Dioxygen Binding Is Controlled by the Protein Environment in Non-heme Fe and 2-Oxoglutarate Oxygenases: A Study on Histone Demethylase PHF8 and an Ethylene-Forming Enzyme

Overview

Journal Chemistry

Specialty Chemistry

Date 2023 Jan 26

PMID 36701641

Authors

Shobhit S Chaturvedi

Midhun George Thomas

Simahudeen Bathir Jaber Sathik Rifayee

Walter White

Jon Wildey

Cait Warner

Christopher J Schofield

Jian Hu

Robert P Hausinger

Tatayana G Karabencheva-Christova

Christo Z Christov

Affiliations

Soon will be listed here.

Abstract

This study investigates dioxygen binding and 2-oxoglutarate (2OG) coordination by two model non-heme Fe /2OG enzymes: a class 7 histone demethylase (PHF8) that catalyzes the hydroxylation of its H3K9me2 histone substrate leading to demethylation reactivity and the ethylene-forming enzyme (EFE), which catalyzes two competing reactions of ethylene generation and substrate l-Arg hydroxylation. Although both enzymes initially bind 2OG by using an off-line 2OG coordination mode, in PHF8, the substrate oxidation requires a transition to an in-line mode, whereas EFE is catalytically productive for ethylene production from 2OG in the off-line mode. We used classical molecular dynamics (MD), quantum mechanics/molecular mechanics (QM/MM) MD and QM/MM metadynamics (QM/MM-MetD) simulations to reveal that it is the dioxygen binding process and, ultimately, the protein environment that control the formation of the in-line Fe -OO⋅ intermediate in PHF8 and the off-line Fe -OO⋅ intermediate in EFE.

Citing Articles

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?.

Thomas M, Rifayee S, Christov C ACS Catal. 2024; 14(24):18550-18569.

PMID: 39722885 PMC: 11668244. DOI: 10.1021/acscatal.4c04010.

PHF8/KDM7B: A Versatile Histone Demethylase and Epigenetic Modifier in Nervous System Disease and Cancers.

Fan T, Xie J, Huang G, Li L, Zeng X, Tao Q Epigenomes. 2024; 8(3).

PMID: 39311138 PMC: 11417953. DOI: 10.3390/epigenomes8030036.

The Unique Role of the Second Coordination Sphere to Unlock and Control Catalysis in Nonheme Fe(II)/2-Oxoglutarate Histone Demethylase KDM2A.

Thomas M, Rifayee S, Chaturvedi S, Gorantla K, White W, Wildey J Inorg Chem. 2024; 63(23):10737-10755.

PMID: 38781256 PMC: 11168414. DOI: 10.1021/acs.inorgchem.4c01365.

Biological formation of ethylene.

Hausinger R, J S Rifayee S, Thomas M, Chatterjee S, Hu J, Christov C RSC Chem Biol. 2023; 4(9):635-646.

PMID: 37654506 PMC: 10467617. DOI: 10.1039/d3cb00066d.

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