Conversion of a disulfide bond into a thioacetal group during echinomycin biosynthesis

Journal Article · Mon Dec 02 00:00:00 EST 2013 · Angewandte Chemie (International Edition)

DOI:https://doi.org/10.1002/anie.201307404· OSTI ID:1191737

Hotta, Kinya ^[1]; Keegan, Ronan M. ^[2]; Ranganathan, Soumya ^[1]; Fang, Minyi ^[1]; Bibby, Jaclyn ^[3]; Winn, Martyn D. ^[4]; Sato, Michio ^[5]; Lian, Mingzhu ^[1]; Watanabe, Kenji ^[5]; Rigden, Daniel J. ^[3]; Kim, Chu-Young ^[1]

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1. National Univ. of Singapore (Singapore)
2. STFC Rutherford Appleton Lab., Oxfordshire (United Kingdom)
3. Univ. of Liverpool (United Kingdom).
4. Daresbury Lab., Daresbury (United Kingdom)
5. Univ. of Shizuoka, Shizouka (Japan)

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.

• Research Organization: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
• Sponsoring Organization: USDOE Office of Science (SC), Basic Energy Sciences (BES)
• OSTI ID: 1191737
• Journal Information: Angewandte Chemie (International Edition), Vol. 53, Issue 3; ISSN 1433-7851
• Country of Publication: United States
• Language: ENGLISH