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Engineering fatty acid synthases for directed polyketide production

Nature Chemical Biology volume 13, pages 363–365 (2017)Cite this article

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Abstract

In this study, we engineered fatty acid synthases (FAS) for the biosynthesis of short-chain fatty acids and polyketides, guided by a combined in vitro and in silico approach. Along with exploring the synthetic capability of FAS, we aim to build a foundation for efficient protein engineering, with the specific goal of harnessing evolutionarily related megadalton-scale polyketide synthases (PKS) for the tailored production of bioactive natural compounds.

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Figure 1: Engineered reaction pathway for 6-HHP.
Figure 2: FAS mediated synthesis and computational modeling.

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Acknowledgements

We thank A. Matijczak and M. Enderle for starting the project with us by establishing purification of Corynebacterium ammoniagenes FAS and cloning first constructs. M.G. and H.G. thank D. Oesterhelt for continuous support over many years and for initiating the collaboration between H.G. and M.G. This work was supported by a Lichtenberg Grant of the Volkswagen Foundation to M.G. (grant number 85 701), the German Federal Ministry of Education and Research to F.B. (grant number 0315450I), the DFG excellence program CNMBP to F.B. (DFG-EXC 171), and the Max Planck Society (H.G., F.B.).

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Author notes

  1. Jan Gajewski and Floris Buelens: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Organic Chemistry and Chemical Biology, Buchmann Institute for Molecular Life Sciences, Cluster of Excellence “Macromolecular Complexes,” Goethe University Frankfurt, Frankfurt am Main, Germany

    Jan Gajewski, Melanie Janßen, Niña Cortina & Martin Grininger

  2. Department of Theoretical and Computational Biophysics, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany

    Floris Buelens & Helmut Grubmüller

  3. Max Planck Institute of Biochemistry, Project Group Biological Chemistry, Martinsried, Germany

    Sascha Serdjukow & Martin Grininger

Authors
  1. Jan Gajewski
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  2. Floris Buelens
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  3. Sascha Serdjukow
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  4. Melanie Janßen
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  6. Helmut Grubmüller
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  7. Martin Grininger
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Contributions

J.G., S.S., M.J. and M.G. performed biochemical studies; J.G. and M.G. analyzed biochemical data; N.C. supported MS-based product analysis; F.B. performed kinetic and atomistic modeling; J.G., F.B., H.G. and M.G. designed research; J.G., F.B., H.G. and M.G. wrote the manuscript.

Corresponding authors

Correspondence to Helmut Grubmüller or Martin Grininger.

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Competing interests

J.G. and M.G. are inventors of EP patent applications 15 174 342.4 (filed on June 26th, 2015) and 15 162 192.7 (filed on April 1st, 2015) on FAS mutations for short FA production.

Supplementary information

Supplementary Text and Figures

Supplementary Results, Supplementary Tables 1–3, Supplementary Figures 1–16 and Supplementary Notes 1–3. (PDF 8370 kb)

Supplementary Software

Modeling implementation for supplementary information. (TAR 10480 kb)

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Gajewski, J., Buelens, F., Serdjukow, S. et al. Engineering fatty acid synthases for directed polyketide production. Nat Chem Biol 13, 363–365 (2017). https://doi.org/10.1038/nchembio.2314

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