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Enantioselective [2+2]-cycloadditions with triplet photoenzymes

Author

Listed:
  • Ningning Sun

    (Huazhong University of Science and Technology (HUST))

  • Jianjian Huang

    (Huazhong University of Science and Technology (HUST))

  • Junyi Qian

    (Northwest University)

  • Tai-Ping Zhou

    (Huazhong University of Science and Technology (HUST))

  • Juan Guo

    (Huazhong University of Science and Technology (HUST))

  • Langyu Tang

    (Huazhong University of Science and Technology (HUST))

  • Wentao Zhang

    (Huazhong University of Science and Technology (HUST))

  • Yaming Deng

    (Huazhong University of Science and Technology (HUST))

  • Weining Zhao

    (Shenzhen Technology University)

  • Guojiao Wu

    (Huazhong University of Science and Technology (HUST))

  • Rong-Zhen Liao

    (Huazhong University of Science and Technology (HUST))

  • Xi Chen

    (Northwest University)

  • Fangrui Zhong

    (Huazhong University of Science and Technology (HUST))

  • Yuzhou Wu

    (Huazhong University of Science and Technology (HUST))

Abstract

Naturally evolved enzymes, despite their astonishingly large variety and functional diversity, operate predominantly through thermochemical activation. Integrating prominent photocatalysis modes into proteins, such as triplet energy transfer, could create artificial photoenzymes that expand the scope of natural biocatalysis1–3. Here, we exploit genetically reprogrammed, chemically evolved photoenzymes embedded with a synthetic triplet photosensitizer that are capable of excited-state enantio-induction4–6. Structural optimization through four rounds of directed evolution afforded proficient variants for the enantioselective intramolecular [2+2]-photocycloaddition of indole derivatives with good substrate generality and excellent enantioselectivities (up to 99% enantiomeric excess). A crystal structure of the photoenzyme–substrate complex elucidated the non-covalent interactions that mediate the reaction stereochemistry. This study expands the energy transfer reactivity7–10 of artificial triplet photoenzymes in a supramolecular protein cavity and unlocks an integrated approach to valuable enantioselective photochemical synthesis that is not accessible with either the synthetic or the biological world alone.

Suggested Citation

  • Ningning Sun & Jianjian Huang & Junyi Qian & Tai-Ping Zhou & Juan Guo & Langyu Tang & Wentao Zhang & Yaming Deng & Weining Zhao & Guojiao Wu & Rong-Zhen Liao & Xi Chen & Fangrui Zhong & Yuzhou Wu, 2022. "Enantioselective [2+2]-cycloadditions with triplet photoenzymes," Nature, Nature, vol. 611(7937), pages 715-720, November.
  • Handle: RePEc:nat:nature:v:611:y:2022:i:7937:d:10.1038_s41586-022-05342-4
    DOI: 10.1038/s41586-022-05342-4
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    Cited by:

    1. Haoran Huang & Tao Yan & Chang Liu & Yuxiang Lu & Zhigang Wu & Xingchu Wang & Jie Wang, 2024. "Genetically encoded Nδ-vinyl histidine for the evolution of enzyme catalytic center," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    2. Jianjian Huang & Tai-Ping Zhou & Ningning Sun & Huaibin Yu & Xixiang Yu & Rong-Zhen Liao & Weijun Yao & Zhifeng Dai & Guojiao Wu & Fangrui Zhong, 2024. "Accessing ladder-shape azetidine-fused indoline pentacycles through intermolecular regiodivergent aza-Paternò–Büchi reactions," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    3. Meng-Fan Wang & Yun-Hu Deng & Yu-Xuan Hong & Jia-Hui Gu & Yong-Yong Cao & Qi Liu & Pierre Braunstein & Jian-Ping Lang, 2023. "In situ observation of a stepwise [2 + 2] photocycloaddition process using fluorescence spectroscopy," Nature Communications, Nature, vol. 14(1), pages 1-9, December.
    4. Amy E. Hutton & Jake Foster & Rebecca Crawshaw & Florence J. Hardy & Linus O. Johannissen & Thomas M. Lister & Emilie F. Gérard & Zachary Birch-Price & Richard Obexer & Sam Hay & Anthony P. Green, 2024. "A non-canonical nucleophile unlocks a new mechanistic pathway in a designed enzyme," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

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