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Gating mechanism of elongating β-ketoacyl-ACP synthases

Author

Listed:
  • Jeffrey T. Mindrebo

    (University of California
    Jack H. Skirball Center for Chemical Biology and Proteomics, Salk Institute for Biological Studies)

  • Ashay Patel

    (University of California)

  • Woojoo E. Kim

    (University of California)

  • Tony D. Davis

    (University of California)

  • Aochiu Chen

    (University of California)

  • Thomas G. Bartholow

    (University of California)

  • James J. Clair

    (University of California
    Jack H. Skirball Center for Chemical Biology and Proteomics, Salk Institute for Biological Studies)

  • J. Andrew McCammon

    (University of California
    University of California)

  • Joseph P. Noel

    (University of California
    Jack H. Skirball Center for Chemical Biology and Proteomics, Salk Institute for Biological Studies
    Howard Hughes Medical Institute, Salk Institute for Biological Studies)

  • Michael D. Burkart

    (University of California)

Abstract

Carbon-carbon bond forming reactions are essential transformations in natural product biosynthesis. During de novo fatty acid and polyketide biosynthesis, β-ketoacyl-acyl carrier protein (ACP) synthases (KS), catalyze this process via a decarboxylative Claisen-like condensation reaction. KSs must recognize multiple chemically distinct ACPs and choreograph a ping-pong mechanism, often in an iterative fashion. Here, we report crystal structures of substrate mimetic bearing ACPs in complex with the elongating KSs from Escherichia coli, FabF and FabB, in order to better understand the stereochemical features governing substrate discrimination by KSs. Complemented by molecular dynamics (MD) simulations and mutagenesis studies, these structures reveal conformational states accessed during KS catalysis. These data taken together support a gating mechanism that regulates acyl-ACP binding and substrate delivery to the KS active site. Two active site loops undergo large conformational excursions during this dynamic gating mechanism and are likely evolutionarily conserved features in elongating KSs.

Suggested Citation

  • Jeffrey T. Mindrebo & Ashay Patel & Woojoo E. Kim & Tony D. Davis & Aochiu Chen & Thomas G. Bartholow & James J. Clair & J. Andrew McCammon & Joseph P. Noel & Michael D. Burkart, 2020. "Gating mechanism of elongating β-ketoacyl-ACP synthases," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-15455-x
    DOI: 10.1038/s41467-020-15455-x
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    Cited by:

    1. Jialiang Wang & Xiaojie Wang & Xixi Li & LiangLiang Kong & Zeqian Du & Dandan Li & Lixia Gou & Hao Wu & Wei Cao & Xiaozheng Wang & Shuangjun Lin & Ting Shi & Zixin Deng & Zhijun Wang & Jingdan Liang, 2023. "C–N bond formation by a polyketide synthase," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    2. Jiashen Zhou & Lin Zhang & Liping Zeng & Lu Yu & Yuanyuan Duan & Siqi Shen & Jingyan Hu & Pan Zhang & Wenyan Song & Xiaoxue Ruan & Jing Jiang & Yinan Zhang & Lu Zhou & Jia Jia & Xudong Hang & Changlin, 2021. "Helicobacter pylori FabX contains a [4Fe-4S] cluster essential for unsaturated fatty acid synthesis," Nature Communications, Nature, vol. 12(1), pages 1-13, December.

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