An Active Site Tyr Residue Guides the Regioselectivity of Lysine Hydroxylation by Nonheme Iron Lysine-4-hydroxylase Enzymes through Proton-Coupled Electron Transfer

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(17), P. 11726 - 11739

Published: April 18, 2024

Lysine dioxygenase (KDO) is an important enzyme in human physiology involved bioprocesses that trigger collagen cross-linking and blood pressure control. There are several KDOs nature; however, little known about the factors govern regio- stereoselectivity of these enzymes. To understand how can selectively hydroxylate their substrate, we did a comprehensive computational study into mechanisms features 4-lysine dioxygenase. In particular, selected snapshot from MD simulation on KDO5 created large QM cluster models (A, B, C) containing 297, 312, 407 atoms, respectively. The largest model predicts regioselectivity matches experimental observation with rate-determining hydrogen atom abstraction C4–H position, followed by fast OH rebound to form 4-hydroxylysine products. calculations show C, dipole moment positioned along bond substrate and, therefore, electrostatic electric field perturbations protein assist creating hydroxylation selectivity. Furthermore, active site Tyr233 residue identified reacts through proton-coupled electron transfer akin axial Trp cytochrome c peroxidase. Thus, upon formation iron(IV)-oxo species catalytic cycle, phenol loses proton nearby Asp179 residue, while at same time, transferred iron create iron(III)-oxo species. This charged tyrosyl directs guides selectivity C4-hydroxylation substrate.

Language: Английский

---

CO₂ Reduction by an Iron(I) Porphyrinate System: Effect of Hydrogen Bonding on the Second Coordination Sphere

Inorganic Chemistry, Journal Year: 2024, Volume and Issue: 63(10), P. 4474 - 4481

Published: Feb. 26, 2024

Transforming CO2 into valuable materials is an important reaction in catalysis, especially because concentrations the atmosphere have been growing steadily due to extensive fossil fuel usage. From environmental perspective, reduction of should be catalyzed by environmentally benign catalyst and avoid use heavy transition-metal ions. In this work, we present a computational study novel iron(I) porphyrin for reduction, namely, with tetraphenylporphyrin ligand analogues. particular, investigated one meso-phenyl groups substituted o-urea, p-urea, or o-2-amide groups. These substituents can provide hydrogen-bonding interactions second coordination sphere bound ligands assist proton relay. Furthermore, our studies bicarbonate phenol as stabilizers donors mechanism. Potential energy landscapes double protonation porphyrinate are reported. The work shows that bridges urea/amide iron center provides tight bonding pattern strong facilitates easy delivery CO2. Specifically, low-energy shuttle mechanism form CO water efficiently. o-urea group locks orientation helps ideal transfer, while there more mobility lesser stability o-amide position instead. Our calculations show leads proton-transfer barriers, line experimental observation. We then applied electric-field-effect estimate effects on two steps reaction. describe perturbations enhance driving forces used make predictions about how catalysts further engineered enhanced processes.

Language: Английский

---

Computational Study Into the Oxidative Ring‐Closure Mechanism During the Biosynthesis of Deoxypodophyllotoxin

Chemistry - A European Journal, Journal Year: 2024, Volume and Issue: 30(22)

Published: Feb. 7, 2024

The nonheme iron dioxygenase deoxypodophyllotoxin synthase performs an oxidative ring-closure reaction as part of natural product synthesis in plants. How the enzyme enables (-)-yatein and avoids substrate hydroxylation remains unknown. To gain insight into mechanism understand details pathways leading to products by-products we performed a comprehensive computational study. work shows that is bound tightly binding pocket with C

Language: Английский

---

Quantum Mechanical Cluster Models for Calculations on Enzymatic Reaction Mechanisms: Set‐Up and Accuracy

Chemistry - A European Journal, Journal Year: 2024, Volume and Issue: 30(60)

Published: Aug. 7, 2024

Enzymes turnover substrates into products with amazing efficiency and selectivity as such have great potential for use in biotechnology pharmaceutical applications. However, details of their catalytic cycles the origins surrounding regio- chemoselectivity enzymatic reaction processes remain unknown, which makes engineering enzymes challenging. Computational modelling can assist experimental work field establish factors that influence rates product distributions. A popular approach is quantum mechanical cluster models take first- second coordination sphere enzyme active site consideration. These QM are widely applied but often results obtained dependent on model choice selection. Herein, we show give highly accurate reproduce distributions free energies activation within several kcal mol

Language: Английский

---

Causal relationship between diet and knee osteoarthritis: A Mendelian randomization analysis

PLoS ONE, Journal Year: 2024, Volume and Issue: 19(1), P. e0297269 - e0297269

Published: Jan. 31, 2024

Background Knee osteoarthritis (KOA) is a common disabling joint disease that affects millions of people worldwide. Diet may play role in the etiology and progression KOA, but evidence for causal relationship limited. We aimed to investigate impact dietary intake on KOA risk using Mendelian randomization (MR). Methods used summary-level data from genome-wide association studies (GWAS) including (n = 335, 394–462, 342), 403, 124). selected 6–77 genetic variants as instrumental variables 18 factors, processed meat, poultry, beef, oily fish, non-oily pork, lamb, frequency alcohol intake, alcoholic beverages, tea, coffee, dried fruit, cereals, cheese, bread, cooked vegetables, salad/raw fresh fruit. performed univariate multivariate MR analyses estimate effect each factor risk. also some sensitivity assess validity hypothesis. Results found higher coffee was associated with increased risk, whereas fruits, grains, fish reduced After adjustment, we affect through obesity, body mass index (BMI), diabetes, hypertension, prolonged standing. Sensitivity did not reveal any pleiotropy. Conclusions Our study provides new influence Specifically, suggest decreased be beneficial preventing mitigating KOA. further are needed elucidate underlying mechanisms confirm our findings different populations.

