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Substrate specificity of a branch of aromatic dioxygenases determined by three distinct motifs

Author

Listed:
  • Chengsen Cui

    (Chinese Academy of Sciences
    National Center of Technology Innovation for Synthetic Biology)

  • Lu-Jia Yang

    (Chinese Academy of Sciences
    National Center of Technology Innovation for Synthetic Biology)

  • Zi-Wei Liu

    (Hubei University)

  • Xian Shu

    (Chinese Academy of Sciences)

  • Wei-Wei Zhang

    (Chinese Academy of Sciences
    Chinese Academy of Sciences)

  • Yuan Gao

    (Chinese Academy of Sciences
    Chinese Academy of Sciences)

  • Yu-Xuan Wang

    (Hubei University)

  • Te Wang

    (Hubei University)

  • Chun-Chi Chen

    (Hubei University
    Hangzhou Normal University)

  • Rey-Ting Guo

    (Hubei University
    Hangzhou Normal University)

  • Shu-Shan Gao

    (Chinese Academy of Sciences
    National Center of Technology Innovation for Synthetic Biology
    Chinese Academy of Sciences)

Abstract

The inversion of substrate size specificity is an evolutionary roadblock for proteins. The Duf4243 dioxygenases GedK and BTG13 are known to catalyze the aromatic cleavage of bulky tricyclic hydroquinone. In this study, we discover a Duf4243 dioxygenase PaD that favors small monocyclic hydroquinones from the penicillic-acid biosynthetic pathway. Sequence alignments between PaD and GedK and BTG13 suggest PaD has three additional motifs, namely motifs 1-3, distributed at different positions in the protein sequence. X-ray crystal structures of PaD with the substrate at high resolution show motifs 1-3 determine three loops (loops 1-3). Most intriguing, loops 1-3 stack together at the top of the pocket, creating a lid-like tertiary structure with a narrow channel and a clearly constricted opening. This drastically changes the substrate specificity by determining the entry and binding of much smaller substrates. Further genome mining suggests Duf4243 dioxygenases with motifs 1-3 belong to an evolutionary branch that is extensively involved in the biosynthesis of natural products and has the ability to degrade diverse monocyclic hydroquinone pollutants. This study showcases how natural enzymes alter the substrate specificity fundamentally by incorporating new small motifs, with a fixed overall scaffold-architecture. It will also offer a theoretical foundation for the engineering of substrate specificity in enzymes and act as a guide for the identification of aromatic dioxygenases with distinct substrate specificities.

Suggested Citation

  • Chengsen Cui & Lu-Jia Yang & Zi-Wei Liu & Xian Shu & Wei-Wei Zhang & Yuan Gao & Yu-Xuan Wang & Te Wang & Chun-Chi Chen & Rey-Ting Guo & Shu-Shan Gao, 2024. "Substrate specificity of a branch of aromatic dioxygenases determined by three distinct motifs," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52101-2
    DOI: 10.1038/s41467-024-52101-2
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    1. Xu Qiu & Yueqian Sang & Hao Wu & Xiao-Song Xue & Zixi Yan & Yachong Wang & Zengrui Cheng & Xiaoyang Wang & Hui Tan & Song Song & Guisheng Zhang & Xiaohui Zhang & K. N. Houk & Ning Jiao, 2021. "Cleaving arene rings for acyclic alkenylnitrile synthesis," Nature, Nature, vol. 597(7874), pages 64-69, September.
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