Document Detail

Broad substrate specificity of the amide synthase in S. hygroscopicus--new 20-membered macrolactones derived from geldanamycin.
MedLine Citation:
PMID:  22136518     Owner:  NLM     Status:  MEDLINE    
The amide synthase of the geldanamycin producer, Streptomyces hygroscopicus, shows a broader chemoselectivity than the corresponding amide synthase present in Actinosynnema pretiosum, the producer of the highly cytotoxic ansamycin antibiotics, the ansamitocins. This was demonstrated when blocked mutants of both strains incapable of biosynthesizing 3-amino-5-hydroxybenzoic acid (AHBA), the polyketide synthase starter unit of both natural products, were supplemented with 3-amino-5-hydroxymethylbenzoic acid instead. Unlike the ansamitocin producer A. pretiosum, S. hygroscopicus processed this modified starter unit not only to the expected 19-membered macrolactams but also to ring enlarged 20-membered macrolactones. The former mutaproducts revealed the sequence of transformations catalyzed by the post-PKS tailoring enzymes in geldanamycin biosynthesis. The unprecedented formation of the macrolactones together with molecular modeling studies shed light on the mode of action of the amide synthase responsible for macrocyclization. Obviously, the 3-hydroxymethyl substituent shows similar reactivity and accessibility toward C-1 of the seco-acid as the arylamino group, while phenolic hydroxyl groups lack this propensity to act as nucleophiles in the macrocyclization. The promiscuity of the amide synthase of S. hygroscopicus was further demonstrated by successful feeding of four other m-hydroxymethylbenzoic acids, leading to formation of the expected 20-membered macrocycles. Good to moderate antiproliferative activities were encountered for three of the five new geldanamycin derivatives, which matched well with a competition assay for Hsp90α.
Simone Eichner; Timo Eichner; Heinz G Floss; Jörg Fohrer; Edgar Hofer; Florenz Sasse; Carsten Zeilinger; Andreas Kirschning
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-01-10
Journal Detail:
Title:  Journal of the American Chemical Society     Volume:  134     ISSN:  1520-5126     ISO Abbreviation:  J. Am. Chem. Soc.     Publication Date:  2012 Jan 
Date Detail:
Created Date:  2012-01-26     Completed Date:  2012-05-22     Revised Date:  2013-06-27    
Medline Journal Info:
Nlm Unique ID:  7503056     Medline TA:  J Am Chem Soc     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1673-9     Citation Subset:  IM    
Copyright Information:
© 2011 American Chemical Society
Institute of Organic Chemistry and Center of Biomolecular Research (BMWZ), Schneiderberg 1B, Leibniz University Hannover, D-30167 Hannover, Germany.
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MeSH Terms
Amide Synthases / chemistry,  metabolism*
Amino Acid Sequence
Benzoquinones / chemistry,  metabolism*
Lactams, Macrocyclic / chemistry,  metabolism*
Models, Molecular
Molecular Sequence Data
Sequence Alignment
Streptomyces / chemistry,  enzymology*
Substrate Specificity
Grant Support
CA76461/CA/NCI NIH HHS; R01 CA076461-02/CA/NCI NIH HHS
Reg. No./Substance:
0/Benzoquinones; 0/Lactams, Macrocyclic; EC 6.3.1.-/Amide Synthases; Z3K3VJ16KU/geldanamycin

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