Effects of Clinical Mutations in the Second Coordination Sphere and Remote Regions on the Catalytic Mechanism of Non‐Heme Fe(II)/2‐Oxoglutarate‐Dependent Aspartyl Hydroxylase AspH

ChemPhysChem, Journal Year: 2024, Volume and Issue: 25(18)

Published: June 6, 2024

Abstract Aspartyl/asparaginyl hydroxylase (AspH) catalyzes the post‐translational hydroxylations of vital human proteins, playing an essential role in maintaining their biological functions. Single‐point mutations Second Coordination Sphere (SCS) and long‐range (LR) residues AspH have been linked to pathological conditions such as ophthalmologic condition Traboulsi syndrome chronic kidney disease (CKD). Although clinical impacts these are established, there is a critical knowledge gap regarding specific atomistic effects on catalytic mechanism AspH. In this study, we report integrated computational investigations potential mechanistic implications four mutant forms with importance: R735W, R735Q, R688Q, G434V. All exhibited altered binding interactions co‐substrate 2‐oxoglutarate (2OG) main substrate ferric‐superoxo ferryl complexes, which for catalysis, compared wild‐type (WT). Importantly, strongly influence energetics frontier molecular orbitals (FMOs) and, thereby, activation energies hydrogen atom transfer (HAT) step WT Insights from our study can contribute enzyme engineering development selective modulators mutants AspH, ultimately aiding treating cancers, CKD.

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

ACS Catalysis, Journal Year: 2024, Volume and Issue: 14(15), P. 11584 - 11590

Published: July 20, 2024

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 FeIV═O ("ferryl") intermediates. Here, we show that similar approach can be used perturb conserved Fe coordination environment 2-oxoglutarate (2OG) dependent oxygenases, versatile class employ highly-reactive ferryl intermediates mediate challenging C–H functionalizations. Replacement one cis-disposed histidine oxygenase VioC with less electron donating Nδ-methyl-histidine (MeHis) preserves both catalytic function reaction selectivity. Significantly, key intermediate responsible activation accumulated wildtype modified protein. In contrast enzymes, where metal-oxo is extremely sensitive nature proximal ligand, rates observed large kinetic isotope effects are only minimally affected by ligand replacement VioC. This study showcases modulating sphere nonheme iron will enhance our understanding factors governing divergent activities.

Language: Английский

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

Physical Chemistry Chemical Physics, Journal Year: 2024, Volume and Issue: 26(30), P. 20325 - 20339

Published: Jan. 1, 2024

γ-Butyrobetaine hydroxylase (BBOX) is a non-heme Fe

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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