ACS Publications. Most Trusted. Most Cited. Most Read
Characterization and Crystal Structure of a Nonheme Diiron Monooxygenase Involved in Platensimycin and Platencin Biosynthesis

OR SEARCH CITATIONS

My Activity
Publications

Figure 1Loading Img
Download Hi-Res ImageDownload to MS-PowerPointCite This:J. Am. Chem. Soc. 2019, 141, 31, 12406-12412
    Article

    Characterization and Crystal Structure of a Nonheme Diiron Monooxygenase Involved in Platensimycin and Platencin Biosynthesis
    Click to copy article linkArticle link copied!

    • Liao-Bin Dong
      Liao-Bin Dong
      Department of Chemistry, and The Scripps Research Institute, Jupiter, Florida 33458, United States
      More by Liao-Bin Dong
    • Yu-Chen Liu
      Yu-Chen Liu
      Department of Chemistry, and The Scripps Research Institute, Jupiter, Florida 33458, United States
      More by Yu-Chen Liu
    • Alexis J. Cepeda
      Alexis J. Cepeda
      Department of Chemistry, and The Scripps Research Institute, Jupiter, Florida 33458, United States
      More by Alexis J. Cepeda
    • Edward Kalkreuter
      Edward Kalkreuter
      Department of Chemistry, and The Scripps Research Institute, Jupiter, Florida 33458, United States
      More by Edward Kalkreuter
    • Ming-Rong Deng
      Ming-Rong Deng
      Department of Chemistry, and The Scripps Research Institute, Jupiter, Florida 33458, United States
      More by Ming-Rong Deng
    • Jeffrey D. Rudolf
      Jeffrey D. Rudolf
      Department of Chemistry, and The Scripps Research Institute, Jupiter, Florida 33458, United States
      More by Jeffrey D. Rudolf
      Orcidhttp://orcid.org/0000-0003-2718-9651
    • Changsoo Chang
      Changsoo Chang
      Midwest Center for Structural Genomics and Structural Biology Center, Biosciences Division, Argonne National Laboratory, Argonne, Illinois 60439, United States
      More by Changsoo Chang
    • Andrzej Joachimiak
      Andrzej Joachimiak
      Midwest Center for Structural Genomics and Structural Biology Center, Biosciences Division, Argonne National Laboratory, Argonne, Illinois 60439, United States
      More by Andrzej Joachimiak
    • George N. Phillips Jr.
      George N. Phillips, Jr.
      Department of Biosciences, Rice University, Houston, Texas 77030, United States
      More by George N. Phillips, Jr.
    • Ben Shen*
      Ben Shen
      Department of Chemistry,  Department of Molecular Medicine  and  Natural Products Library Initiative, and The Scripps Research Institute, Jupiter, Florida 33458, United States
      *[email protected]
      More by Ben Shen
      Orcidhttp://orcid.org/0000-0002-9750-5982
    Other Access OptionsSupporting Information (1)

    Journal of the American Chemical Society

    Cite this: J. Am. Chem. Soc. 2019, 141, 31, 12406–12412
    Click to copy citationCitation copied!
    https://doi.org/10.1021/jacs.9b06183
    Published July 10, 2019
    Copyright © 2019 American Chemical Society
    Request reuse permissions

    Abstract

    Click to copy section linkSection link copied!
    Abstract Image

    Nonheme diiron monooxygenases make up a rapidly growing family of oxygenases that are rarely identified in secondary metabolism. Herein, we report the in vivo, in vitro, and structural characterizations of a nonheme diiron monooxygenase, PtmU3, that installs a C-5 β-hydroxyl group in the unified biosynthesis of platensimycin and platencin, two highly functionalized diterpenoids that act as potent and selective inhibitors of bacterial and mammalian fatty acid synthases. This hydroxylation sets the stage for the subsequent A-ring cleavage step key to the unique diterpene-derived scaffolds of platensimycin and platencin. PtmU3 adopts an unprecedented triosephosphate isomerase (TIM) barrel structural fold for this class of enzymes and possesses a noncanonical diiron active site architecture with a saturated six-coordinate iron center lacking a μ-oxo bridge. This study reveals the first member of a previously unidentified superfamily of TIM-barrel-fold enzymes for metal-dependent dioxygen activation, with the majority predicted to act on CoA-linked substrates, thus expanding our knowledge of nature’s repertoire of nonheme diiron monooxygenases and TIM-barrel-fold enzymes.

