Position: Professor of Biological Chemistry
Division: Molecular Microbiology
Address: College of Life Sciences,
University of Dundee,
Dundee
Telephone: +44 1382 384979, int ext. 84979
Email: d.m.f.vanaalten@dundee.ac.uk
Website: Aalten Lab
Carbohydrates are essential building blocks of polysaccharide structures and glycans on the microbial and human cell. Interactions of these carbohydrates with proteins that synthesize, recognise or modify them are essential steps in a wide range of processes such as microbial cell wall synthesis/recognition, cell signalling pathways and the human immune system.
My lab is interested in studying the structural aspects and mechanism of protein-carbohydrate interactions, and applies the knowledge gained from these approaches to design molecules that modulate these interactions in biological systems and have applications as research tools or leads for the development of chemotherapeuticals. We use a multidisciplinary approach, involving X-ray crystallography, enzymology, mutagenesis, affinity measurements, high-throughput screening and novel computational techniques. Examples of recent research of the lab are:
1) Chitinases: chitinases play key roles in the proper assembly of the fungal cell wall and human signalling pathways involved in asthma, arthritis and cancer. We have determined structures of these enzymes, leading to an understanding of the reaction mechanism (see picture 1) and developed potent drug-like inhibitors [1,2].
2) Carbohydrate esterases: family 4 carbohydrate esterases are microbial enzymes that de-N-acetylate carbohydrate polymers in the cell wall to evade the lytic action of glycoside hydrolases secreted by the human immune system. We have defined the first structure and zinc-dependent reaction mechanism of this important class of enzymes, and have identified potent inhibitors by screening strategies (see picture 2) [3].
3) Structural mechanisms of O-GlcNAc signalling: modification of serines/threonines on intracellular proteins with O-GlcNAc prevents these residues from becoming phosphorylated. This transient and dynamic post-translational modification has been shown to play a key role in regulating the activities of proteins involved in several signal-transduction pathways linked to diabetes, cancer and Alzheimer's. We have recently determined the structure and reaction mechanism of an O-GlcNAcase, the enzyme that removes the O-GlcNAc modification, and a complex with the diabetogenic compound PUGNac (see picture 3) [4].
In addition to our work on protein-carbohydrate interactions we have intensive collaborations with Prof. Philip Cohen (to study signal transduction pathways involved in inflammation) and Prof. Dario Alessi (to determine the structure of the LKB1 tumour suppressor complex [5] and study the signal-transduction mechanisms of the PI-3 kinase pathway [6] and kinase cascades involved in hypertension).
