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Exploration of the Substrate Promiscuity of Biosynthetic Tailoring Enzymes as a New Source of Structural Diversity for Polyene Macrolide Antifungals
Author(s) -
SantosAberturas Javier,
Engel Jennifer,
Dickerhoff Jonathan,
Dörr Mark,
Rudroff Florian,
Weisz Klaus,
Bornscheuer Uwe T.
Publication year - 2015
Publication title -
chemcatchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.497
H-Index - 106
eISSN - 1867-3899
pISSN - 1867-3880
DOI - 10.1002/cctc.201402773
Subject(s) - polyene , chemistry , substrate (aquarium) , enzyme , stereochemistry , combinatorial chemistry , biochemistry , biology , ecology
Even though there is an urgent need for new antifungals with improved clinical properties, the substrate promiscuity of tailoring enzymes has been poorly studied as a source of new structural diversity for polyene macrolides. We explore the acceptance of different polyene macrolides by the glutamine amidotransferase PscA and the catalytic effect of different homologous P450 cytochromes on a common scaffold, the pimaricin precursor 4,5‐desepoxypimaricin. By combining these two parallel strategies, we present three new pimaricin derivatives and a new lucensomycin variant. Our results show that P450 cytochromes devoted to the modification of the polyol region of polyene macrolides are not as substrate‐specific as previously thought and highlight PscA as a versatile small‐ring polyene‐modifying enzyme that allows the preparation of new carboxamide derivatives. We also provide useful information for the future production of previously unconceived epoxidized polyene macrolide antifungals.