Research Activities
The Glycobiology Institute, directed
by Prof. Raymond Dwek, has focused
its research activities on understanding the biological roles of
protein
and lipid glycosylation. The use of sugar analogues (imino sugars) to
inhibit
the biosynthesis and catabolism of glycoconjugates is being exploited
by Terry Butters.
Chemistry and biology of imino sugar
inhibitors
The use of small molecule inhibitors to enzymes involved in
glycoconjugate metabolism is being explored in a number of therapeutic
applications. Most of the projects aim to understand the biochemical
mechanism for action of inhibitors in a cellular
environment. These projects are expected to:
i) contribute to the design of
improved therapeutics
ii) dissect the pathways of
glycoconjugate metabolism in cells and in vivo
Imino Sugars
The discovery that monosaccharide analogues (imino sugars) that contain
a nitrogen in the ring instead of oxygen, are potent inhibitors
of glycosidases has led to important developments in biochemistry.
These
include affinity purification of glycosidases, site directed analysis
of
catalytic mechanisms, and as tools for probing the biosynthesis and
function
of protein glycoconjugates .
The
glucose analogues, castanospermine and deoxynojirimycin have found
important
applications in controlling certain virus
infections and diabetes.
Comparison of the
structural
features of glucose and N-butyl-deoxynojirimycin:
The most exciting discovery that glucose (and galactose) imino
sugars
have inhibitory activity against the UDP-glucose:ceramide
glucosyltransferase
allows manipulation of the glycolipid
biosynthetic pathway. This has an important therapeutic application in
the treatment of inherited metabolic storage disorders such as Gaucher
and Tay-Sachs disease, where the catabolism of lipids is impaired.
Transferase
inhibition, using imino sugars, reduces the levels of cellular
glycolipid
and thus reduces the burden of stored metabolites. This strategy for
the
treatment of glycolipid based storage disorders has been termed
substrate
deprivation and may provide a useful adjunct to enzyme replacement
therapy
in certain disease states.
Useful links to inherited disorders are also available to the Gaucher
Association and to Rare
Genetic Diseases in Children