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Heterologous Production of Fungal Maleidrides Reveals the Cryptic Cyclization Involved in their Biosynthesis
Author(s) -
Williams Katherine,
Szwalbe Agnieszka J.,
Mulholland Nicholas P.,
Vincent Jason L.,
Bailey Andrew M.,
Willis Christine L.,
Simpson Thomas J.,
Cox Russell J.
Publication year - 2016
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201511882
Subject(s) - biosynthesis , heterologous , heterologous expression , biochemistry , chemistry , polyketide , polyketide synthase , stereochemistry , enzyme , aspergillus nidulans , isomerase , thioesterase , gene , biology , recombinant dna , mutant
Fungal maleidrides are an important family of bioactive secondary metabolites that consist of 7, 8, or 9‐membered carbocycles with one or two fused maleic anhydride moieties. The biosynthesis of byssochlamic acid (a nonadride) and agnestadride A (a heptadride) was investigated through gene disruption and heterologous expression experiments. The results reveal that the precursors for cyclization are formed by an iterative highly reducing fungal polyketide synthase supported by a hydrolase, together with two citrate‐processing enzymes. The enigmatic ring formation is catalyzed by two proteins with homology to ketosteroid isomerases, and assisted by two proteins with homology to phosphatidylethanolamine‐binding proteins.