IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v12y2021i1d10.1038_s41467-021-22497-2.html
   My bibliography  Save this article

Computationally-guided exchange of substrate selectivity motifs in a modular polyketide synthase acyltransferase

Author

Listed:
  • Edward Kalkreuter

    (NC State University
    Comparative Medicine Institute, NC State University
    The Scripps Research Institute)

  • Kyle S. Bingham

    (NC State University
    UNC Chapel Hill School of Medicine)

  • Aaron M. Keeler

    (NC State University)

  • Andrew N. Lowell

    (University of Michigan
    Virginia Tech)

  • Jennifer J. Schmidt

    (University of Michigan)

  • David H. Sherman

    (University of Michigan
    University of Michigan)

  • Gavin J. Williams

    (NC State University
    Comparative Medicine Institute, NC State University)

Abstract

Polyketides, one of the largest classes of natural products, are often clinically relevant. The ability to engineer polyketide biosynthesis to produce analogs is critically important. Acyltransferases (ATs) of modular polyketide synthases (PKSs) catalyze the installation of malonyl-CoA extenders into polyketide scaffolds. ATs have been targeted extensively to site-selectively introduce various extenders into polyketides. Yet, a complete inventory of AT residues responsible for substrate selection has not been established, limiting the scope of AT engineering. Here, molecular dynamics simulations are used to prioritize ~50 mutations within the active site of EryAT6 from erythromycin biosynthesis, leading to identification of two previously unexplored structural motifs. Exchanging both motifs with those from ATs with alternative extender specificities provides chimeric PKS modules with expanded and inverted substrate specificity. Our enhanced understanding of AT substrate selectivity and application of this motif-swapping strategy are expected to advance our ability to engineer PKSs towards designer polyketides.

Suggested Citation

  • Edward Kalkreuter & Kyle S. Bingham & Aaron M. Keeler & Andrew N. Lowell & Jennifer J. Schmidt & David H. Sherman & Gavin J. Williams, 2021. "Computationally-guided exchange of substrate selectivity motifs in a modular polyketide synthase acyltransferase," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22497-2
    DOI: 10.1038/s41467-021-22497-2
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-021-22497-2
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-021-22497-2?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Jianhua Wei & Xuan Zhang & Yucong Zhou & Xingnuo Cheng & Zhi Lin & Mancheng Tang & Jianting Zheng & Binju Wang & Qianjin Kang & Linquan Bai, 2022. "Endowing homodimeric carbamoyltransferase GdmN with iterative functions through structural characterization and mechanistic studies," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    2. Allwin D. McDonald & Peyton M. Higgins & Andrew R. Buller, 2022. "Substrate multiplexed protein engineering facilitates promiscuous biocatalytic synthesis," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    3. Guifa Zhai & Yan Zhu & Guo Sun & Fan Zhou & Yangning Sun & Zhou Hong & Chuan Dong & Peter F. Leadlay & Kui Hong & Zixin Deng & Fuling Zhou & Yuhui Sun, 2023. "Insights into azalomycin F assembly-line contribute to evolution-guided polyketide synthase engineering and identification of intermodular recognition," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22497-2. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.