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Niemann-Pick C-like Endolysosomal Dysfunction in DHDDS Patient Cells, a Congenital Disorder of Glycosylation, Can Be Treated with Miglustat.
Int J Mol Sci
February 2025
Medicines Discovery Institute, Main Building, Cardiff University, Cardiff CF10 3AT, UK.
DHDDS (dehydrodolichol diphosphate synthetase) and NgBR (Nogo-B Receptor) collectively form an enzymatic complex important for the synthesis of dolichol, a key component of protein N-glycosylation. Mutations in and the gene encoding NgBR ( are associated with neurodevelopmental disorders that clinically present with epilepsy, motor impairments, and developmental delay. Previous work has demonstrated both DHDDS and NgBR can also interact with NPC2 (Niemann-Pick C (NPC) type 2), a protein which functions to traffic cholesterol out of the lysosome and, when mutated, can cause a lysosomal storage disorder (NPC disease) characterised by an accumulation of cholesterol and glycosphingolipids.
View Article and Find Full Text PDFA stable GH31 α-glucosidase as a model system for the study of mutations leading to human glycogen storage disease type II.
J Enzyme Inhib Med Chem
December 2025
Department of Biology, University of Naples "Federico II", Naples, Italy.
GH31 glycosidases are widespread across organisms, but remarkably, less than 1% of them have been biochemically characterised to date. Among them, human lysosomal acid α-glucosidase (GAA) stands out due to its link to Pompe disease, a rare lysosomal storage disorder caused by its deficiency. This disease results in glycogen accumulation, severe cellular damage, motor impairment, and premature death.
View Article and Find Full Text PDFLysosome-Specific Delivery of β-Glucosidase Enzyme Using Protein-Glycopolypeptide Conjugate via Protein Engineering and Bioconjugation.
Bioconjug Chem
February 2025
Department of Chemical Sciences, Indian Institute of Science Education and Research, Kolkata, Mohanpur, Nadia, West Bengal 741246, India.
Lysosomal enzyme replacement therapy () holds potential for treating lysosomal storage disorders, but achieving targeted delivery of deficient therapeutic enzymes remains a significant challenge. This study presents a novel approach for the lysosome-specific delivery of the β-glucosidase () enzyme by covalently conjugating lysosome-targeting mannose-6-phosphate functionalized glycopolypeptides (). We used a protein-glycopolypeptide conjugate developed through advanced protein engineering and bioconjugation techniques.
View Article and Find Full Text PDFLysosomes actively regulate their lumenal pH, which is necessary for optimal enzymatic activity. Endocytic processes are involved in many diseases, including Alzheimer's disease, in which sub-optimal lysosomal function has been reported. To measure acidification, pH-sensitive probes can be delivered to endosomes and lysosomes using labeled dextran polymers or proteins.
View Article and Find Full Text PDFTRAM-LAG1-CLN8 family proteins are acyltransferases regulating phospholipid composition.
Sci Adv
February 2025
MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
The diversity of cellular phospholipids, crucial for membrane homeostasis and function, arises from enzymatic remodeling of their fatty acyl chains. In this work, we reveal that poorly understood TRAM-LAG1-CLN8 domain (TLCD)-containing proteins are phospholipid remodeling enzymes. We demonstrate that TLCD1 is an evolutionarily conserved lysophosphatidylethanolamine acyltransferase, which regulates cellular phospholipid composition and generates previously undescribed fatty acid and thiamine (vitamin B1) esters as its secondary products.
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