Publisher： John Wiley & Sons Inc
E-ISSN： 1521-3757|126|3|843-847
ISSN： 0044-8249
Source： ANGEWANDTE CHEMIE, Vol.126, Iss.3, 2014-01, pp. : 843-847
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Abstract
AbstractEchinomycin 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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