title: 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.
authors.forename: Kinya
authors.initials: K
authors.lastname: Hotta
authors.forename: Ronan M
authors.initials: RM
authors.lastname: Keegan
authors.forename: Soumya
authors.initials: S
authors.lastname: Ranganathan
authors.forename: Minyi
authors.initials: M
authors.lastname: Fang
authors.forename: Jaclyn
authors.initials: J
authors.lastname: Bibby
authors.forename: Martyn D
authors.initials: MD
authors.lastname: Winn
authors.forename: Michio
authors.initials: M
authors.lastname: Sato
authors.forename: Mingzhu
authors.initials: M
authors.lastname: Lian
authors.forename: Kenji
authors.initials: K
authors.lastname: Watanabe
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rigden
authors.forename: Chu-Young
authors.initials: CY
authors.lastname: Kim
mesh_terms: D002384:Catalysis; D018360:Crystallography, X-Ray; D004220:Disulfides / Q000737:chemistry*; D004448:Echinomycin / Q000096:biosynthesis* / Q000737:chemistry; D006710:Homocysteine / Q000096:biosynthesis / Q000737:chemistry; D006860:Hydrogen Bonding; D008715:Methionine / Q000737:chemistry / Q000378:metabolism; D008780:Methyltransferases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011810:Quinoxalines / Q000737:chemistry
chemical_list: D004220:Disulfides; D011810:Quinoxalines; D006710:Homocysteine; C031945:triostin A; D004448:Echinomycin; D008715:Methionine; D008780:Methyltransferases