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Conversion of a Disulfide Bond into a Thioacetal Group during Echinomycin Biosynthesis
Author(s) -
Hotta Kinya,
Keegan Ronan M.,
Ranganathan Soumya,
Fang Minyi,
Bibby Jaclyn,
Winn Martyn D.,
Sato Michio,
Lian Mingzhu,
Watanabe Kenji,
Rigden Daniel J.,
Kim ChuYoung
Publication year - 2014
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201307404
Subject(s) - thioacetal , chemistry , stereochemistry , depsipeptide , methyltransferase , combinatorial chemistry , peptide bond , natural product , biosynthesis , methylation , enzyme , organic chemistry , acetal , biochemistry , gene
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.