Gaucher disease is caused by mutations in human acid β‐glucosidase or glucocerebrosidase (GCase), the enzyme responsible for hydrolysis of glucosyl ceramide in the lysosomes. Imino‐ and azasugars such as 1‐deoxynojirimycin and isofagomine are strong inhibitors of the enzyme and are of interest in pharmacological chaperone therapy of the disease. Despite several crystal structures of the enzyme with the imino‐ and azasugars bound in the active site having been resolved, the actual acid–base chemistry of the binding is not known. In this study we show, using photoinduced electron transfer (PET), that 1‐deoxynojirimycin and isofagomine derivatives are protonated by human acid β‐glucosidase when bound, even if they are completely unprotonated outside the enzyme. While isofagomine derivative protonation to some degree was foreshadowed by earlier crystal structures, 1‐deoxynojirimycin derivatives were not believed to act as basic amines in the enzyme.
The α‐ and β‐cyclodextrins with two dimethylamino groups or two trimethylethylenediamino groups attached to the primary face were synthesized and their pKa values were determined by potentiometric titration. The complexation of the four cyclodextrin analogues with zinc and copper was studied by NMR and showed one or two cyclodextrins bound to the metal. Inclusion of 4‐halophenols in the metal complexes were also studied.
Gaucher disease is caused by mutations in human acid β‐glucosidase or glucocerebrosidase (GCase), the enzyme responsible for hydrolysis of glucosyl ceramide in the lysosomes. Imino‐ and azasugars such as 1‐deoxynojirimycin and isofagomine are strong inhibitors of the enzyme and are of interest in pharmacological chaperone therapy of the disease. Despite several crystal structures of the enzyme with the imino‐ and azasugars bound in the active site having been resolved, the actual acid–base chemistry of the binding is not known. In this study we show, using photoinduced electron transfer (PET), that 1‐deoxynojirimycin and isofagomine derivatives are protonated by human acid β‐glucosidase when bound, even if they are completely unprotonated outside the enzyme. While isofagomine derivative protonation to some degree was foreshadowed by earlier crystal structures, 1‐deoxynojirimycin derivatives were not believed to act as basic amines in the enzyme.
Ligand cross-linking is known to
improve the colloidal stability
of nanoparticles, particularly in aqueous solutions. However, most
cross-linking is performed chemically, in which it is difficult to
limit interparticle cross-linking, unless performed at low concentrations.
Photochemical cross-linking is a promising approach but usually requires
ultraviolet (UV) light to initiate. Using such high-energy photons
can be harmful to systems in which the ligand–nanoparticle
bond is fairly weak, as is the case for the commonly used semiconductor
quantum dots (QDs). Here, we introduce a novel approach to cross-link
thiolated ligands on QDs by utilizing the photocatalytic activity
of QDs upon absorbing visible light. We show that using visible light
leads to better ligand cross-linking by avoiding the problem of ligand
dissociation that occurs upon UV light exposure. Once cross-linked,
the ligands significantly enhance the colloidal stability of those
same QDs that facilitated cross-linking.
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