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Triepoxide formation by a flavin-dependent monooxygenase in monensin biosynthesis.

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.

SUBMITTER: Wang Q

PROVIDER: S-EPMC10560226 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Triepoxide formation by a flavin-dependent monooxygenase in monensin biosynthesis.

Wang Qian Q Liu Ning N Deng Yaming Y Guan Yuze Y Xiao Hongli H Nitka Tara A TA Yang Hui H Yadav Anju A Vukovic Lela L Mathews Irimpan I II Chen Xi X Kim Chu-Young CY

Nature communications 20231007 1

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. O ...[more]

PMID: 37805629

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Triepoxide formation by a flavin-dependent monooxygenase in monensin biosynthesis.

Publications

Triepoxide formation by a flavin-dependent monooxygenase in monensin biosynthesis.

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