The fungal cell wall as a target for antifungal therapies

Partner 9

Division of Molecular Microbiology and Biological Chemistry
University of Dundee (UK)

Principal scientist
Dr Daan M. F. van Aalten

Other scientists
Dr H. Dorfmueller, Dr R. Hurtado-Guerrero

Wellcome Trust Biocentre, School of Life Sciences,
PO Box DD1 5EH Dundee, Scotland, UK,
+44 1382 344979 - Fax +44 1382 345764

Experience of the participating organisation and scientists

Participating organisation

The proposed work will be carried out by Dr van Aalten laboratory, established 4 years ago at the Wellcome Trust Biocentre in Dundee, has established experience in the use of X-ray crystallography and novel computational techniques for the structural analysis of novel antimicrobial targets and small molecule leads with chemotherapeutic potential. Together with a team of 10 research scientists, most of which are already working on antifungal targets, Dr van Aalten is harvesting the results from the fungal genome sequencing projects, cloning, expressing, crystallising and solving the structures of novel targets. State-of-the-art equipment is available in Dundee for diffraction experiments and diffraction data is also collected at the ESRF synchrotron, on a two-monthly basis. Dr van Aalten was recently promoted to reader and was admitted to the prestiguous EMBO Young Investigator Programme.

Participating scientists

Dr van Aalten, the leader of the Group, has over 5 years experience with enzymes involved in fungal cell wall metabolism. He has strong links with Dr W. Hunter and the St-Andrews group of structural biologists. Significant results have been obtained in two areas:

Chitinases. Family 18 chitinases are enzymes that hydrolyse the chitin component in the fungal cell wall and play a role in cell division and morphogenesis. Over the past ten years, Dr van Aalten has made significant contributions to the understanding of the unique structure and reaction mechanism of these enzymes. Using X-ray crystallography, he has determined the structure of a bacterial chitinase and its reaction mechanism . He then embarked on a systematic characterization of the available chitinase inhibitors, some of which interfere with fungal cell wall morphogenesis. For instance, crystallographic studies with inhibitors have revealed how carbohydrate/peptide-based natural product inhibitors bind to this family of enzymes, providing new leads for the rational design of chitinase inhibitors. Combined with novel software developed in the van Aalten lab, these structures have lead to the identification of several new chitinase inhibitors.
Chilectins. Chitinase-like lectins (Chilectins) are evolutionary inactivated chitinases that appear to play a role in human innate defense against chitinious pathogens, such as fungi. Although their structure is remarkably similar to the family 18 chitinases, the nature of their ligands was until recently poorly understood. However, Dr van Aalten has recently published the structure of several complexes of one of these Chilectins, HCGP-39, showing that these proteins are able to directly interact with chitooligosaccharides - fragments of the fungal cell wall (with low mM affinity). This has opened up an exciting new field in the area of human immune system - fungal pathogen interactions.

Relevant publications

van Aalten, D.M.F., Synstad, B., Brurberg, M.B., Hough, E., Riise, B.W., Eijsink, V.G.H., Wierenga, R. K., (2000) Structure of a two-domain chitotriosidase from Serratia marcescens at 1.9 Å resolution, Proc. Natl. Acad. Sci. USA, 97:5842-5847.

van Aalten, D.M.F., Komander, D., Synstad, B., Gåseidnes, S., Peter, M.G., Eijsink, V.G.H. (2001) Structural insights into the catalytic mechanism of a family 18 exo-chitinase, Proc. Natl. Acad. Sci. USA, 98:8979-8984.

Houston, D.R., Shiomi, K. , Arai, N., Omura, S., Peter, M.G., Turberg, A., Synstad, B., Eijsink, V.G.H., van Aalten, D.M.F. (2002) High-resolution structures of a chitinase complexed with natural product cyclopentapeptide inhibitors: Mimicry of carbohydrate substrate, Proc. Natl. Acad. Sci. USA, 99:9127-9132.

Rao, F.V., Houston, D.R., Boot, R.G., Aerts, J.M.F.G., Sakuda, S., van Aalten, D.M.F. (2003) Crystal structures of allosamidin derivatives in complex with human macrophage chitinase, J. Biol. Chem., 278:20110-20116.

Houston, D.R., Recklies, A.D., Krupa, J.C., van Aalten, D.M.F. (2003) Structure and ligand-induced conformational change of the 39-kD glycoprotein from human articular chondrocytes, J. Biol. Chem., 278:30206-30212.

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