Language: Английский

---

Enhanced Reactivity through Equatorial Sulfur Coordination in Nonheme Iron(IV)–Oxo Complexes: Insights from Experiment and Theory

Inorganic Chemistry, Journal Year: 2024, Volume and Issue: 63(15), P. 6752 - 6766

Published: March 29, 2024

Sulfur ligation in metalloenzymes often gives the active site unique properties, whether it is axial cysteinate ligand cytochrome P450s or equatorial sulfur/thiol nonheme iron enzymes. To understand sulfur to complexes and how affects structural, spectroscopic, intrinsic properties of species catalysis substrates, we pursued a systematic study compared with amine-ligated iron(IV)–oxo complexes. We synthesized characterized biomimetic N4S-ligated complex obtained results an analogous N5-ligated complex. Our work shows that amine for replacement framework leads rate enhancement oxygen atom hydrogen transfer reactions. Moreover, sulfur-ligated reacts through different reaction mechanism as complex, where former hydride latter reacting via radical pathways. show reactivity differences are caused by dramatic change redox potential between two studies highlight importance implementing into physicochemical oxidant its reactivity.

Language: Английский

---

Machine learning-aided engineering of a cytochrome P450 for optimal bioconversion of lignin fragments

Physical Chemistry Chemical Physics, Journal Year: 2024, Volume and Issue: 26(25), P. 17577 - 17587

Published: Jan. 1, 2024

Using molecular dynamics, machine learning, and density functional theory calculations we make predictions on engineered cytochrome P450 structures their product distributions.

Language: Английский

---

Insights into Cytochrome P450 Enzyme Catalyzed Defluorination of Aromatic Fluorides

Angewandte Chemie International Edition, Journal Year: 2023, Volume and Issue: 62(42)

Published: Aug. 29, 2023

Density functional calculations establish a novel mechanism of aromatic defluorination by P450 Compound I. This is achieved via either an initial epoxide intermediate or through 1,2-fluorine shift in electrophilic intermediate, which highlights that the P450s can defluorinate fluoroarenes. However, absence proton donor strong Fe-F bond be obtained as shown from calculations.

Language: Английский

---

Computational Modeling of the Enzymatic Achmatowicz Rearrangement by Heme-Dependent Chloroperoxidase: Reaction Mechanism, Enantiopreference, Regioselectivity, and Substrate Specificity

Journal of Chemical Information and Modeling, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 31, 2025

The chloroperoxidase from Caldariomyces fumago (CfCPO) catalyzes the oxidative ring expansion of α-heterofunctionalized furans via Achmatowicz rearrangement, providing an elegant tool to convert furan rings into complex-prefunctionalized scaffolds. However, mechanism this transformation remains unclear. Herein, CfCPO-catalyzed reaction rac-1-(2-furyl)ethanol (1a) is studied by quantum chemical calculations and molecular dynamics simulations. reveal that conversion follows general reaction. Notably, binding 1a enzyme's active site influences Compound I (Cpd I) formation, (R)-1a enantiomer results in a lower barrier compared (S)-1a, explaining observed (R)-enantiopreference toward racemic substrate. Additionally, due weaker steric hindrance between porphyrin substrate, nucleophilic attack Cpd on core preferred at less-substituted C4=C5 bond, rationale for experimentally regioselectivity. Finally, bottleneck residues substrate delivery channel also surroundings are proposed be responsible specificity CfCPO. This study lays theoretical foundation rational design new CPOs catalyze rearrangement with broader spectrum or specific stereopreference.

Language: Английский

---

Mechanism of Regio- and Enantioselective Hydroxylation of Arachidonic Acid Catalyzed by Human CYP2E1: A Combined Molecular Dynamics and Quantum Mechanics/Molecular Mechanics Study

Journal of Chemical Information and Modeling, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 11, 2025

Regio- and enantioselective hydroxylation of free fatty acids by human cytochrome P450 2E1 (CYP2E1) plays an important role in metabolic regulation has significant pathological implications. Despite extensive research, the detailed mechanism CYP2E1 remains incompletely understood. To clarify origins regioselectivity enantioselectivity observed for CYP2E1-mediated acid hydroxylation, molecular dynamics (MD) simulations quantum mechanics/molecular mechanics (QM/MM) calculations were performed. MD provided key insights into proximity arachidonic acid's carbon atoms to reactive iron(IV)-oxo moiety compound I (Cpd I), with ω-1 position being closest, indicating higher reactivity at this site. QM/MM identified hydrogen abstraction as rate-determining step, ω-1S transition state exhibiting lowest energy barrier, consistent experimentally enantioselectivity. Energy decomposition analysis revealed that variations mechanical (ΔEQM) significantly influence reaction barriers, most efficient occurring ω-2R positions. These findings underscore importance substrate positioning within active site determining product selectivity. Comparisons two related P450s, P450BM3 P450SPα, further highlighted critical architecture modulating While surrounding residues do not directly dictate selectivity, they shape environment positioning. Furthermore, our a previously unrecognized catalytic Ala299. provide deeper mechanistic understanding offer valuable its precise engineering targeted C-H functionalization.

Language: Английский

---