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Protein Glycosylation: The Clash of the Titans

Imperiali, Barbara (1997) Protein Glycosylation: The Clash of the Titans. Accounts of Chemical Research, 30 (11). pp. 452-459. ISSN 0001-4842. https://resolver.caltech.edu/CaltechAUTHORS:20180124-104708944

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Abstract

Enzymes catalyze a variety of transformations with spectacular rate enhancements while demonstrating exquisite selectivities. Information from complementary structural and mechanistic studies has yielded insight into the inner workings of many enzyme-catalyzed reactions. In particular, studies of transformations that involve the interaction of one or more small-molecule substrates with soluble enzymes have met with notable success. There remain, however, a number of reactions, including those involving the covalent modification of macromolecular substrates, that confound us by their complexity. One such transformation, asparagine-linked glycosylation, involves the enzyme-catalyzed modification of an asparagine side chain in a nascent polypeptide with a triantennary tetradecasaccharide (GlcNAc_2Man_9Glc_3) moiety. This first committed step in the biosynthesis of N-linked glycoproteins is catalyzed by oligosaccharyl transferase (OT), a heteromeric membrane-associated enzyme complex, found in the lumen of the endoplasmic reticulum (ER) of eukaryotic cells. Glycosyl transfer to the nitrogen of the carboxamide side chain of an asparagine occurs through the intermediacy of a dolichol-linked pyrophosphate donor as illustrated in Figure 1. The primary peptide sequence requirements for the glycosylation process include a minimum -Asn-Xaa-Ser/Thr- tripeptide recognition motif where Xaa can be any of the 20 natural amino acids except proline. Thus, while OT exhibits rather simple substrate requirements, the enzyme catalyzes an unusual and specific reaction wherein the nucleophilicity of the asparagine side chain must be greatly enhanced to form a covalent linkage with the oligosaccharide. After transfer of the initial tetradecasaccharide, subsequent diversification of the primary glycoprotein conjugates arises from enzyme-catalyzed processing steps that occur in both the ER and the Golgi apparatus. Specifically, the core oligosaccharide structures are subject to the action of an elaborate array of glycosyl hydrolase and glycosyl transferase enzymes. The latter class of enzymes catalyzes the incorporation of a broader diversity of carbohydrate units including fucose, sialic acid, and galactose. The collective action of these enzymes generates the structural diversity associated with mature N-linked glycoproteins in eukaryotic cells.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1021/ar950226kDOIArticle
http://pubs.acs.org/doi/abs/10.1021/ar950226kPublisherArticle
Additional Information:© 1997 American Chemical Society. Publication Date (Web): November 13, 1997. The work described in this Account was only possible because of the outstanding intellectual and experimental contribution of my graduate students and postdoctorals. I gratefully acknowledge their dedicated efforts. This program is funded the National Institutes of Health (GM 39334).
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Funding AgencyGrant Number
NIHGM 39334
Issue or Number:11
Record Number:CaltechAUTHORS:20180124-104708944
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20180124-104708944
Official Citation:Protein Glycosylation:  The Clash of the Titans. Barbara Imperiali. Accounts of Chemical Research 1997 30 (11), 452-459. DOI: 10.1021/ar950226k
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:84502
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:25 Jan 2018 17:35
Last Modified:03 Oct 2019 19:19

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