Conversion of a disulfide bond into a thioacetal group during echinomycin biosynthesis
Hotta, K. Keegan, R.M. Ranganathan, S. Fang, M. Bibby, J. Winn, M.D. Sato, M. Lian, M. Watanabe, K. Rigden, D.J.
Keegan, R.M.
Ranganathan, S.
Fang, M.
Bibby, J.
Winn, M.D.
Sato, M.
Lian, M.
Watanabe, K.
Rigden, D.J.
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Alternative Title
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. Disulfide to thioacetal: The S-adenosyl-L-methionine (SAM)-dependent methyltransferase Ecm 18 converts the disulfide bond of triostin A into a thioacetal linkage to form echinomycin. The 1.50 Å crystal structure of Ecm 18 in complex with its reaction products S-adenosyl-L-homocysteine (SAH) and echinomycin provides insight into how Ecm 18 catalyzes this unusual transformation. Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Keywords
biosynthesis, disulfides, peptides, thioacetals, transferases
Source Title
Angewandte Chemie - International Edition
Publisher
Series/Report No.
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Date
2014
DOI
10.1002/anie.201307404
Type
Article