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

Sudheesh Devadas,

Midhun George Thomas, Simahudeen Bathir Jaber Sathik Rifayee

et al.

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

Disproportionation of H2O2 to Dioxygen on a Nonheme Iron Center. A Computational Study DOI Open Access
Henrik P. H. Wong, Frédéric Banse, Sam P. de Visser

et al.

ChemCatChem, Journal Year: 2023, Volume and Issue: 15(22)

Published: Sept. 6, 2023

Abstract Hydrogen peroxide is a versatile reductant that under the right conditions can react to form dioxygen in an electrochemical reaction. This reaction has low carbon footprint and applications are being sought for batteries. In this work computational study presented on recently reported nonheme iron(II) complex where we mechanistic pathways leading formation from H 2 O . The shows upon reduction of iron(III)‐hydroperoxo species it rapidly leads through heterolytic cleavage bond iron(IV)‐oxo(hydroxo). dimerization two iron(IV)‐oxo(hydroxo) complexes then with small barriers. Dissociation dimer expels exothermic An alternative mechanism μ‐1,2‐peroxo‐μ‐1,1‐hydroperoxodiiron(II) intermediate was also tested but found be highly endergonic. These studies highlight feasibilities complexes.

Language: Английский

Citations

2
Identification of potential inhibitors targeting yellow fever virus helicase through ligand and structure-based computational studies DOI
Sumera Zaib, Nehal Rana, Hafiz Saqib Ali

et al.

Journal of Biomolecular Structure and Dynamics, Journal Year: 2023, Volume and Issue: unknown, P. 1 - 18

Published: Dec. 18, 2023

Yellow fever is a flavivirus having plus-sensed RNA which encodes single polyprotein. Host proteases cut this polyprotein into seven nonstructural proteins including vital NS3 protein. The present study aims to identify the most effective inhibitor against helicase (NS3) using different advanced ligand and structure-based computational studies. A set of 300 ligands was selected by chemical structural similarity model, are similar S-adenosyl-l-cysteine infiniSee. This tool screens billions compounds through search from in-built spaces (CHEMriya, Galaxi, KnowledgeSpace REALSpace). pharmacophore designed in library that showed same features. According sequence ligands, six (29, 87, 99, 116, 148, 208) were taken for designing Subsequently, best shared-features docked FlexX functionality SeeSAR their optibrium properties analyzed. Afterward, ADME improved replacing unfavorable fragments, resulted generation new compounds. (301, 302, 303 304) pharmacokinetics toxicological evaluated SwissADME. optimal yellow 2-amino-N-(4-(dimethylamino)thiazol-2-yl)-4-methyloxazole-5-carboxamide (302), exhibits promising potential drug development.

Language: Английский

Citations

1
Radical-relay C(sp3)–H azidation catalyzed by an engineered nonheme iron enzyme DOI
Qun Zhao, Jinyan Rui, Xiongyi Huang

et al.

Methods in enzymology on CD-ROM/Methods in enzymology, Journal Year: 2024, Volume and Issue: unknown, P. 195 - 213

Published: Jan. 1, 2024

Language: Английский

Citations

0
What is the Origin of the Regioselective C3‐Hydroxylation of L‐Arg by the Nonheme Iron Enzyme Capreomycin C? DOI Creative Commons
Yuanxin Cao, Henrik P. H. Wong, Jim Warwicker

et al.

Chemistry - A European Journal, Journal Year: 2024, Volume and Issue: 30(66)

Published: Aug. 27, 2024

Abstract The nonheme iron dioxygenase capreomycin C (CmnC) hydroxylates a free L‐arginine amino acid regio‐ and stereospecifically at the 3 ‐position as part of antibiotics biosynthesis. Little is known on its structure, catalytic cycle substrate specificity and, therefore, comprehensive computational study was performed. A large QM cluster model CmnC created 297 atoms mechanisms for −H, 4 −H 5 hydroxylation −C desaturation were investigated. All low‐energy pathways correspond to radical reaction with an initial hydrogen atom abstraction followed by OH rebound form alcohol product complexes. work compared alternative L‐Arg hydroxylating dioxygenases differences in active site polarity are compared. We show that tight bonding network binding pocket positions ideal orientation activation, whereby polar groups induce electric field effect guides selectivity.

Language: Английский

Citations

0
Origins of Catalysis in Non‐Heme Fe(II)/2‐Oxoglutarate‐Dependent Histone Lysine Demethylase KDM4A with Differently Methylated Histone H3 Peptides DOI

Sudheesh Devadas,

Midhun George Thomas, Simahudeen Bathir Jaber Sathik Rifayee

et al.

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

Citations

0