This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Several forms of congenital muscular dystrophy have been related to errors in the assembly of a tetrasaccharide glycan starting from the unusual alpha O-Man modified serine and threonine residues in the central mucin-like region of the glycoprotein. The POMGnT1 enzyme adds a GlcNAc residue to the O-Man, and defects in its activity give rise to Muscle-Eye-Brain disease, a form of muscular dystrophy. A clinical assay for this defect currently relies on benzyl mannose as a substrate, with the activity monitored by incorporation of radio-labled GlcNAc. This suffers from disadvantages on two counts. First, benzyl mannose is not a good substrate, and second, detection with radioactivity is undesirable. With the evaluation of several synthetic mannosylated glycopeptides from dystroglycan sequences, superior substrates have been identified.
The aim of this project is to prepare relevant mannoyslated glycopeptides, incorporating a fluorescent probe at the N-terminus, to take advantage of their superior substrate characteristics and to allow for sensitive detection of products and reactants using HPLC methods, enhancing the utility of the existing clinical assay. The project brings together expertise in POMGnT1 and its assay in the Schachter lab, and glycopeptide synthesis and in vitro assays at CCRC.
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|Li, Xiuru; Fang, Tao; Boons, Geert-Jan (2014) Preparation of well-defined antibody-drug conjugates through glycan remodeling and strain-promoted azide-alkyne cycloadditions. Angew Chem Int Ed Engl 53:7179-82|
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