Degrading heparan sulfate : structural and functional analysis of sulfatases for drug discovery applications
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Heparan sulfate proteoglycans (HSPGs) are a fundamental and evolving part of the cell surface and within the extracellular matrix (ECM). Turnover of HSPGs is aided by sulfatases, a family of enzymes which catalyzes cleavage of sulfate esters and plays an important role in step-wise degradation and lysosomal turnover of HSPGs. Deficiency of glycosaminoglycan (GAG) degradation due to autosomal recessive gene mutations causes a subclass of lysosomal storage disorders called mucopolysaccharidoses (MPSs), where there is accumulation of incomplete degradation products in the lysosome. Many of MPS type disorders are paired with severe neurocognitive deficiencies, hence, the difficulty in treatment. Out of eight human heparan sulfate degrading lysosomal sulfatases, three are described here: N-acetylglucosamine-6-sulfatase (GNS), arylsulfatase K and arylsulfatase G. Overall, this work explores various approaches to drug discovery through small fragment screening and computational-based protein engineering. The resulting fragment based screening performed on GNS identified an allosteric binding site, which can be used for the rational design of molecular chaperones that function to stabilise misfolded GNS in MPS IIID patients. The approach to engineer the pH optimum of GNS activity could serve as a way to treat an ultra-low molecular weight heparin (ULMWH) overdose.
Thesis, PhD Doctor of Philosophy
Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/
Embargo Date: 2027-11-07
Embargo Reason: Thesis restricted in accordance with University regulations. Restricted until 7th November 2027
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