Fe ion coordination direction and refresh mechanism in off-line αKG-dependent hydroxylase

International Journal of Biological Macromolecules, Journal Year: 2025, Volume and Issue: unknown, P. 140942 - 140942

Published: Feb. 1, 2025

Language: Английский

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Computational studies on the functional and structural impact of pathogenic mutations in enzymes

Protein Science, Journal Year: 2025, Volume and Issue: 34(4)

Published: March 21, 2025

Enzymes are critical biological catalysts involved in maintaining the intricate balance of metabolic processes within living organisms. Mutations enzymes can result disruptions to their functionality that may lead a range diseases. This review focuses on computational studies investigate effects disease-associated mutations various enzymes. Through molecular dynamics simulations, multiscale calculations, and machine learning approaches, provide detailed insights into how impact enzyme structure, dynamics, catalytic activity. emphasizes increasing simulations understanding mechanisms behind (dis)function by highlighting application key methodologies selected examples, aiding prediction mutation development therapeutic strategies.

Language: Английский

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Three distinct strategies lead to programmable aliphatic C−H oxidation in bicyclomycin biosynthesis

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: May 19, 2025

Language: Английский

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How Do Variants of Residues in the First Coordination Sphere, Second Coordination Sphere, and Remote Areas Influence the Catalytic Mechanism of Non-Heme Fe(II)/2-Oxoglutarate Dependent Ethylene-Forming Enzyme?

ACS Catalysis, Journal Year: 2024, Volume and Issue: 14(24), P. 18550 - 18569

Published: Dec. 5, 2024

The ethylene-forming enzyme (EFE) is a Fe(II)/2-oxoglutarate (2OG) and l-arginine (l-Arg)-dependent oxygenase that primarily decomposes 2OG into ethylene while also catalyzing l-Arg hydroxylation. While the hydroxylation mechanism in EFE similar to other Fe(II)/2OG-dependent oxygenases, formation of unique. Various redesign strategies have aimed increase production EFE, but success has been limited, highlighting need for alternate approaches. It crucial incorporate an accurate comprehensive description integrative multidimensional effects protein environment enhance strategy metalloenzymes, particularly EFE. This involves understanding role second coordination sphere (SCS) long-range (LR) interacting residues, correlated motions, electronic structure, intrinsic electric field (IntEF), as well stabilization transition states reaction intermediates. In this study, we employ molecular dynamics-based quantum mechanics/molecular mechanics approach examine on reactions catalyzed by variants from first (FCS, D191E), SCS (A198V R171A) LR (E215A). study uncovers how substitutions at different positions similarly impact posing distinct reaction. Results predict effect controlling mode Fe(II) center. Specifically, suggests D191E uniquely prefers transitioning

Language: Английский

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Mechanistic investigation of sustainable heme-inspired biocatalytic synthesis of cyclopropanes for challenging substrates

Communications Chemistry, Journal Year: 2024, Volume and Issue: 7(1)

Published: Nov. 29, 2024

Engineered heme proteins exhibit excellent sustainable catalytic carbene transfer reactivities toward olefins for value-added cyclopropanes. However, unactivated and electron-deficient remain challenging in such reactions. To help design efficient heme-inspired biocatalysts these difficult situations, a systematic quantum chemical mechanistic study was performed to investigate effects of olefin substituents, non-native amino acid axial ligands, natural non-natural macrocycles with the widely used ethyl diazoacetate. Results show that substrate acrylate has much higher barrier than electron-rich styrene. For styrene, predicted trend is consistent experimentally analogue cofactors, which can significantly reduce barriers. acrylate, while best ligand only marginally improves reactivity versus native histidine model, couple computationally studied dramatically barriers level comparable These results will facilitate development better this area. enabling transformation cyclopropanes, however, exploiting reactions remains challenging. Here, authors perform diazoacetate, revealing potential an biocatalyst.

Language: Английский

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[Ti{H 5 -1-(Sime3)-3-(R)-C9h5}Cl2(Oet)] Half-Sandwich Complexes: Synthesis, Solid-State Structure, Hirshfeld Surface Analysis and Theoretical Studies

Published: Jan. 1, 2024

Language: Английский

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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

Chemistry - A European Journal, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 2, 2024

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

Language: Английский

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Designing lysyl hydroxylase inhibitors for oral submucous fibrosis — Insights from molecular dynamics

International Journal of Biological Macromolecules, Journal Year: 2024, Volume and Issue: unknown, P. 139304 - 139304

Published: Dec. 1, 2024

Language: Английский

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