    Copyright © 2019 American Chemical Society

    Subjects

    what are subjects

    Read this article

    To access this article, please review the available access options below.

    Get instant access

    Purchase Access

    Read this article for 48 hours. Check out below using your ACS ID or as a guest.

    Recommended

    Access through Your Institution

    You may have access to this article through your institution.

    Your institution does not have access to this content. Add or change your institution or let them know you’d like them to include access.

    Supporting Information

    Click to copy section linkSection link copied!

    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.9b06183.

    • Materials; methods; detailed experimental procedures; bioinformatic analysis; in vivo, in vitro, and structural characterizations of PtmU3; and structural elucidation of 8 and 12 (PDF)

    Terms & Conditions

    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

    Cited By

    Click to copy section linkSection link copied!
    Citation Statements
    Explore this article's citation statements on scite.ai
    powered by  Scite

    This article is cited by 25 publications.

    1. Jiadian Wang, Qin Xie, Xinmeng Wang, Mengfei Long, Yanying Chen, Zheng Liu, Meng Xia, Juan Guo, Zeping Wang, Rongfeng Wang, Siyu Shen, Yun Lu, Yan Yin, Yating Hu, Wei Gao, Xiao Zhang, Ping Su, Luqi Huang. Discovery of Key Cytochrome P450 Monooxygenase (C20ox) Enables the Complete Synthesis of Tripterifordin and Neotripterifordin. ACS Catalysis 2025, 15 (3) , 2690-2702. https://doi.org/10.1021/acscatal.4c07121
    2. Zong-Xu Gao, Hongliang Wang, Ai-Hong Su, Qian-Ying Li, Zhen Liang, Yue-Qing Zhang, Xu-Yuan Liu, Ming-Zhu Zhu, Hai-Xia Zhang, Yue-Tong Hou, Xin Li, Long-Ru Sun, Jian Li, Ze-Jun Xu, Hong-Xiang Lou. Asymmetric Synthesis and Biological Evaluation of Platensilin, Platensimycin, Platencin, and Their Analogs via a Bioinspired Skeletal Reconstruction Approach. Journal of the American Chemical Society 2024, 146 (28) , 18967-18978. https://doi.org/10.1021/jacs.4c02256
    3. Dimitris Kallifidas, Dipesh Dhakal, Manyun Chen, Qi-Yin Chen, Sofia Kokkaliari, Nicole A. Colon Rosa, Ranjala Ratnayake, Steven D. Bruner, Valerie J. Paul, Yousong Ding, Hendrik Luesch. Biosynthesis of Dolastatin 10 in Marine Cyanobacteria, a Prototype for Multiple Approved Cancer Drugs. Organic Letters 2024, 26 (7) , 1321-1325. https://doi.org/10.1021/acs.orglett.3c04083
    4. Chang Liu, Magan M. Powell, Guodong Rao, R. David Britt, Jonathan Rittle. Bioinformatic Discovery of a Cambialistic Monooxygenase. Journal of the American Chemical Society 2024, 146 (3) , 1783-1788. https://doi.org/10.1021/jacs.3c12131
    5. Magan M. Powell, Guodong Rao, R. David Britt, Jonathan Rittle. Enzymatic Hydroxylation of Aliphatic C–H Bonds by a Mn/Fe Cofactor. Journal of the American Chemical Society 2023, 145 (30) , 16526-16537. https://doi.org/10.1021/jacs.3c03419
    6. Álvaro Pérez, José F. Quílez del Moral, Alberto Galisteo, Juan M. Amaro, Alejandro F. Barrero. Bioinspired Synthesis of Platensimycin from Natural ent-Kaurenoic Acids. Organic Letters 2023, 25 (29) , 5401-5405. https://doi.org/10.1021/acs.orglett.3c01470
