Aspartic acid residues in BBE-like enzymes from <i>Morus alba</i> promote a function shift from oxidative cyclization to dehydrogenation.

ABSTRACT: Berberine bridge enzyme (BBE)-like enzymes catalyze various oxidative cyclization and dehydrogenation reactions in natural product biosynthesis, but the molecular mechanism underlying the selectivity remains unknown. Here, we elucidated the catalytic mechanism of BBE-like oxidases from Morus alba involved in the oxidative cyclization and dehydrogenation of moracin C. X-ray crystal structures of a functionally promiscuous flavin adenine dinucleotide (FAD)-bound oxidase, MaDS1, with and without an oxidative dehydrogenation product were determined at 2.03 Å and 2.21 Å resolution, respectively. Structure-guided mutagenesis and sequence analysis have identified a conserved aspartic acid that directs the reaction toward the oxidative dehydrogenation pathway. A combination of density funct

SUBMITTER: Guo N 

PROVIDER: S-EPMC12403149 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature