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Publication Abstract from PubMed

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.

Structural Basis for Enzymatic Off-Loading of Hybrid Polyketides by Dieckmann Condensation.,Cogan DP, Ly J, Nair SK ACS Chem Biol. 2020 Oct 16;15(10):2783-2791. doi: 10.1021/acschembio.0c00579., Epub 2020 Oct 5. PMID:33017142^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.