Triepoxide formation by a flavin-dependent monooxygenase in monensin biosynthesis

Qian Wang, Ning Liu, Yaming Deng, Yuze Guan, Hongli Xiao, Tara A. Nitka, Hui Yang, Anju Yadav, Lela Vukovic, Irimpan I. Mathews, Xi Chen () and Chu-Young Kim ()
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Qian Wang: The University of Texas at El Paso
Ning Liu: Northwest University
Yaming Deng: Northwest University
Yuze Guan: Northwest University
Hongli Xiao: Northwest University
Tara A. Nitka: The University of Texas at El Paso
Hui Yang: Northwest University
Anju Yadav: The University of Texas at El Paso
Lela Vukovic: The University of Texas at El Paso
Irimpan I. Mathews: SLAC National Accelerator Laboratory
Xi Chen: Northwest University
Chu-Young Kim: The University of Texas at El Paso

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract Monensin A is a prototypical natural polyether polyketide antibiotic. It acts by binding a metal cation and facilitating its transport across the cell membrane. Biosynthesis of monensin A involves construction of a polyene polyketide backbone, subsequent epoxidation of the alkenes, and, lastly, formation of cyclic ethers via epoxide-opening cyclization. MonCI, a flavin-dependent monooxygenase, is thought to transform all three alkenes in the intermediate polyketide premonensin A into epoxides. Our crystallographic study has revealed that MonCI’s exquisite stereocontrol is due to the preorganization of the active site residues which allows only one specific face of the alkene to approach the reactive C(4a)-hydroperoxyflavin moiety. Furthermore, MonCI has an unusually large substrate-binding cavity that can accommodate premonensin A in an extended or folded conformation which allows any of the three alkenes to be placed next to C(4a)-hydroperoxyflavin. MonCI, with its ability to perform multiple epoxidations on the same substrate in a stereospecific manner, demonstrates the extraordinary versatility of the flavin-dependent monooxygenase family of enzymes.

Date: 2023
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DOI: 10.1038/s41467-023-41889-0

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