Document Detail


SylC catalyzes ureido-bond formation during biosynthesis of the proteasome inhibitor syringolin A.
MedLine Citation:
PMID:  19968303     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Syringolins are a class of cyclic tripeptide natural products that are potent and irreversible inhibitors of the eukaryotic proteasome. In addition to being hybrid NRPS/PKS molecules, they also feature an unusual ureido-linkage (red) between two amino acid monomers. Here we report the first in vitro characterization of enzymatic ureido-linkage formation which is catalyzed by an NRPS, SylC. Using (13)C- and (18)O-labeling studies, we show that biosynthesis occurs via N-carboxylation to form an initial N-carboxy-aminoacyl-S-Ppant enzyme intermediate which undergoes intramolecular cyclization followed by condensation with a second amino acid to form the ureido-containing dipeptide product.
Authors:
Heidi J Imker; Christopher T Walsh; William M Wuest
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Journal of the American Chemical Society     Volume:  131     ISSN:  1520-5126     ISO Abbreviation:  J. Am. Chem. Soc.     Publication Date:  2009 Dec 
Date Detail:
Created Date:  2009-12-23     Completed Date:  2010-03-02     Revised Date:  2013-05-31    
Medline Journal Info:
Nlm Unique ID:  7503056     Medline TA:  J Am Chem Soc     Country:  United States    
Other Details:
Languages:  eng     Pagination:  18263-5     Citation Subset:  IM    
Affiliation:
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115. USA.
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MeSH Terms
Descriptor/Qualifier:
Amino Acids / chemistry
Catalysis
Peptides, Cyclic / biosynthesis*,  chemical synthesis
Proteasome Inhibitors*
Urea / chemistry
Grant Support
ID/Acronym/Agency:
GM49338/GM/NIGMS NIH HHS; R01 GM049338-17/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Amino Acids; 0/Peptides, Cyclic; 0/Proteasome Inhibitors; 0/syringolin A; 57-13-6/Urea
Comments/Corrections

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


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