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Biosynthesis and Heterologous Production of Vioprolides: Rational Biosynthetic Engineering and Unprecedented 4‐Methylazetidinecarboxylic Acid Formation
Author(s) -
Yan Fu,
Auerbach David,
Chai Yi,
Keller Lena,
Tu Qiang,
Hüttel Stephan,
Glemser Amelie,
Grab Hanusch A.,
Bach Thorsten,
Zhang Youming,
Müller Rolf
Publication year - 2018
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.201802479
Subject(s) - biosynthesis , heterologous , production (economics) , biochemistry , chemistry , biology , enzyme , gene , macroeconomics , economics
Vioprolides are a promising class of anticancer and antifungal lead compounds produced by the myxobacterium Cystobacter violaceus Cb vi35. Previously nothing had been reported about their biosynthesis, including the origin of the unusual 4‐methylazetidinecarboxylic acid (MAZ) moiety. We describe the vioprolide biosynthetic gene cluster and solve the production obstacle by expression in three heterologous hosts. Starting from unstable production in the wild type at the single‐digit mg L −1 scale, we developed a stable host that eventually allowed for yields of up to half a gram per liter in fermenters. Gene inactivations coupled with isotope feeding studies identified an S‐adenosylmethionine (SAM)‐dependent enzyme and a methyltransferase as being responsible for the generation of the MAZ building block by a proposed mechanism unprecedented in bacteria. Furthermore, nonnatural vioprolide derivatives were generated via rational genetic engineering.