Substrate Placement Influences Reactivity in Non-heme Fe(II) Halogenases and Hydroxylases

Kulik, Heather J.; Drennan, Catherine L.

doi:10.1074/jbc.m112.415570

Cited by 68 publications

(78 citation statements)

References 55 publications

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“…The concept that substrate positioning is the main determinant in halogenation is also supported by additional computational and electron paramagnetic resonance spectroscopy studies. 287–290 Furthermore, geometries and molecular orbitals accessed within the catalytic trajectory may play an additional role in selectivity. 291 …”

Section: Non-heme Iron-dependent Halogenasesmentioning

confidence: 99%

Enzymatic Halogenation and Dehalogenation Reactions: Pervasive and Mechanistically Diverse

et al. 2017

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Naturally produced halogenated compounds are ubiquitous across all domains of life where they perform a multitude of biological functions and adopt a diversity of chemical structures. Accordingly, a diverse collection of enzyme catalysts to install and remove halogens from organic scaffolds has evolved in nature. Accounting for the different chemical properties of the four halogen atoms (fluorine, chlorine, bromine, and iodine) and the diversity and chemical reactivity of their organic substrates, enzymes performing biosynthetic and degradative halogenation chemistry utilize numerous mechanistic strategies involving oxidation, reduction, and substitution. Biosynthetic halogenation reactions range from simple aromatic substitutions to stereoselective C-H functionalizations on remote carbon centers and can initiate the formation of simple to complex ring structures. Dehalogenating enzymes, on the other hand, are best known for removing halogen atoms from man-made organohalogens, yet also function naturally, albeit rarely, in metabolic pathways. This review details the scope and mechanism of nature’s halogenation and dehalogenation enzymatic strategies, highlights gaps in our understanding, and posits where new advances in the field might arise in the near future.

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Section: Non-heme Iron-dependent Halogenasesmentioning

confidence: 99%

Enzymatic Halogenation and Dehalogenation Reactions: Pervasive and Mechanistically Diverse

et al. 2017

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“…19,20 Recently, it has been shown that the O 2 reactivity of the α-KG-bound halogenase SyrB2 results in a 5C trigonal bipyramidal Fe(IV)=O intermediate with the Fe–O vector perpendicular to the C–H bond of the substrate. H-atom abstraction by an Fe(IV)=O π* molecular orbital leads to an intermediate where the Fe(III)–OH moiety is oriented away from the substrate carbon radical and the halide is primed for rebound halogenation.…”

Section: Introductionmentioning

confidence: 99%

The Role of Chloride in the Mechanism of O₂ Activation at the Mononuclear Nonheme Fe(II) Center of the Halogenase HctB

et al. 2014

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Mononuclear nonheme Fe(II) (MNH) and α-ketoglutarate (α-KG) dependent halogenases activate O2 to perform oxidative halogenations of activated and nonactivated carbon centers. While the mechanism of halide incorporation into a substrate has been investigated, the mechanism by which halogenases prevent oxidations in the absence of chloride is still obscure. Here, we characterize the impact of chloride on the metal center coordination and reactivity of the fatty acyl-halogenase HctB. Stopped-flow kinetic studies show that the oxidative transformation of the Fe(II)-α-KG-enzyme complex is >200-fold accelerated by saturating concentrations of chloride in both the absence and presence of a covalently bound substrate. By contrast, the presence of substrate, which generally brings about O2 activation at enzymatic MNH centers, only has an ∼10-fold effect in the absence of chloride. Circular dichroism (CD) and magnetic CD (MCD) studies demonstrate that chloride binding triggers changes in the metal center ligation: chloride binding induces the proper binding of the substrate as shown by variable-temperature, variable-field (VTVH) MCD studies of non-α-KG-containing forms and the conversion from six-coordinate (6C) to 5C/6C mixtures when α-KG is bound. In the presence of substrate, a site with square pyramidal five-coordinate (5C) geometry is observed, which is required for O2 activation at enzymatic MNH centers. In the absence of substrate an unusual trigonal bipyramidal site is formed, which accounts for the observed slow, uncoupled reactivity. Molecular dynamics simulations suggest that the binding of chloride to the metal center of HctB leads to a conformational change in the enzyme that makes the active site more accessible to the substrate and thus facilitates the formation of the catalytically competent enzyme–substrate complex. Results are discussed in relation to other MNH dependent halogenases.

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“…The halogenase shows barely detectable hydroxylase activity with its native substrate, approximately equivalent halogenase and hydroxylase activities with the L-2-aminobutyric acid adduct, and primarily hydroxylation activity toward the tethered L-norvaline at position C5 with minor halogenation activity at C4 (66). Density functional theory applied to SyBr2 with its native and non-native tethered substrates shows that the phosphopantetheine moiety of the carrier protein also has an influence on the positioning of the substrate in the active site, ultimately dictating the halogenation versus hydroxylation activity (67).…”

Section: Halogenationmentioning

confidence: 99%

Catalytic Mechanisms of Fe(II)- and 2-Oxoglutarate-dependent Oxygenases

Martinez

Hausinger

2015

Journal of Biological Chemistry

378

451

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Substrate Placement Influences Reactivity in Non-heme Fe(II) Halogenases and Hydroxylases

Cited by 68 publications

References 55 publications

Enzymatic Halogenation and Dehalogenation Reactions: Pervasive and Mechanistically Diverse

Enzymatic Halogenation and Dehalogenation Reactions: Pervasive and Mechanistically Diverse

The Role of Chloride in the Mechanism of O₂ Activation at the Mononuclear Nonheme Fe(II) Center of the Halogenase HctB

Catalytic Mechanisms of Fe(II)- and 2-Oxoglutarate-dependent Oxygenases

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Substrate Placement Influences Reactivity in Non-heme Fe(II) Halogenases and Hydroxylases

Cited by 68 publications

References 55 publications

Enzymatic Halogenation and Dehalogenation Reactions: Pervasive and Mechanistically Diverse

Enzymatic Halogenation and Dehalogenation Reactions: Pervasive and Mechanistically Diverse

The Role of Chloride in the Mechanism of O2 Activation at the Mononuclear Nonheme Fe(II) Center of the Halogenase HctB

Catalytic Mechanisms of Fe(II)- and 2-Oxoglutarate-dependent Oxygenases

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The Role of Chloride in the Mechanism of O₂ Activation at the Mononuclear Nonheme Fe(II) Center of the Halogenase HctB