8UP4

Crystal structure of Lsd18 (a flavin-dependent monooxygenase)

Summary for 8UP4

• Entry DOI: 10.2210/pdb8up4/pdb
• Descriptor: Flavin-dependent monooxygenase Lsd18, FLAVIN-ADENINE DINUCLEOTIDE, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: a flavin-dependent monooxygenase, epoxidase, flavoprotein
• Biological source: Streptomyces lasalocidi
• Total number of polymer chains: 2
• Total formula weight: 106935.40

Authors

Wang, Q.,Chen, X.,Kim, C.Y. (deposition date: 2023-10-20, release date: 2024-12-18, Last modification date: 2025-06-18)

Primary citation

Wang, Q.,Deng, Y.,Viera, D.,Liu, X.,Liu, N.,Hu, Y.,Hu, X.,Wei, H.,Zhou, Q.,Lan, T.,He, W.,Chen, X.,Kim, C.Y.
Structural Basis of Sequential Enantioselective Epoxidation by a Flavin-Dependent Monooxygenase in Lasalocid A Biosynthesis.
Angew.Chem.Int.Ed.Engl., 64:e202504982-e202504982, 2025

PubMed Abstract: Polyether polyketides are a structurally diverse group of natural products known for their antimicrobial and antiproliferative activities. Lasalocid A is a canonical natural polyether produced by the soil bacterium Streptomyces lasalocidi. In lasalocid A biosynthesis, a polyene polyketide intermediate is converted into a bisepoxide by the flavin-dependent monooxygenase enzyme Lsd18. Remarkably, Lsd18 acts on two distinct C═C groups in the substrate molecule, forming two (R,R) epoxides. We have determined the X-ray crystal structures of Lsd18 in the substrate-free, substrate-bound, and product-bound forms. Our work has revealed that Lsd18 has an extra-large substrate-binding pocket that allows the polyene to adopt different conformations within the enzyme pocket. This feature enables Lsd18 to epoxidate both of the C═C groups. Additionally, a subpocket located near the Lsd18 active site controls stereoselectivity by dictating which face of the C═C group is placed next to the flavin. Molecular understanding of how Lsd18 transforms a polyene into a bisepoxide during lasalocid A biosynthesis lays the foundation for the production of designer polyethers for drug development.

PubMed: 40199722
DOI: 10.1002/anie.202504982

Experimental method

X-RAY DIFFRACTION (1.51 Å)