Structural highlights
Publication Abstract from PubMedBiosynthetic enzymes evolutionarily gain novel functions, thereby expanding the structural diversity of natural products to the benefit of host organisms. Diels-Alderases (DAs), functionally unique enzymes catalysing [4 + 2] cycloaddition reactions, have received considerable research interest. However, their evolutionary mechanisms remain obscure. Here, we investigate the evolutionary origins of the intermolecular DAs in the biosynthesis of Moraceae plant-derived Diels-Alder-type secondary metabolites. Our findings suggest that these DAs have evolved from an ancestor functioning as a flavin adenine dinucleotide (FAD)-dependent oxidocyclase (OC), which catalyses the oxidative cyclisation reactions of isoprenoid-substituted phenolic compounds. Through crystal structure determination, computational calculations, and site-directed mutagenesis experiments, we identified several critical substitutions, including S348L, A357L, D389E and H418R that alter the substrate-binding mode and enable the OCs to gain intermolecular DA activity during evolution. This work provides mechanistic insights into the evolutionary rationale of DAs and paves the way for mining and engineering new DAs from other protein families. The evolutionary origin of naturally occurring intermolecular Diels-Alderases from Morus alba.,Ding Q, Guo N, Gao L, McKee M, Wu D, Yang J, Fan J, Weng JK, Lei X Nat Commun. 2024 Mar 20;15(1):2492. doi: 10.1038/s41467-024-46845-0. PMID:38509059[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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