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Characterization of Acyl Carrier Protein-Dependent Glycosyltransferase in Mitomycin C Biosynthesis
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    Characterization of Acyl Carrier Protein-Dependent Glycosyltransferase in Mitomycin C Biosynthesis
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    • Hai P. Nguyen
      Hai P. Nguyen
      Department of Biochemistry, Duke University Medical Center, Durham, North Carolina 27710, United States
    • Kenichi Yokoyama*
      Kenichi Yokoyama
      Department of Biochemistry, Duke University Medical Center, Durham, North Carolina 27710, United States
      Department of Chemistry, Duke University, Durham, North Carolina 27708-0354, United States
      *E-mail: [email protected]
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    Biochemistry

    Cite this: Biochemistry 2019, 58, 25, 2804–2808
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    https://doi.org/10.1021/acs.biochem.9b00379
    Published June 7, 2019
    Copyright © 2019 American Chemical Society

    Abstract

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    Mitomycins make up a group of antitumor natural products that are biosynthesized from aminohydroxybenzoic acid (AHBA) and N-acetylglucosamine (GlcNAc). While the biosynthetic gene cluster was reported two decades ago, the mechanism by which the two building blocks, AHBA and GlcNAc, are coupled during biosynthesis remained uncharacterized. Here we report evidence that AHBA is first loaded onto an MmcB acyl carrier protein (ACP) by a MitE acyl ACP synthetase, followed by a transfer of GlcNAc from UDP-GlcNAc by MitB. The results suggest that the early steps of mitomycin biosynthesis proceed via intermediates linked to MmcB.

    Copyright © 2019 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.biochem.9b00379.

    • Methods and materials; sodium dodecyl sulfate–polyacrylamide gel electrophoresis of MmcB, MitE, and MitB; UV–vis absorption, mass, and NMR spectra of SNAc-AHBA-GlcNAc; and mass spectra of AHBA-cystamine and AHBA-GlcNAc-cystamine (PDF)

    Accession Codes

    MitB (UniProt entry Q9WW09), MitE (UniProt entry Q9X5R7), and MmcB (UniProt entry Q9X5S0).

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    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.

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    This article is cited by 13 publications.

    1. Danna Dong, Mingyu Xia, Sili Wang, Pengfei Fang, Wen Liu. Structural Basis of Substrate Recognition by the Postmitosane Modification Enzyme MitM in Mitomycin Biosynthesis. Biochemistry 2024, 63 (17) , 2217-2224. https://doi.org/10.1021/acs.biochem.4c00330
    2. Xiaorong Chen, Rui He, Aiai Sun, Jinyue Pu, Hai-Xue Pan, Gong-Li Tang. A Secreted BBE-Like Enzyme Acting as a Drug-Binding Efflux Carrier Confers Microbial Self-Resistance to Mitomycin C. Organic Letters 2024, 26 (6) , 1233-1237. https://doi.org/10.1021/acs.orglett.4c00042
    3. Sili Wang, Yiyuan Cheng, Xiaofeng Wang, Qian Yang, Wen Liu. Tracing of Acyl Carrier Protein-channeled Mitomycin Intermediates in Streptomyces caespitosus Facilitates Characterization of the Biosynthetic Steps for AHBA–GlcN Formation and Processing. Journal of the American Chemical Society 2022, 144 (32) , 14945-14956. https://doi.org/10.1021/jacs.2c06969
    4. Kathleen Abt, Raquel Castelo-Branco, Pedro N. Leão. Biosynthesis of Chlorinated Lactylates in Sphaerospermopsis sp. LEGE 00249. Journal of Natural Products 2021, 84 (2) , 278-286. https://doi.org/10.1021/acs.jnatprod.0c00950
    5. Vikram V. Shende, Katherine D. Bauman, Bradley S. Moore. The shikimate pathway: gateway to metabolic diversity. Natural Product Reports 2024, 41 (4) , 604-648. https://doi.org/10.1039/D3NP00037K
    6. Leigh E. Skala, Benjamin Philmus, Taifo Mahmud. Modifications of Protein‐Bound Substrates by Trans ‐Acting Enzymes in Natural Products Biosynthesis. ChemBioChem 2024, 25 (8) https://doi.org/10.1002/cbic.202400056
    7. Auday A. Eida, Arash Samadi, Takeshi Tsunoda, Taifo Mahmud. Modifications of Acyl Carrier Protein‐Bound Glycosylated Polyketides in Pactamycin Biosynthesis. Chemistry – A European Journal 2023, 29 (33) https://doi.org/10.1002/chem.202301056
    8. Qiu-Yue Nie, Yu Hu, Xian-Feng Hou, Gong-Li Tang. Biosynthesis of DNA-Alkylating Antitumor Natural Products. Molecules 2022, 27 (19) , 6387. https://doi.org/10.3390/molecules27196387
    9. Adelfo Escalante, Rubén Mendoza-Flores, Guillermo Gosset, Francisco Bolívar. The aminoshikimic acid pathway in bacteria as source of precursors for the synthesis of antibacterial and antiviral compounds. Journal of Industrial Microbiology and Biotechnology 2021, 48 (9-10) https://doi.org/10.1093/jimb/kuab053
    10. Dongjin Leng, Yong Sheng, Hengyu Wang, Jianhua Wei, Yixin Ou, Zixin Deng, Linquan Bai, Qianjin Kang. Determination of the Protein-Protein Interactions within Acyl Carrier Protein (MmcB)-Dependent Modifications in the Biosynthesis of Mitomycin. Molecules 2021, 26 (22) , 6791. https://doi.org/10.3390/molecules26226791
    11. I Dewa Made Kresna, Luis Linares-Otoya, Tobias Milzarek, Elke R. Duell, Mahsa Mir Mohseni, Ute Mettal, Gabriele M. König, Tobias A. M. Gulder, Till F. Schäberle. In vitro characterization of 3-chloro-4-hydroxybenzoic acid building block formation in ambigol biosynthesis. Organic & Biomolecular Chemistry 2021, 19 (10) , 2302-2311. https://doi.org/10.1039/D0OB02372H
    12. Matthew M. Draelos, Anyarat Thanapipatsiri, Hilda Sucipto, Kenichi Yokoyama. Cryptic phosphorylation in nucleoside natural product biosynthesis. Nature Chemical Biology 2021, 17 (2) , 213-221. https://doi.org/10.1038/s41589-020-00656-8
    13. Yasushi Ogasawara, Yo Nakagawa, Chitose Maruyama, Yoshimitsu Hamano, Tohru Dairi. In vitro characterization of MitE and MitB: Formation of N-acetylglucosaminyl-3-amino-5-hydroxybenzoyl-MmcB as a key intermediate in the biosynthesis of antitumor antibiotic mitomycins. Bioorganic & Medicinal Chemistry Letters 2019, 29 (16) , 2076-2078. https://doi.org/10.1016/j.bmcl.2019.07.009

    Biochemistry

    Cite this: Biochemistry 2019, 58, 25, 2804–2808
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.biochem.9b00379
    Published June 7, 2019
    Copyright © 2019 American Chemical Society

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