    7. Jia Liu, Zikuan Wang, Xianhang Sang, Xuan Zhang, Binju Wang. Peroxo-Diiron(III/III) as the Reactive Intermediate for N-Hydroxylation Reactions in the Multidomain Metalloenzyme SznF: Evidence from Molecular Dynamics and Quantum Mechanical/Molecular Mechanical Calculations. ACS Catalysis 2023, 13 (9) , 5808-5818. https://doi.org/10.1021/acscatal.3c00174
    8. Fumitaka Kudo, Takuji Chikuma, Mizuki Nambu, Taichi Chisuga, Shimpei Sumimoto, Arihiro Iwasaki, Kiyotake Suenaga, Akimasa Miyanaga, Tadashi Eguchi. Unique Initiation and Termination Mechanisms Involved in the Biosynthesis of a Hybrid Polyketide-Nonribosomal Peptide Lyngbyapeptin B Produced by the Marine Cyanobacterium Moorena bouillonii. ACS Chemical Biology 2023, 18 (4) , 875-883. https://doi.org/10.1021/acschembio.3c00011
    9. Shiqing Zhang, Xinyi Li, Yijing Wang, Lijuan Yan, Jingjing Wei, Yongjun Liu. Computational Study of the C5-Hydroxylation Mechanism Catalyzed by the Diiron Monooxygenase PtmU3 as Part of the Platensimycin Biosynthesis. Inorganic Chemistry 2021, 60 (23) , 17783-17796. https://doi.org/10.1021/acs.inorgchem.1c02407
    10. Cheng-Jian Zheng, Edward Kalkreuter, Bo-Yi Fan, Yu-Chen Liu, Liao-Bin Dong, Ben Shen. PtmC Catalyzes the Final Step of Thioplatensimycin, Thioplatencin, and Thioplatensilin Biosynthesis and Expands the Scope of Arylamine N-Acetyltransferases. ACS Chemical Biology 2021, 16 (1) , 96-105. https://doi.org/10.1021/acschembio.0c00773
    11. Yuya Kakumu, Ayesha Ahmed Chaudhri, Eric J. N. Helfrich. The role and mechanisms of canonical and non-canonical tailoring enzymes in bacterial terpenoid biosynthesis. Natural Product Reports 2025, 235 https://doi.org/10.1039/D4NP00048J
    12. Makoto HIBI. Elucidation of Microbial Metabolism of Extraterrestrial Organic Compounds and Discovery of Their Enzyme Systems. KAGAKU TO SEIBUTSU 2024, 62 (2) , 76-81. https://doi.org/10.1271/kagakutoseibutsu.62.76
    13. Kai Gong, Daojing Yong, Jun Fu, Aiying Li, Youming Zhang, Ruijuan Li. Diterpenoids from Streptomyces : Structures, Biosyntheses and Bioactivities. ChemBioChem 2022, 23 (17) https://doi.org/10.1002/cbic.202200231
    14. Tai‐Ping Zhou, Wen‐Hao Deng, Yuzhou Wu, Rong‐Zhen Liao. QM/MM Calculations Suggest Concerted O−O Bond Cleavage and Substrate Oxidation by Nonheme Diiron Toluene/o‐Xylene Monooxygenase. Chemistry – An Asian Journal 2022, 17 (16) https://doi.org/10.1002/asia.202200490
    15. Hongdan Zhu, Jolyon Aarons, Qian Peng. High spin polarized Fe 2 cluster combined with vicinal nonmetallic sites for catalytic ammonia synthesis from a theoretical perspective. Inorganic Chemistry Frontiers 2021, 8 (24) , 5299-5311. https://doi.org/10.1039/D1QI01083B
    16. Makoto Hibi, Dai Fukuda, Chihiro Kenchu, Masutoshi Nojiri, Ryotaro Hara, Michiki Takeuchi, Shunsuke Aburaya, Wataru Aoki, Kimihiko Mizutani, Yoshihiko Yasohara, Mitsuyoshi Ueda, Bunzo Mikami, Satomi Takahashi, Jun Ogawa. A three-component monooxygenase from Rhodococcus wratislaviensis may expand industrial applications of bacterial enzymes. Communications Biology 2021, 4 (1) https://doi.org/10.1038/s42003-020-01555-3
