主催: The Japanese Society for Medical Mycology
The cell wall of A. fumigatus is a unique structure which does not exist for human cells. It enables the fungus to resist against external aggressions, but, at the same time, it is its Achilles' heel since it is a major drug target as shown by the commercial launch of echinocandins that block cell wall biosynthesis.
Polysaccharides represent the major part of the fungal cell wall and are responsible for its rigidity and plasticity. Five structural polysaccharides are present in the cell wall of A. fumigatus mycelium and conidia: β1-3)glucan, chitin, galactomannan, β1-3)glucan and β1-3/1-4)glucan. β1-3)glucan is highly branched with β1-6) linkages constituting a three-dimensional network with a large number of side-chains and ramifications. Other polysaccharides such as chitin, galactomannan and β1-3/1-4)glucan are cross-linked to the branched β1-3/1-6)glucan network. β(1-3)glucans are synthesized by a plasma membrane-bound β(1-3) glucan synthase complex which uses UDP-glucose as a substrate, and extrudes linear β(1-3)glucan chains through the membrane into the periplasmic space. A single catalytic FKS1 subunit is present in the genome of A. fumigatus and is essential. The regulation of the glucan synthase of A. fumigatus and the enzymes responsible for remodeling β(1-3) glucan remains however poorly understood.The chitin synthases that are responsible for the synthesis of linear chains of β(1-4) N-acetylgucosamine from the substrate UDP-N-acetylglucosamine are also a family of integral membrane proteins. Eight genes were found in A. fumigatus. The significance of each of these genes not understood but none of the CHS genes of A. fumigatus is essential.Three glucan synthase genes have been identified and none of the A. fumigatus genes is essential. Orthologs of most yeast mannosyltransferase genes can be found in the genome of A. fumigatus. How orthologs of the yeast mannosyltransferases synthesise a mannan chain different in A. fumigatus from S. cerevisiae remains a mystery. The addition of galactofuranose residues to the mannan core to form side-chains is also not understood.
The current knowledge of the function of these cell wall enzymes and the role of the different polysaccharides in the cell wall organisation will be discussed in my talk with special emphasis on the use of cell wall as a drug target.
