Document Detail


Proteomics guided discovery of flavopeptins: anti-proliferative aldehydes synthesized by a reductase domain-containing non-ribosomal peptide synthetase.
MedLine Citation:
PMID:  23763305     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Due to the importance of proteases in regulating cellular processes, the development of protease inhibitors has garnered great attention. Peptide-based aldehydes are a class of compounds that exhibit inhibitory activities against various proteases and proteasomes in the context of anti-proliferative treatments for cancer and other diseases. More than a dozen peptide-based natural products containing aldehydes have been discovered such as chymostatin, leupeptin, and fellutamide; however, the biosynthetic origin of the aldehyde functionality has yet to be elucidated. Herein we describe the discovery of a new group of lipopeptide aldehydes, the flavopeptins, and the corresponding biosynthetic pathway arising from an orphan gene cluster in Streptomyces sp. NRRL-F6652, a close relative of Streptomyces flavogriseus ATCC 33331. This research was initiated using a proteomics approach that screens for expressed enzymes involved in secondary metabolism in microorganisms. Flavopeptins are synthesized through a non-ribosomal peptide synthetase containing a terminal NAD(P)H-dependent reductase domain likely for the reductive release of the peptide with a C-terminal aldehyde. Solid-phase peptide synthesis of several flavopeptin species and derivatives enabled structural verification and subsequent screening of biological activity. Flavopeptins exhibit sub-micromolar inhibition activities against cysteine proteases such as papain and calpain as well as the human 20S proteasome. They also show anti-proliferative activities against multiple myeloma and lymphoma cell lines.
Authors:
Yunqiu Chen; Ryan A McClure; Yupeng Zheng; Regan J Thomson; Neil L Kelleher
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2013-07-02
Journal Detail:
Title:  Journal of the American Chemical Society     Volume:  135     ISSN:  1520-5126     ISO Abbreviation:  J. Am. Chem. Soc.     Publication Date:  2013 Jul 
Date Detail:
Created Date:  2013-07-18     Completed Date:  2014-02-13     Revised Date:  2014-07-20    
Medline Journal Info:
Nlm Unique ID:  7503056     Medline TA:  J Am Chem Soc     Country:  United States    
Other Details:
Languages:  eng     Pagination:  10449-56     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Aldehydes / chemistry,  metabolism,  pharmacology*
Antineoplastic Agents / chemistry,  metabolism,  pharmacology*
Calpain / antagonists & inhibitors,  metabolism
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Molecular Conformation
Oligopeptides / biosynthesis,  chemistry,  pharmacology*
Oxidoreductases / chemistry,  metabolism*
Papain / antagonists & inhibitors,  metabolism
Peptide Synthases / chemistry,  metabolism*
Proteasome Inhibitors / chemistry,  metabolism,  pharmacology*
Proteomics*
Structure-Activity Relationship
Grant Support
ID/Acronym/Agency:
GM067725/GM/NIGMS NIH HHS; P30 CA060553/CA/NCI NIH HHS; R01 GM067725/GM/NIGMS NIH HHS; T32 GM105538/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Aldehydes; 0/Antineoplastic Agents; 0/Oligopeptides; 0/Proteasome Inhibitors; EC 1.-/Oxidoreductases; EC 3.4.22.-/Calpain; EC 3.4.22.2/Papain; EC 6.3.2.-/Peptide Synthases; EC 6.3.2.-/non-ribosomal peptide synthase
Comments/Corrections

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


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