Insights into the Desaturation of Cyclopeptin and its C3 Epimer Catalyzed by a non‐Heme Iron Enzyme: Structural Characterization and Mechanism Elucidation

Liao, Hsuan-Jen; Li, Jikun; Huang, Jhih‐Liang; Davidson, Madison; Kurnikov, Igor V.; Lin, Tzong-Shyan; Lee, Justin L.; Kurnikova, Maria; Guo, Yisong; Chan, Nei-Li; Chang, Wei‐chen

doi:10.1002/ange.201710567

Angewandte Chemie

2018

DOI: 10.1002/ange.201710567

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Insights into the Desaturation of Cyclopeptin and its C3 Epimer Catalyzed by a non‐Heme Iron Enzyme: Structural Characterization and Mechanism Elucidation

Hsuan-Jen Liao

Jikun Li

Jhih‐Liang Huang

et al.

Abstract: AsqJ,a ni ron(II)-and 2-oxoglutarate-dependent enzyme found in viridicatin-type alkaloid biosynthetic pathways,c atalyzess equential desaturation and epoxidation to produce cyclopenins.C rystal structures of AsqJ bound to cyclopeptin and its C3 epimer are reported. Meanwhile, ad etailed mechanistic study was carried out to decipher the desaturation mechanism. These findings suggest that apathway involving hydrogen atom abstraction at the C10 position of the substrate by as hort-lived Fe IV -oxo species and the… Show more

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Cited by 3 publications

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Mechanism for the Halogenation and Azidation of Lysine Catalyzed by Non‐heme Iron BesD Enzyme

Chen

2022

Chemistry An Asian Journal

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Selective halogenation is important in synthetic chemistry. BesD, a new member of the non‐heme Fe(II)/α‐ketoglutarate (αKG)‐dependent halogenase family, can activate the sp3 C−H bond and halogenate lysine, in particular without a carrier protein. Using the density functional calculations, a chlorination mechanism in BesD has been proposed, mainly including the formation of Cl−Fe(IV)=O through the αKG decarboxylation, the isomerization of Cl−Fe(IV)=O, the substrate hydrogen abstraction by Fe(IV)=O, and the rebound of chloro to the substrate carbon radical. The hydrogen abstraction is rate‐limiting. The isomerization of Cl−Fe(IV)=O is essential for the hydrogen abstraction and the chiral selectivity. The BesD‐catalyzed bromination and azidation of lysine adopt the same mechanism as the chlorination. The hardly‐changed overall barriers indicate that the introduced ligands (X) do not affect the reaction rate significantly, implying that the X‐introduced reactions catalyzed by BesD may be extended to other X anions.

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Mechanism for the Halogenation and Azidation of Lysine Catalyzed by Non‐heme Iron BesD Enzyme

Chen

2022

Chemistry An Asian Journal

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Enzyme Engineering Enables Inversion of Substrate Stereopreference of the Halogenase WelO5*

et al. 2022

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Enzymatic late-stage diversification of small molecules has the potential to rapidly generate diversity in compound libraries dedicated to drug discovery. In this context, freestanding Fe(II)/ α-ketoglutarate-dependent halogenases have raised particular interest as this enzyme family allows the otherwise difficult regio-and stereoselective halogenation of unactivated C(sp 3 )À H bonds. Here, we report the development of two engineered variants of the halogenase WelO5* for the racemic resolution of a mixture of stereoisomers generated in the synthesis of a bioactive martinelline-derived fragment. By screening a 3-site combinatorial variant library, we could identify two variants exhibiting exquisite substrate selectivity towards the desired enantiomers. Strikingly, the inversion of substrate stereopreference between the halogenase variants was achieved by varying only three residues in the active site. Protein crystallization and subsequent structure elucidation of the wildtype enzyme and a WelO5* variant shed light on the factors governing substrate acceptance and selectivity.

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Electrostatic Perturbations from the Protein Affect C−H Bond Strengths of the Substrate and Enable Negative Catalysis in the TmpA Biosynthesis Enzyme

Lin

Ali

Visser

2021

Chemistry A European J

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The nonheme iron dioxygenase 2‐(trimethylammonio)‐ethylphosphonate dioxygenase (TmpA) is an enzyme involved in the regio‐ and chemoselective hydroxylation at the C1‐position of the substrate as part of the biosynthesis of glycine betaine in bacteria and carnitine in humans. To understand how the enzyme avoids breaking the weak C2−H bond in favor of C1‐hydroxylation, we set up a cluster model of 242 atoms representing the first and second coordination sphere of the metal center and substrate binding pocket, and investigated possible reaction mechanisms of substrate activation by an iron(IV)‐oxo species by density functional theory methods. In agreement with experimental product distributions, the calculations predict a favorable C1‐hydroxylation pathway. The calculations show that the selectivity is guided through electrostatic perturbations inside the protein from charged residues, external electric fields and electric dipole moments. In particular, charged residues influence and perturb the homolytic bond strength of the C1−H and C2−H bonds of the substrate, and strongly strengthens the C2−H bond in the substrate‐bound orientation.

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Insights into the Desaturation of Cyclopeptin and its C3 Epimer Catalyzed by a non‐Heme Iron Enzyme: Structural Characterization and Mechanism Elucidation

Cited by 3 publications

References 32 publications

Mechanism for the Halogenation and Azidation of Lysine Catalyzed by Non‐heme Iron BesD Enzyme

Mechanism for the Halogenation and Azidation of Lysine Catalyzed by Non‐heme Iron BesD Enzyme

Enzyme Engineering Enables Inversion of Substrate Stereopreference of the Halogenase WelO5*

Electrostatic Perturbations from the Protein Affect C−H Bond Strengths of the Substrate and Enable Negative Catalysis in the TmpA Biosynthesis Enzyme

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