Conversion of a Disulfide Bond into a Thioacetal Group during Echinomycin Biosynthesis |
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| Authors: | Dr. Kinya Hotta Dr. Ronan M. Keegan Soumya Ranganathan Minyi Fang Dr. Jaclyn Bibby Dr. Martyn D. Winn Dr. Michio Sato Mingzhu Lian Prof. Dr. Kenji Watanabe Dr. Daniel J. Rigden Prof. Dr. Chu‐Young Kim |
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| Affiliation: | 1. Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore 117543 (Singapore);2. Current address: School of Biosciences, The University of Nottingham, Malaysia Campus, Selangor 43500 (Malaysia);3. Research Complex at Harwell, STFC Rutherford Appleton Laboratory, Harwell, Oxfordshire (UK);4. Institute of Integrative Biology, University of Liverpool, Crown Street, Liverpool (UK);5. Department of Chemistry, University of Liverpool, Liverpool (UK);6. Science and Technology Facilities Council, Daresbury Laboratory, Daresbury (UK);7. Department of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422‐8526 (Japan) |
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| Abstract: | Echinomycin is a nonribosomal depsipeptide natural product with a range of interesting bioactivities that make it an important target for drug discovery and development. It contains a thioacetal bridge, a unique chemical motif derived from the disulfide bond of its precursor antibiotic triostin A by the action of an S‐adenosyl‐L ‐methionine‐dependent methyltransferase, Ecm18. The crystal structure of Ecm18 in complex with its reaction products S‐adenosyl‐L ‐homocysteine and echinomycin was determined at 1.50 Å resolution. Phasing was achieved using a new molecular replacement package called AMPLE, which automatically derives search models from structure predictions based on ab initio protein modelling. Structural analysis indicates that a combination of proximity effects, medium effects, and catalysis by strain drives the unique transformation of the disulfide bond into the thioacetal linkage. |
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| Keywords: | biosynthesis disulfides peptides transferases thioacetals |
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