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

Autor: Su L; Université de Lorraine, CNRS, IMoPA, F-54000, Nancy, France.; Université de Lorraine, INRAE, DynAMic, F-54000, Nancy, France.; Max-Planck-Institute for Terrestrial Microbiology, Department of Natural Products in Organismic Interactions, 35043, Marburg, Germany., Hôtel L; Université de Lorraine, INRAE, DynAMic, F-54000, Nancy, France., Paris C; Université de Lorraine, LIBio, F-54000, Nancy, France., Chepkirui C; Institute of Microbiology, Eidgenössische Technische Hochschule (ETH) Zurich, 8093, Zurich, Switzerland., Brachmann AO; Institute of Microbiology, Eidgenössische Technische Hochschule (ETH) Zurich, 8093, Zurich, Switzerland., Piel J; Institute of Microbiology, Eidgenössische Technische Hochschule (ETH) Zurich, 8093, Zurich, Switzerland., Jacob C; Université de Lorraine, CNRS, IMoPA, F-54000, Nancy, France. christophe.jacob@univ-lorraine.fr., Aigle B; Université de Lorraine, INRAE, DynAMic, F-54000, Nancy, France. bertrand.aigle@univ-lorraine.fr., Weissman KJ; Université de Lorraine, CNRS, IMoPA, F-54000, Nancy, France. kira.weissman@univ-lorraine.fr.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Jan 26; Vol. 13 (1), pp. 515. Date of Electronic Publication: 2022 Jan 26.
DOI: 10.1038/s41467-022-27955-z
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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