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    Structural and Computational Bases for Dramatic Skeletal Rearrangement in Anditomin Biosynthesis
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    • Yu Nakashima
      Yu Nakashima
      Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
      More by Yu Nakashima
    • Takaaki Mitsuhashi
      Takaaki Mitsuhashi
      Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
      More by Takaaki Mitsuhashi
    • Yudai Matsuda
      Yudai Matsuda
      Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
      Department of Chemistry, City University of Hong Kong, 83 Tat Chee Avenue, Kowloon, Hong Kong SAR, China
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      Orcidhttp://orcid.org/0000-0001-5650-4732
    • Miki Senda
      Miki Senda
      Structural Biology Research Center, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK), 1-1 Oho, Tsukuba, Ibaraki 305-0801, Japan
      More by Miki Senda
    • Hajime Sato
      Hajime Sato
      Graduate School of Pharmaceutical Science, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8675, Japan
      Cluster of Pioneering Research (CPR), Advanced Elements Chemistry Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
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    • Mami Yamazaki
      Mami Yamazaki
      Graduate School of Pharmaceutical Science, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8675, Japan
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    • Masanobu Uchiyama*
      Masanobu Uchiyama
      Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
      Cluster of Pioneering Research (CPR), Advanced Elements Chemistry Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
      *[email protected]
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      Orcidhttp://orcid.org/0000-0001-6385-5944
    • Toshiya Senda*
      Toshiya Senda
      Structural Biology Research Center, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK), 1-1 Oho, Tsukuba, Ibaraki 305-0801, Japan
      Department of Materials Structure Science, School of High Energy Accelerator Science, The Graduate University for Advanced Studies (Soken-dai), 1−1 Oho, Tsukuba, Ibaraki 305−0801, Japan
      *[email protected]
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    • Ikuro Abe*
      Ikuro Abe
      Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
      Collaborative Research Institute for Innovative Microbiology, The University of Tokyo, Yayoi 1-1-1, Bunkyo-ku, Tokyo 113-8657, Japan
      *[email protected]
      More by Ikuro Abe
      Orcidhttp://orcid.org/0000-0002-3640-888X
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    Journal of the American Chemical Society

    Cite this: J. Am. Chem. Soc. 2018, 140, 30, 9743–9750
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    https://doi.org/10.1021/jacs.8b06084
    Published July 4, 2018
    Copyright © 2018 American Chemical Society
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    Abstract

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    AndA, an Fe(II)/α-ketoglutarate (αKG)-dependent enzyme, is the key enzyme that constructs the unique and congested bridged-ring system of anditomin (1), by catalyzing consecutive dehydrogenation and isomerization reactions. Although we previously characterized AndA to some extent, the means by which the enzyme facilitates this drastic structural reconstruction have remained elusive. In this study, we have solved three X-ray crystal structures of AndA, in its apo form and in the complexes with Fe(II), αKG, and two substrates. The crystal structures and mutational experiments identified several key amino acid residues important for the catalysis and provided insight into how AndA controls the reaction. Furthermore, computational calculations validated the proposed reaction mechanism for the bridged-ring formation and also revealed the requirement of a series of conformational changes during the transformation.

    Copyright © 2018 American Chemical Society

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.8b06084.

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    Cite this: J. Am. Chem. Soc. 2018, 140, 30, 9743–9750
    Click to copy citationCitation copied!
    https://doi.org/10.1021/jacs.8b06084
    Published July 4, 2018
    Copyright © 2018 American Chemical Society
    Request reuse permissions

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