    17. Matías L. Nóbile, Abigail M. Stricker, Lucas Marchesano, Adolfo M. Iribarren, Elizabeth S. Lewkowicz. N-oxygenation of amino compounds: Early stages in its application to the biocatalyzed preparation of bioactive compounds. Biotechnology Advances 2021, 51 , 107726. https://doi.org/10.1016/j.biotechadv.2021.107726
    18. Elvira Romero, Bethan S. Jones, Bethany N. Hogg, Arnau Rué Casamajo, Martin A. Hayes, Sabine L. Flitsch, Nicholas J. Turner, Christian Schnepel. Enzymkatalysierte späte Modifizierungen: Besser spät als nie. Angewandte Chemie 2021, 133 (31) , 16962-16993. https://doi.org/10.1002/ange.202014931
    19. Elvira Romero, Bethan S. Jones, Bethany N. Hogg, Arnau Rué Casamajo, Martin A. Hayes, Sabine L. Flitsch, Nicholas J. Turner, Christian Schnepel. Enzymatic Late‐Stage Modifications: Better Late Than Never. Angewandte Chemie International Edition 2021, 60 (31) , 16824-16855. https://doi.org/10.1002/anie.202014931
    20. Jeffrey D. Rudolf, Tyler A. Alsup, Baofu Xu, Zining Li. Bacterial terpenome. Natural Product Reports 2021, 38 (5) , 905-980. https://doi.org/10.1039/D0NP00066C
    21. Molly J. McBride, Sarah R. Pope, Kai Hu, C. Denise Okafor, Emily P. Balskus, J. Martin Bollinger, Amie K. Boal. Structure and assembly of the diiron cofactor in the heme-oxygenase–like domain of the N -nitrosourea–producing enzyme SznF. Proceedings of the National Academy of Sciences 2021, 118 (4) https://doi.org/10.1073/pnas.2015931118
    22. Gina L. Morgan, Bo Li. In Vitro Reconstitution Reveals a Central Role for the N‐Oxygenase PvfB in (Dihydro)pyrazine‐ N ‐oxide and Valdiazen Biosynthesis. Angewandte Chemie 2020, 132 (48) , 21571-21575. https://doi.org/10.1002/ange.202005554
    23. Gina L. Morgan, Bo Li. In Vitro Reconstitution Reveals a Central Role for the N‐Oxygenase PvfB in (Dihydro)pyrazine‐ N ‐oxide and Valdiazen Biosynthesis. Angewandte Chemie International Edition 2020, 59 (48) , 21387-21391. https://doi.org/10.1002/anie.202005554
    24. Lauren J. Rajakovich, Bo Zhang, Molly J. McBride, Amie K. Boal, Carsten Krebs, J. Martin Bollinger. Emerging Structural and Functional Diversity in Proteins With Dioxygen-Reactive Dinuclear Transition Metal Cofactors. 2020, 215-250. https://doi.org/10.1016/B978-0-12-409547-2.14864-4
    25. Robert A. Hill, Andrew Sutherland. Hot off the press. Natural Product Reports 2019, 36 (10) , 1378-1382. https://doi.org/10.1039/C9NP90041A
    Download PDF
    Go to Journal of the American Chemical Society
    Get e-Alerts
    Get e-Alerts

    Journal of the American Chemical Society

    Cite this: J. Am. Chem. Soc. 2019, 141, 31, 12406–12412
    Click to copy citationCitation copied!
    https://doi.org/10.1021/jacs.9b06183
    Published July 10, 2019
    Copyright © 2019 American Chemical Society
    Request reuse permissions

    Article Views

    4283

    Altmetric

    -

    Citations

    25
    Learn about these metrics

    Article Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.

    Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.

    The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated.