Unusual catalytic strategy by non-heme Fe(<scp>ii</scp>)/2-oxoglutarate-dependent aspartyl hydroxylase AspH

Krishnan, Anandhu; Waheed, Sodiq O.; Varghese, Ann; Cherilakkudy, Fathima Hameed; Schofield, Christopher J.; Karabencheva-Christova, Tatyana G.

doi:10.1039/d3sc05974j

Cited by 5 publications

(3 citation statements)

References 236 publications

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“…23−37 Similarly, mutations of second and outer coordination sphere residues have advanced our understanding of 2OG oxygenase catalysis. 38 However, performing structure−function relationships to probe the role of the conserved bis-histidine coordination environment has proven challenging, as mutation of either of the cis-disposed ligands abolishes catalytic function. If we were able to make functional ligand replacements, we could begin to address important questions such as the effect of ligand strength on Fe IV �O reactivity or positioning ("in-line" vs "offline" 39,40 ) across family members.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Given the broad array of valuable transformations catalyzed by 2OG oxygenases, there is considerable interest in understanding how their active site features govern the structure and reactivity of catalytic intermediates. To this end, a range of spectroscopic, kinetic, structural, and computational studies have advanced our understanding of the 2OG oxygenase catalytic cycles. − Similarly, mutations of second and outer coordination sphere residues have advanced our understanding of 2OG oxygenase catalysis . However, performing structure–function relationships to probe the role of the conserved bis-histidine coordination environment has proven challenging, as mutation of either of the cis-disposed ligands abolishes catalytic function.…”

Section: Introductionmentioning

confidence: 99%

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Probing Ferryl Reactivity in a Nonheme Iron Oxygenase Using an Expanded Genetic Code

Hardy,

Quesne,

Gérard

et al. 2024

ACS Catal.

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The ability to introduce noncanonical amino acids as axial ligands in heme enzymes has provided a powerful experimental tool for studying the structure and reactivity of their Fe IV �O ("ferryl") intermediates. Here, we show that a similar approach can be used to perturb the conserved Fe coordination environment of 2-oxoglutarate (2OG) dependent oxygenases, a versatile class of enzymes that employ highly-reactive ferryl intermediates to mediate challenging C−H functionalizations. Replacement of one of the cis-disposed histidine ligands in the oxygenase VioC with a less electron donating N δ -methylhistidine (MeHis) preserves both catalytic function and reaction selectivity. Significantly, the key ferryl intermediate responsible for C−H activation can be accumulated in both the wildtype and the modified protein. In contrast to heme enzymes, where metal-oxo reactivity is extremely sensitive to the nature of the proximal ligand, the rates of C−H activation and the observed large kinetic isotope effects are only minimally affected by axial ligand replacement in VioC. This study showcases a powerful tool for modulating the coordination sphere of nonheme iron enzymes that will enhance our understanding of the factors governing their divergent activities.

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Section: ■ Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Probing Ferryl Reactivity in a Nonheme Iron Oxygenase Using an Expanded Genetic Code

Hardy,

Quesne,

Gérard

et al. 2024

ACS Catal.

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“…A serials of recent studies conducted by Schofield et al profoundly revealed how the enzyme protein environment and the structure of the substrate interactively regulate the function of the enzyme. 25–28 Investigation of the catalytic rearrangement reaction mechanism of THP by BBOX at the molecular level potentially not only provides deeper and newer insights into the 2OG enzyme family but also broadens our understanding of radical-based enzymatic catalysis.…”

Section: Introductionmentioning

confidence: 99%

Theoretical investigation of the reaction mechanism of THP oxidative rearrangement catalysed by BBOX

Meng,

Sun,

Liu

et al. 2024

Phys. Chem. Chem. Phys.

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Origins of Catalysis in Non‐Heme Fe(II)/2‐Oxoglutarate‐Dependent Histone Lysine Demethylase KDM4A with Differently Methylated Histone H3 Peptides

Devadas,

Thomas,

Rifayee

et al. 2024

Chemistry A European J

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Histone lysine demethylase 4A (KDM4A), a non‐heme Fe(II)/2‐oxoglutarate (2OG) dependent oxygenase that catalyzes the demethylation of tri‐methylated lysine residues at the 9, 27, and 36 positions of histone H3 (H3K9me3, H3K27me3, and H3K36me3). These methylated residues show contrasting transcriptional roles; therefore, understanding KDM4A’s catalytic mechanisms with these substrates is essential to explain the factors that control the different sequence‐dependent demethylations. In this study, we use molecular dynamics (MD)‐based combined quantum mechanics/molecular mechanics (QM/MM) methods to investigate determinants of KDM4A catalysis with H3K9me3, H3K27me3 and H3K36me3 substrates. In KDM4A‐H3(5‐14)K9me3 and KDM4A‐H3(23‐32)K27me3 ferryl complexes, the O‐H distance positively correlates with the activation barrier of the rate‐limiting step, however in the KDM4A‐H3(32‐41)K36me3, no direct one‐to‐one relationship was found implying that the synergistic effects between the geometric parameters, second sphere interactions and the intrinsic electric field contribute for the effective catalysis for this substrate. The intrinsic electric field along the Fe‐O bond changes between the three complexes and shows a positive correlation with the HAT activation barrier, suggesting that modulating electric field can be used for fine engineering KDM catalysis with a specific substrate. The results reveal how KDM4A uses a combination of strategies to enable near equally efficient demethylation of different H3Kme3 residues.

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Unusual catalytic strategy by non-heme Fe(ii)/2-oxoglutarate-dependent aspartyl hydroxylase AspH

Abstract: Biocatalytic C-H oxidation reactions are of important synthetic utility, provide a sustainable route for selective synthesis of important organic molecules, and are an integral part of fundamental cell processes. The...

Cited by 5 publications

References 236 publications

Probing Ferryl Reactivity in a Nonheme Iron Oxygenase Using an Expanded Genetic Code

Probing Ferryl Reactivity in a Nonheme Iron Oxygenase Using an Expanded Genetic Code

Theoretical investigation of the reaction mechanism of THP oxidative rearrangement catalysed by BBOX

Origins of Catalysis in Non‐Heme Fe(II)/2‐Oxoglutarate‐Dependent Histone Lysine Demethylase KDM4A with Differently Methylated Histone H3 Peptides

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