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Free Piperazic Acid as a Precursor to Nonribosomal Peptides

  • Zi-Wang Wei
    Zi-Wang Wei
    Department of Chemistry, The University of British Columbia, Vancouver, British Columbia V6T 1Z1, Canada
    More by Zi-Wang Wei
  • Haruka Niikura
    Haruka Niikura
    Department of Chemistry, The University of British Columbia, Vancouver, British Columbia V6T 1Z1, Canada
  • Kalindi D. Morgan
    Kalindi D. Morgan
    Department of Chemistry, The University of British Columbia, Vancouver, British Columbia V6T 1Z1, Canada
  • Condurache M. Vacariu
    Condurache M. Vacariu
    Department of Chemistry, The University of British Columbia, Vancouver, British Columbia V6T 1Z1, Canada
  • Raymond J. Andersen
    Raymond J. Andersen
    Department of Chemistry  and  Department of Earth, Ocean and Atmospheric Science, The University of British Columbia, Vancouver, British Columbia V6T 1Z1, Canada
  • , and 
  • Katherine S. Ryan*
    Katherine S. Ryan
    Department of Chemistry, The University of British Columbia, Vancouver, British Columbia V6T 1Z1, Canada
    *Email: [email protected]
Cite this: J. Am. Chem. Soc. 2022, 144, 30, 13556–13564
Publication Date (Web):July 22, 2022
https://doi.org/10.1021/jacs.2c03660
Copyright © 2022 American Chemical Society

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    Abstract

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    Piperazic acid (Piz) is a nonproteinogenic amino acid possessing a rare nitrogen–nitrogen bond. However, little is known about how Piz is incorporated into nonribosomal peptides, including whether adenylation domains specific to Piz exist. In this study, we show that free piperazic acid is directly adenylated and then incorporated into the incarnatapeptin nonribosomal peptides through isotopic incorporation studies. We also use in vitro reconstitution to demonstrate adenylation of free piperazic acid with a three-domain nonribosomal peptide synthetase from the incarnatapeptin gene cluster. We furthermore use bioinformatics and site-directed mutagenesis to outline consensus sequences for the adenylation of piperazic acid, which can now be used for the prediction of gene clusters linked to piperazic-acid-containing peptides. Finally, we discover a fusion protein of a piperazate synthase and an adenylation domain, highlighting the close biosynthetic relationship of piperazic acid formation and its adenylation. Altogether, our work demonstrates the evolution of biosynthetic systems for the activation of free piperazic acid through adenylation, a pathway we suggest is likely to be employed in the majority of pathways to piperazic-acid-containing peptides.

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.2c03660.

    • Experimental methods (Tables S1–S6) (Figures S1–S19) (PDF)

    • List of potential adenylation domains (XLSX)

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    Cited By

    This article is cited by 7 publications.

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    2. Huiming Huang, Liangguang Yue, Fayu Deng, Xiaoyu Wang, Ning Wang, Hu Chen, Huayue Li. NMR-Metabolomic Profiling and Genome Mining Drive the Discovery of Cyclic Decapeptides from a Marine Streptomyces. Journal of Natural Products 2023, 86 (9) , 2122-2130. https://doi.org/10.1021/acs.jnatprod.3c00310
    3. Daniel Shin, Woong Sub Byun, Sangwook Kang, Ilnam Kang, Eun Seo Bae, Joon Soo An, Ji Hyeon Im, Jiyoon Park, Eunji Kim, Keebeom Ko, Sunghoon Hwang, Honghui Lee, Yun Kwon, Yoon-Joo Ko, Suckchang Hong, Sang-Jip Nam, Seung Bum Kim, William Fenical, Yeo Joon Yoon, Jang-Cheon Cho, Sang Kook Lee, Dong-Chan Oh. Targeted and Logical Discovery of Piperazic Acid-Bearing Natural Products Based on Genomic and Spectroscopic Signatures. Journal of the American Chemical Society 2023, 145 (36) , 19676-19690. https://doi.org/10.1021/jacs.3c04699
    4. Bo-Siyuan Jian, Shao-Lun Chiou, Chun-Chia Hsu, Josh Ho, Yu-Wei Wu, John Chu. Bioinformatic Analysis Reveals both Oversampled and Underexplored Biosynthetic Diversity in Nonribosomal Peptides. ACS Chemical Biology 2023, 18 (3) , 476-483. https://doi.org/10.1021/acschembio.2c00761
    5. Shuige Zhao, Yuwei Xia, Haishan Liu, Tongxu Cui, Peng Fu, Weiming Zhu. A Cyclohexapeptide and Its Rare Glycosides from Marine Sponge-Derived Streptomyces sp. OUCMDZ-4539. Organic Letters 2022, 24 (37) , 6750-6754. https://doi.org/10.1021/acs.orglett.2c02520
    6. Loïc Martinet, Aymeric Naômé, Lucas C. D. Rezende, Déborah Tellatin, Bernard Pignon, Jean-Denis Docquier, Filomena Sannio, Dominique Baiwir, Gabriel Mazzucchelli, Michel Frédérich, Sébastien Rigali. Lunaemycins, New Cyclic Hexapeptide Antibiotics from the Cave Moonmilk-Dweller Streptomyces lunaelactis MM109T. International Journal of Molecular Sciences 2023, 24 (2) , 1114. https://doi.org/10.3390/ijms24021114
    7. Robert A. Hill, Andrew Sutherland. Hot off the Press. Natural Product Reports 2022, 39 (10) , 1904-1909. https://doi.org/10.1039/D2NP90034C

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