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Title: Towards detailed structural understanding of α-ʟ-fucosidase : insights through X-ray crystallography and inhibitor-binding
Author: Wright, Daniel Wayne
ISNI:       0000 0004 5368 723X
Awarding Body: University of York
Current Institution: University of York
Date of Award: 2015
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Carbohydrates are one of the most abundant biomolecules and are fundamental to the correct function of many biological processes. The monosaccharide ʟ-fucose is incorporated into biological polymers including oligo and polysaccharides, and glycoproteins. ʟ-fucose is often appended to the end of a glycan chain, and as such is recognised by lectins in a number of molecular recognition events. Due to this, the monosaccharide plays a critical role in the immune response, the colonisation of bacteria in mammals, and cancer. Two enzymes regulate homeostasis of ʟ-fucosylated biomolecules, GDP-ʟ-fucosyltransferases append the sugar to nascent biomolecules while α-ʟ-fucosidases catalyse its cleavage. Two α-ʟ-fucosidases exist in the human genome. Deficiency of one of these enzymes causes the lysosomal storage disorder fucosidosis, and the enzyme is upregulated in a number of cancers. Meanwhile, the other enzyme has been shown to play a critical role in enabling the adhesion of the pathogen Helicobacter pylori to mammals. Thus, inhibition of α-ʟ-fucosidase activity is clinically relevant. In this work, the 1.6 - 2.1 Å X-ray crystal structures of α-ʟ-fucosidase inhibitors complexed with a bacterial α-ʟ-fucosidase are presented and discussed. Of the inhibitors discussed, the majority comprise 5-membered iminocyclitols, a potent yet infrequently used framework for inhibition of glycoside hydrolases, and their mode of binding to the enzyme in an E3 conformation is elaborated from crystal structures. Further, the crystallographic observation of the interaction between a 6-membered ring inhibitor comprising an aziridine moiety as an electrophilic trap and a glycoside hydrolase is reported for the first time. Finally, efforts towards the purification and crystallisation of α-ʟ-fucosidases from Homo sapiens are documented. The results reported herein may aid in the rational design of more potent inhibitors of α-ʟ-fucosidase in the future and may help direct future efforts towards the crystallisation and structure solution of the clinically important human enzymes.
Supervisor: Davies, Gideon J. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available