title: A model of antimycin A binding based on structure-activity studies of synthetic antimycin A analogues.
abstract: The structural factors of antimycin A molecule required for inhibitory action were studied using newly synthesized antimycin A derivatives with bovine heart submitochondrial particles, in order to probe the interaction between antimycin A and its binding site. In particular, we focused upon the roles of the amide bond bridge, which connects the salicylic acid and dilactone ring moieties, and the 3-formylamino group in the salicylic acid moiety. The lack of formation of an intramolecular hydrogen-bond between phenolic OH and amide carbonyl groups resulted in a remarkable loss of the activity (by four orders of magnitude), indicating that this hydrogen-bond is essential for the inhibition. This result suggested that both the phenolic OH and the carbonyl groups form a hydrogen-bond with some residues at a fixed conformation. In addition, the inhibitory potency was remarkably decreased by N-methylation of the amide bond moiety, indicating that the NH group might function in hydrogen-bond interaction with the binding site. The N-methylation of 3-formylamino group also resulted in a decrease in the activity, probably due to a loss of the rotational freedom of this functional group. Molecular orbital calculation studies with respect to the conformation of the 3-formylamino group indicated that this group takes an active conformation when the formyl carbonyl projects to the opposite side of the phenolic OH group. Based upon a series of structure-activity studies of synthetic antimycin A analogues, we propose a tentative model for antimycin A binding in its binding cavity.
authors.affiliation: Department of Agricultural Chemistry, Kyoto University, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Miyoshi
authors.forename: N
authors.initials: N
authors.lastname: Tokutake
authors.forename: Y
authors.initials: Y
authors.lastname: Imaeda
authors.forename: T
authors.initials: T
authors.lastname: Akagi
authors.forename: H
authors.initials: H
authors.lastname: Iwamura
mesh_terms: D000577:Amides / Q000737:chemistry; D000588:Amines / Q000737:chemistry; D000818:Animals; D000968:Antimycin A / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D002417:Cattle; D006860:Hydrogen Bonding; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D000588:Amines; D000968:Antimycin A