Glycosyltransferases Goal: An improved understanding of the mechanism and specificity of glycosyltransferases, including protein N-glycosylation catalyzed by oligosaccharyltransferase. Glycosyltransferases catalyze the reaction of numerous glycosyl donors and a wide variety of carbohydrate or protein acceptors.  Research in our group involves glycosylation of N-acetylglucosamine (GlcNAc) derivatives such as a sugar nucleotide (e.g., UDP-GlcNAc) or a lipid-linked saccharide (e.g., GlcNAc-b-(1,3)-GlcNAc-a-PP-dolichol) to a carbohydrate (e.g., lactose) or peptide (e.g., Bz-Asn-Leu-Thr-NH2), respectively.  In addition, other reactions that utilize sugar nucleotides (i.e., C-4 epimerases, C-2 epimerases, 5,6-dehydratase/reductase) are also under investigations in collaborative research.  Using synthetic probes of catalytic mechanism, this diverse group of enzymes is the subject of ongoing study. Another group of glycosyltransferases are part of the so-called “dolichol pathway” involved in the biosynthesis of the complex triantennary oligosaccharide donor required in the formation of N-linked glycoproteins.  To elucidate the catalytic mechanism of several enzymes in this pathway, we have synthesized several new carbohydrates, including sugar nucleotides and lipid-linked saccharides.  The final enzyme in this pathway is oligosaccharyltransferase (OST).  OST is a membrane-bound, heterooligomeric protein that we isolate from yeast. Initial research in our group centered on the use of synthetically accessible small substrates, characterization of the chemical structure of the glycopeptide product, and the use of isotopically labeled (1H, 13C, 15N) peptide acceptor substrates for mechanistic studies. More recent research focused on the use of larger peptides and proteins as substrates and has led to extensive studies with invertase-derived peptides of varying length. Kinetic data combined with structure-activity data has allowed us to develop a working hypothesis concerning peptide substrate recognition by OST. Current research involves the synthesis of a variety of isotopically labeled donor substrates and inhibitors designed to answer specific mechanistic questions. As in the research with the folate polyglutamates and trypanothione, the goal here is to understand the mechanism of this reaction in sufficient detail that it will be feasible to design and synthesize potent and specific inhibitors for use in the study of cellular glycoprotein biosynthesis. Links related to Glycosyltransferases and OST Researchers interested in Glycosyltransferases and OST Marcus Aebi at ETH. Reid Gilmore at the University of Massachusetts. Barbara Imperiali at MIT. Andrea Vasella at ETHZ. If you are a researcher interested in glycosyltransferases, including OST please drop us a note and we will add you to our list!

Last updated: March 2003
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