Loss of Single‐Domain Function in a Modular Assembly Line Alters the Size and Shape of a Complex Polyketide

Peng, Huiyun; Ishida, Keishi; Hertweck, Christian

doi:10.1002/ange.201911315

Cited by 6 publications

(2 citation statements)

References 52 publications

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“…Great efforts have been devoted to achieving the rational engineering of modular PKS assembly-lines in the past three decades 44,45 . Although the mutual simulation between homologous PKS assemblylines based on the comparative analyses has been proven to be a feasible engineering method [46][47][48] , it is limited to PKS assembly-lines with homologous gene clusters. Meanwhile, this strategy only takes the homology of inter-PKS assembly-lines into account whereas there existed homologous regions within a PKS assembly-line.…”

Section: Discussionmentioning

confidence: 99%

Insights into azalomycin F assembly-line contribute to evolution-guided polyketide synthase engineering and identification of intermodular recognition

et al. 2023

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Modular polyketide synthase (PKS) is an ingenious core machine that catalyzes abundant polyketides in nature. Exploring interactions among modules in PKS is very important for understanding the overall biosynthetic process and for engineering PKS assembly-lines. Here, we show that intermodular recognition between the enoylreductase domain ER1/2 inside module 1/2 and the ketosynthase domain KS3 inside module 3 is required for the cross-module enoylreduction in azalomycin F (AZL) biosynthesis. We also show that KS4 of module 4 acts as a gatekeeper facilitating cross-module enoylreduction. Additionally, evidence is provided that module 3 and module 6 in the AZL PKS are evolutionarily homologous, which makes evolution-oriented PKS engineering possible. These results reveal intermodular recognition, furthering understanding of the mechanism of the PKS assembly-line, thus providing different insights into PKS engineering. This also reveals that gene duplication/conversion and subsequent combinations may be a neofunctionalization process in modular PKS assembly-lines, hence providing a different case for supporting the investigation of modular PKS evolution.

show abstract

Section: Discussionmentioning

confidence: 99%

Insights into azalomycin F assembly-line contribute to evolution-guided polyketide synthase engineering and identification of intermodular recognition

et al. 2023

View full text Add to dashboard Cite

show abstract

“…Great efforts have been devoted trying to achieve the rational engineering of modular PKS assembly-lines in the past three decades 44,45 . Although the mutual simulation between homologous PKS assembly-lines based on the comparative analyses have been proved to be a feasible engineering method [46][47][48] , it is limited to PKS assembly-lines with homologous gene clusters.…”

Section: Discussionmentioning

confidence: 99%

Insights into azalomycin F assembly-line contribute to evolution-guided polyketide synthase engineering and identification of intermodular recognition

Zhai

Zhu

Sun

et al. 2022

Preprint

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Exploring interactions among modules in modular polyketide synthase (PKS) is very important for understanding the overall biosynthetic process and for engineering PKS assembly-lines. Herein, we show that intermodule recognition between the enoylreductase domain ER1/2 inside module 1/2 and the ketosynthase domain KS3 inside module 3 is required for the cross-module enoylreduction in azalomycin F (AZL) biosynthesis. We also show that KS4 of module 4 acts as a gatekeeper facilitating cross-module enoylreduction. Additionally, evidence is provided that module 3 and module 6 in the AZL PKS are evolutionarily homologous, which make evolution-oriented PKS engineering possible. These results reveal an unprecedented intermodule recognition furthering understanding of the mechanism of the PKS assembly-line, thus providing new insights into PKS engineering. It also reveals that gene duplication/conversion and subsequent combinations may be a neofunctionalization process in modular PKS assembly-lines, hence providing a new case for supporting investigation of modular PKS evolution.

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Cross‐Module Enoylreduction in the Azalomycin F Polyketide Synthase

Zhai

Wang

et al. 2020

Angewandte Chemie

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The colinearity of canonical modular polyketide synthases, which creates a direct link between multienzyme structure and the chemical structure of the biosynthetic end‐product, has become a cornerstone of knowledge‐based genome mining. Herein, we report genetic and enzymatic evidence for the remarkable role of an enoylreductase in the polyketide synthase for azalomycin F biosynthesis. This internal enoylreductase domain, previously identified as acting only in the second of two chain extension cycles on an initial iterative module, is shown to also catalyze enoylreduction in trans within the next module. The mechanism for this rare deviation from colinearity appears to involve direct cross‐modular interaction of the reductase with the longer acyl chain, rather than back transfer of the substrate into the iterative module, suggesting an additional and surprising plasticity in natural PKS assembly‐line catalysis.

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Loss of Single‐Domain Function in a Modular Assembly Line Alters the Size and Shape of a Complex Polyketide

Abstract: Supportinginformation and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.org/10.

Cited by 6 publications

References 52 publications

Insights into azalomycin F assembly-line contribute to evolution-guided polyketide synthase engineering and identification of intermodular recognition

Insights into azalomycin F assembly-line contribute to evolution-guided polyketide synthase engineering and identification of intermodular recognition

Insights into azalomycin F assembly-line contribute to evolution-guided polyketide synthase engineering and identification of intermodular recognition

Cross‐Module Enoylreduction in the Azalomycin F Polyketide Synthase

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