Engineering the stambomycin modular polyketide synthase yields 37-membered mini-stambomycins

Li Su, Laurence Hôtel, Cédric Paris, Clara Chepkirui, Alexander O. Brachmann, Jörn Piel, Christophe Jacob (), Bertrand Aigle () and Kira J. Weissman ()
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Li Su: Université de Lorraine, CNRS, IMoPA
Laurence Hôtel: Université de Lorraine, INRAE, DynAMic
Cédric Paris: Université de Lorraine, LIBio
Clara Chepkirui: Institute of Microbiology, Eidgenössische Technische Hochschule (ETH) Zurich
Alexander O. Brachmann: Institute of Microbiology, Eidgenössische Technische Hochschule (ETH) Zurich
Jörn Piel: Institute of Microbiology, Eidgenössische Technische Hochschule (ETH) Zurich
Christophe Jacob: Université de Lorraine, CNRS, IMoPA
Bertrand Aigle: Université de Lorraine, INRAE, DynAMic
Kira J. Weissman: Université de Lorraine, CNRS, IMoPA

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract The modular organization of the type I polyketide synthases (PKSs) would seem propitious for rational engineering of desirable analogous. However, despite decades of efforts, such experiments remain largely inefficient. Here, we combine multiple, state-of-the-art approaches to reprogram the stambomycin PKS by deleting seven internal modules. One system produces the target 37-membered mini-stambomycin metabolites − a reduction in chain length of 14 carbons relative to the 51-membered parental compounds − but also substantial quantities of shunt metabolites. Our data also support an unprecedented off-loading mechanism of such stalled intermediates involving the C-terminal thioesterase domain of the PKS. The mini-stambomycin yields are reduced relative to wild type, likely reflecting the poor tolerance of the modules downstream of the modified interfaces to the non-native substrates. Overall, we identify factors contributing to the productivity of engineered whole assembly lines, but our findings also highlight the need for further research to increase production titers.

Date: 2022
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DOI: 10.1038/s41467-022-27955-z

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