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Conversion of a Disulfide Bond into a Thioacetal Group during Echinomycin Biosynthesis

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  • This work was supported by a National University of Singapore–Japan Society for the Promotion of Science Joint Research Project grant (C.-Y.K.), the Biotechnology and Biological Science Research Council (BB/H01330X/1; D.J.R. and M.W.), the 2011 CCP4/OIST School in Protein Crystallography, and the Japan Society for the Promotion of Science (LS103; K.W.). Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences (DE-AC02-06CH11357). Use of the IMCA-CAT beamline 17-ID at the Advanced Photon Source was supported by the companies of the Industrial Macromolecular Crystallography Association through a contract with the Hauptman–Woodward Medical Research Institute. We would like to thank Dr. Andrey Lebedev of the CCP4 group for his expert advice on ligand building and structure solution. The computational infrastructure used by AMPLE in this work was provided by the Research Complex at Harwell and CCP4.

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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