processes. It must provide the cell with sufficient mechanical strength to withstand changes in osmotic pressure imposed by the environment. Concurrently, the cell wall must retain adequate plasticity to allow for cell growth, cell division and the formation of a myriad of cell types during the life cycle of the fungus. In addition to maintaining cell shape and integrity in the face of environmental stress, the wall allows the fungal cell to interact with its surroundings. The cell wall mediates the adhesion of cells to one another and the substratum, and serves as a signaling center to activate signal transduction pathways within the cell. Disruptions of cell wall structure have a profound effect on the growth and morphology of the fungal cell, often rendering it susceptible to lysis and death. Given the vital role that the cell wall plays in fungal physiology, the cell wall has long been considered an excellent target for anti-fungal agents. Fungal cell walls are structurally unique and differ significantly from the cellulose-based plant cell wall. Fungal cell walls are comprised of glycoproteins and polysaccharides, mainly glucan and chitin. Additional minor cell wall compo- nents are present and vary amongst species of fungi. The glycoproteins present in the cell wall are extensively modified with both N- and O-linked carbohydrates and, in many instances, contain a glycosylphosphatidylinositol (GPI) an- chor as well. The glucan component is predominately beta- 1,3-glucan, long linear chains of beta-1,3-linked glucose. Glucans having alternate linkages, such as beta-1,6-glucan, are found within some cell walls. Chitin is manufactured as chains of beta-1,4-linked N-acetylglucosamine residues and is typically less abundant than either the glycoprotein or glucan portions of the wall. The composition of the cell wall is subject to change and may vary within a single fungal isolate depending upon the conditions and stage of growth. The glycoprotein, glucan and chitin components are extensively cross-linked together to form a complex network, which forms the structural basis of the cell wall (Fig. 1). The formation and remodeling of the cell wall involves numerous biosynthetic pathways and the concerted actions of hundreds of gene products within the fungal cell. Mutational, genomic and proteomic analyses of model fungal systems, such as Saccharomyces cerevisiae, Schizosaccharomyces pombe, Candida albicans, Aspergillus fumigatus and Neuro- spora crassa, are beginning to elucidate the role of various pathways and individual proteins in the establishment of the cell wall (Fig. 2). The chitin component of the fungal cell wall Chitin, a long linear homopolymer of beta-1,4-linked N-acetylglucosamine, is considered to be a relatively minor, yet structurally important, component of the fungal cell wall. Chitin accounts for only 1–2% of the yeast cell wall by dry weight, (1,2) whereas the cell walls of filamentous fungi, such as Neurospora and Aspergillus, are reported to contain 10 – 20% chitin. (3,4) In both yeasts and filamentous fungi, chitin micro- fibrils are formed from inter-chain hydrogen bonding. These crystalline polymers have an enormous tensile strength and significantly contribute to the overall integrity of the cell wall. When chitin synthesis is disrupted, the wall becomes disordered and the fungal cell becomes malformed and osmotically unstable. (5,6) Department of Biological Sciences, The University at Buffalo, Buffalo, New York, 14260. *Correspondence to: Stephen J. Free, Dept. of Biological Sciences, Cooke Hall room 109, The University at Buffalo, Buffalo, NY 14260. E-mail: free@buffalo.edu DOI 10.1002/bies.20441 Published online in Wiley InterScience (www.interscience.wiley.com). BioEssays 28:799–808, ß 2006 Wiley Periodicals, Inc. BioEssays 28.8 799 Review articles