Product of epoxide ring opening of cerulenin-hemiaminal by NcmC. Cerulenin is an epoxydodecadienamide isolated from several fungi species, including Acremonium, Acrocylindrum and Helicoceras Cephalosporium caerulens. It inhibits the biosynthesis of several lipids by interfering with enzyme function. It has a role as an antifungal agent, an antiinfective agent, an antilipemic drug, an antimetabolite, a fatty acid synthesis inhibitor and an antimicrobial agent. It is a monocarboxylic acid amide and an epoxide.In fatty acid synthesis inhibits b-keto-acyl-ACP synthase. In sterol synthesis, inhibits HMG-CoA synthetase activity. Interconversion of cerulenin from its linear to cyclic hemiaminal form,occurs in polar protic solvents. It is this hemiaminal form which is substrate of epoxide ring opening by NcmC
While several bioactive natural products that contain tetramate or pyridone heterocycles have been described, information on the enzymology underpinning these functionalities has been limited. Here we biochemically characterize an off-loading Dieckmann cyclase, NcmC, that installs the tetramate headgroup in nocamycin, a hybrid polyketide/nonribosomal peptide natural product. Crystal structures of the enzyme (1.6 A) and its covalent complex with the epoxide cerulenin (1.6 A) guide additional structure-based mutagenesis and product-profile analyses. Our results offer mechanistic insights into how the conserved thioesterase-like scaffold has been adapted to perform a new chemical reaction, namely, heterocyclization. Additional bioinformatics combined with docking and modeling identifies likely candidates for heterocycle formation in underexplored gene clusters and uncovers a modular basis of substrate recognition by the two subdomains of these Dieckmann cyclases.
