Download MendeleyCrystal Structure and Catalytic Mechanism of the cis-Eunicellane Cyclase AriE.
Li, F.R., Yang, Q., He, J., Sun, X., Pan, X., Xu, H.M., Rudolf, J.D., Dong, L.B.(2025) Chemistry : e202500012-e202500012
- PubMed: 40265331
- DOI: https://doi.org/10.1002/chem.202500012
- Primary Citation of Related Structures:
9LPB - PubMed Abstract:
Eunicellane diterpenoids, with over 360 known examples characterized by a cis- or trans-6/10-bicyclic carbon skeleton, exhibit diverse biological activities. To date, five eunicellane cyclases (ECs) have been reported: cis-ECs (Bnd4, CpDTS2 and EcTPS1) and trans-ECs (AlbS and MicA), yet the structural basis and molecular mechanisms governing their distinct cis- or trans-cyclization modes remain unsolved. Here, we present the crystal structure of a cis-EC AriE from Amycolatopsis arida, which catalyzes geranylgeranyl diphosphate to form cis-6/10-fused bicyclic benditerpe-2,6,15-triene (1) in aridacin biosynthesis. Through surface entropy reduction, we obtained the 1.87 ? resolution structure of AriED128A. Structure-guided mutagenesis identified W73 as a key regulatory hotspot controlling product diversity, with its variants generating diverse diterpene products. Y203A converted AriE into a highly specific (-)-(R)-cembrene A synthase. Our findings provide the first structural insights into this type of terpene synthase and demonstrate the feasibility of engineering EC variants for selective product formation.
Organizational Affiliation:
China Pharmaceutical University, School of Traditional Chinese Pharmacy, CHINA.
