Document Detail


Complexity generation in fungal peptidyl alkaloid biosynthesis: a two-enzyme pathway to the hexacyclic MDR export pump inhibitor ardeemin.
MedLine Citation:
PMID:  23330675     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Ardeemins are hexacyclic peptidyl alkaloids isolated from Aspergillus fischeri as agents that block efflux of anticancer drugs by MultiDrug Resistance (MDR) export pumps. To evaluate the biosynthetic logic and enzymatic machinery for ardeemin framework assembly, we sequenced the A. fischeri genome and identified the ardABC gene cluster. Through both genetic deletions and biochemical characterizations of purified ArdA and ArdB we show this ArdAB enzyme pair is sufficient to convert anthranilate (Ant), L-Ala, and L-Trp to ardeemin. ArdA is a 430 kDa trimodular nonribosomal peptide synthase (NRPS) that converts the three building blocks into a fumiquinazoline (FQ) regioisomer termed ardeemin FQ. ArdB is a prenyltransferase that takes tricyclic ardeemin FQ and dimethylallyl diphosphate to the hexacyclic ardeemin scaffold via prenylation at C2 of the Trp-derived indole moiety with intramolecular capture by an amide NH of the fumiquinazoline ring. The two-enzyme ArdAB pathway reveals remarkable efficiency in construction of the hexacyclic peptidyl alkaloid scaffold.
Authors:
Stuart W Haynes; Xue Gao; Yi Tang; Christopher T Walsh
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Validation Studies     Date:  2013-02-06
Journal Detail:
Title:  ACS chemical biology     Volume:  8     ISSN:  1554-8937     ISO Abbreviation:  ACS Chem. Biol.     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-04-19     Completed Date:  2013-10-17     Revised Date:  2013-12-03    
Medline Journal Info:
Nlm Unique ID:  101282906     Medline TA:  ACS Chem Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  741-8     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Alkaloids / biosynthesis*
Aspergillus / enzymology,  genetics,  metabolism*
Base Sequence
Computational Biology
DNA Primers
Genes, Fungal
Indole Alkaloids / pharmacology*
Multidrug Resistance-Associated Proteins / antagonists & inhibitors*
Polymerase Chain Reaction
Grant Support
ID/Acronym/Agency:
GM092217/GM/NIGMS NIH HHS; GM20011/GM/NIGMS NIH HHS; GM49338/GM/NIGMS NIH HHS; R01 GM020011/GM/NIGMS NIH HHS; R01 GM049338/GM/NIGMS NIH HHS; R01 GM092217/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Alkaloids; 0/DNA Primers; 0/Indole Alkaloids; 0/Multidrug Resistance-Associated Proteins; 0/ardeemin

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


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