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

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.