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

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.
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Contributor : Kira Weissman-Sourmail Connect in order to contact the contributor
Submitted on : Wednesday, January 26, 2022 - 7:53:36 PM
Last modification on : Tuesday, May 10, 2022 - 3:40:44 AM

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Li Su, Laurence Hôtel, Cédric Paris, Clara Chepkirui, Alexander Brachmann, et al.. Engineering the stambomycin modular polyketide synthase yields 37-membered mini-stambomycins. Nature Communications, Nature Publishing Group, 2022, 13 (1), pp.515. ⟨10.1038/s41467-022-27955-z⟩. ⟨hal-03544763⟩



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