Structural Insight into the Catalytic Mechanism of the Endoperoxide Synthase FtmOx1

Wu, Lian; Wang, Zhanfeng; Cen, Yixin; Wang, Binju; Zhou, Jiahai

doi:10.1002/ange.202112063

Cited by 8 publications

(2 citation statements)

References 72 publications

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“… Accordingly, NvfI introduces three oxygen atoms in one catalytic cycle of the nonheme iron enzyme. This feature of the NvfI reaction is different from the reaction of the previously characterized Fe(II)/αKG-dependent fumitremorgin B endoperoxidase FtmOx1, which only installs the endoperoxide group without forming an additional hydroxyl group. − Furthermore, assays using 18 O 2 and H 2 18 O suggested that the two oxygen atoms in the endoperoxide are derived from molecular oxygen while the oxygen atom in the hydroxyl group is derived from water, indicating that solvent exchange processes occur during the NvfI reaction.…”

Section: Mononuclear Nonheme Iron Enzymesmentioning

confidence: 63%

Unusual Dioxygen-Dependent Reactions Catalyzed by Nonheme Iron Enzymes in Natural Product Biosynthesis

Ushimaru

Abe

2022

ACS Catal.

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Nonheme iron-dependent enzymatic reactions play crucial roles in building and modifying bioactive organic molecules in all major classes of natural product pathways. While the enzymes have evolved to use a limited repertoire of protein folding and metal binding sites, the oxidation reactions they catalyze are astonishingly diverse, spanning from complex rearrangements to uncommon bond formation and cleavage reactions. This review summarizes recent discoveries that have significantly expanded our understanding of unusual nonheme iron enzyme catalysis in natural product biosynthesis, covering the literature published between 2017 and August 2022.

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Section: Mononuclear Nonheme Iron Enzymesmentioning

confidence: 63%

Unusual Dioxygen-Dependent Reactions Catalyzed by Nonheme Iron Enzymes in Natural Product Biosynthesis

Ushimaru

Abe

2022

ACS Catal.

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“…(1) Does the proximal Tyr residue (Y94 in CthEgtB or Y377 in MthEgtB) function as a redox-active residue by donating an H atom (Scheme 1a), or as a general acid-base catalyst in assisting proton transfer (route I in Scheme 1b)? Even though redoxactive Tyr residues are found to be involved in the catalysis of many other non-heme enzymes, [34][35][36][37][38][39][40][41][42][43][44] kinetic experiments tend to support the general acid-base role of this proximal Tyr residue in EgtB.…”

Section: Introductionmentioning

confidence: 99%

Origins of the Selective C−S Bond Formation by the Non-Heme Iron EgtB

Liao

et al. 2022

Preprint

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The nonheme iron EgtB and OvoA are sulfoxide synthases that catalyze oxidative C−S bond formation in the synthesis of ergothioneine and ovothiol. Despite the extensively experimental and computational studies of the catalytic mecha-nisms of these enzymes, the root causes for the selective C−S bond formation remains elusive. Using combined molecu-lar dynamics (MD) simulations and quantum mechanics/molecular mechanics (QM/MM) method, we show here that coordination dynamics of the sulfoxide intermediate is involved in the catalysis of nonheme iron EgtB. Such coordina-tion switch from S to O atom is driven by the S/ electrostatic interactions, which promotes efficiently the observed stereoselective C-S bond formation while bypassing cysteine dioxygenation. As such, the present mechanism high-lights the critical role of coordination dynamics in catalysis, and it is in agreement with all available experimental data, including regioselectivity, stereoselectivity and KIE results.

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Coordination Switch Drives Selective C−S Bond Formation by the Non‐Heme Sulfoxide Synthases**

Liao

et al. 2022

Angewandte Chemie

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The non-heme iron ergothioneine synthase (EgtB) is a sulfoxide synthase that catalyzes oxidative CÀ S bond formation in the synthesis of ergothioneine, which plays roles against oxidative stress in cells. Despite extensive experimental and computational studies of the catalytic mechanisms of EgtB, the root causes for the selective CÀ S bond formation remain elusive. Using quantum mechanics/molecular mechanics (QM/ MM) calculations, we show herein that a coordination switch of the sulfoxide intermediate is involved in the catalysis of the non-heme iron EgtB. This coordination switch from the S to the O atom is driven by the S/π electrostatic interactions, which efficiently promotes the observed stereoselective CÀ S bond formation while bypassing cysteine dioxygenation. The present mechanism is in agreement with all available experimental data, including regioselectivity, stereoselectivity and KIE results. This match underscores the critical role of coordination switching in the catalysis of non-heme enzymes.

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Structural Insight into the Catalytic Mechanism of the Endoperoxide Synthase FtmOx1

Cited by 8 publications

References 72 publications

Unusual Dioxygen-Dependent Reactions Catalyzed by Nonheme Iron Enzymes in Natural Product Biosynthesis

Unusual Dioxygen-Dependent Reactions Catalyzed by Nonheme Iron Enzymes in Natural Product Biosynthesis

Origins of the Selective C−S Bond Formation by the Non-Heme Iron EgtB

Coordination Switch Drives Selective C−S Bond Formation by the Non‐Heme Sulfoxide Synthases**

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