Document Detail


Neoglycopeptides as inhibitors of oligosaccharyl transferase: insight into negotiating product inhibition.
MedLine Citation:
PMID:  12498885     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Linear hexapeptides featuring the asparagine mimetics alanine-beta-hydrazide, alanine-beta-hydroxylamine, and 1,3-diaminobutanoic acid have been synthesized as oligosaccharyl transferase (OT) substrate mimetics and chemoselectively N-glycosylated to obtain the corresponding neoglycopeptides as OT product mimetics. The effect of glycosylation on the binding of these asparagine surrogates is in stark contrast with the effect of modification of native asparagine. In native N-linked glycosylation, product inhibition is minimal and glycopeptides show very low affinity for OT. In contrast, glycosylation of the substrate mimetics maintains or even improves affinity of the corresponding product mimetic for OT. Conformational considerations suggest that the flexibility of the N-glycosyl linkage in these neoglycopeptides allows them to be accommodated in the OT binding site while the native trans glycosyl amide linkage is rejected. These results provide insight into how OT minimizes product inhibition, thereby ensuring effective substrate turnover.
Authors:
Stéphane Peluso; Maria de L Ufret; Mary K O'Reilly; Barbara Imperiali
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Chemistry & biology     Volume:  9     ISSN:  1074-5521     ISO Abbreviation:  Chem. Biol.     Publication Date:  2002 Dec 
Date Detail:
Created Date:  2002-12-24     Completed Date:  2003-10-31     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  9500160     Medline TA:  Chem Biol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1323-8     Citation Subset:  IM    
Affiliation:
Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
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MeSH Terms
Descriptor/Qualifier:
Binding, Competitive
Carbohydrate Conformation
Glycopeptides / chemical synthesis*,  chemistry,  pharmacology*
Hexosyltransferases*
Membrane Proteins*
Molecular Mimicry
Saccharomyces cerevisiae Proteins
Structure-Activity Relationship
Transferases / antagonists & inhibitors*
Grant Support
ID/Acronym/Agency:
GM-39334/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Glycopeptides; 0/Membrane Proteins; 0/Saccharomyces cerevisiae Proteins; EC 2.-/Transferases; EC 2.4.1.-/Hexosyltransferases; EC 2.4.1.119/dolichyl-diphosphooligosaccharide - protein glycotransferase
Comments/Corrections
Comment In:
Chem Biol. 2002 Dec;9(12):1266-8   [PMID:  12498877 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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