Insights into the metabolic mechanism of PBDEs catalyzed by cytochrome P450 enzyme 3A4: A QM/MM study

Zhang, Ruiming; Li, Pengfei; Shi, Xiangli; Zhang, Ruiying; Wang, Junjie; Li, Yanwei; Zhang, Qingzhu; Wang, Wenxing

doi:10.1016/j.chemosphere.2021.130430

Cited by 12 publications

(2 citation statements)

References 69 publications

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“…All missing hydrogen atoms in the original crystal structure were added automatically using the HBUILD module in the CHARMM package. , After adding all hydrogen atoms, the obtained protein system was solvated in a TIP3P water droplet of 40 Å radius, centered at the nitrogen atom of the substrate. This nonperiodic treatment with a finite solvent shell has been widely employed in radical enzyme system setup − for further molecular dynamic simulations and QM/MM calculations. , Finally, to neutralize the negative charge of the solvated system, 15 sodium ions were randomly added to the surface of the protein. The model consists of 30745 atoms, including 785 amino acid residues, 6125 TIP3P water molecules (including 191 crystal water molecules), 15 sodium ions, and the substrate t4D-HP (Figure S2).…”

Section: Methodsmentioning

confidence: 99%

Cysteine Radical and Glutamate Collaboratively Enable C–H Bond Activation and C–N Bond Cleavage in a Glycyl Radical Enzyme HplG

Deng,

Liao

2024

J. Chem. Inf. Model.

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Hydroxyprolines are abundant in nature and widely utilized by many living organisms. Isomerization of trans-4-hydroxy-d-proline (t4D-HP) to generate 2-amino-4-ketopentanoate has been found to need a glycyl radical enzyme HplG, which catalyzes the cleavage of the C–N bond, while dehydration of trans-4-hydroxy-l-proline involves a homologous enzyme of HplG. Herein, molecular dynamics simulations and quantum mechanics/molecular mechanics (QM/MM) calculations are employed to understand the reaction mechanism of HplG. Two possible reaction pathways of HplG have been explored to decipher the origin of its chemoselectivity. The QM/MM calculations reveal that the isomerization proceeds via an initial hydrogen shift from the Cγ site of t4D-HP to a catalytic cysteine radical, followed by cleavage of the Cδ−N bond in t4D-HP to form a radical intermediate that captures a hydrogen atom from the cysteine. Activation of the Cδ−H bond in t4D-HP to bring about dehydration of t4D-HP possesses an extremely high energy barrier, thus rendering the dehydration pathway implausible in HplG. On the basis of the current calculations, conserved residue Glu429 plays a pivotal role in the isomerization pathway: the hydrogen bonding between it and t4D-HP weakens the hydroxyalkyl Cγ–Hγ bond, and it acts as a proton acceptor to trigger the cleavage of the C–N bond in t4D-HP. Our current QM/MM calculations rationalize the origin of the experimentally observed chemoselectivity of HplG and propose an H-bond-assisted bond activation strategy in radical-containing enzymes. These findings have general implications on radical-mediated enzymatic catalysis and expand our understanding of how nature wisely and selectively activates the C–H bond to modulate catalytic selectivity.

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Section: Methodsmentioning

confidence: 99%

Cysteine Radical and Glutamate Collaboratively Enable C–H Bond Activation and C–N Bond Cleavage in a Glycyl Radical Enzyme HplG

Deng,

Liao

2024

J. Chem. Inf. Model.

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“…In the past two decades, molecular modeling techniques, such as molecular dynamics (MD) simulations and quantum chemical calculations, have been extensively used to shed light on the binding and metabolism of xenobiotics in various biomacromolecules including CYPs [38][39][40][41][42][43]. In this work, five OPFRs detected widely in the environment, including TDCIPP, tris(1-chloro-2-propyl) phosphate (TCIPP), tris(2-chloroethyl) phosphate (TCEP), triethyl phosphate (TEP), and EHDPHP (Figure S1 in the Supplementary Materials), were employed to investigate the reaction mechanism leading to their diester metabolites through the density functional theory (DFT) calculations.…”

Section: Introductionmentioning

confidence: 99%

Computational Insight into Biotransformation Profiles of Organophosphorus Flame Retardants to Their Diester Metabolites by Cytochrome P450

Jia

Yao

et al. 2022

Molecules

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Biotransformation of organophosphorus flame retardants (OPFRs) mediated by cytochrome P450 enzymes (CYPs) has a potential correlation with their toxicological effects on humans. In this work, we employed five typical OPFRs including tris(1,3-dichloro-2-propyl) phosphate (TDCIPP), tris(1-chloro-2-propyl) phosphate (TCIPP), tri(2-chloroethyl) phosphate (TCEP), triethyl phosphate (TEP), and 2-ethylhexyl diphenyl phosphate (EHDPHP), and performed density functional theory (DFT) calculations to clarify the CYP-catalyzed biotransformation of five OPFRs to their diester metabolites. The DFT results show that the reaction mechanism consists of Cα-hydroxylation and O-dealkylation steps, and the biotransformation activities of five OPFRs may follow the order of TCEP ≈ TEP ≈ EHDPHP > TCIPP > TDCIPP. We further performed molecular dynamics (MD) simulations to unravel the binding interactions of five OPFRs in the CYP3A4 isoform. Binding mode analyses demonstrate that CYP3A4-mediated metabolism of TDCIPP, TCIPP, TCEP, and TEP can produce the diester metabolites, while EHDPHP metabolism may generate para-hydroxyEHDPHP as the primary metabolite. Moreover, the EHDPHP and TDCIPP have higher binding potential to CYP3A4 than TCIPP, TCEP, and TEP. This work reports the biotransformation profiles and binding features of five OPFRs in CYP, which can provide meaningful clues for the further studies of the metabolic fates of OPFRs and toxicological effects associated with the relevant metabolites.

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Integrated toxicology, metabolomics, and transcriptomics analyses reveal the biodegradation and adaptation mechanisms to BDE-47 in Pseudomonas plecoglossicida

Qi¹,

Zhu²,

Yuan³

et al. 2023

Chemical Engineering Journal

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Insights into the metabolic mechanism of PBDEs catalyzed by cytochrome P450 enzyme 3A4: A QM/MM study

Cited by 12 publications

References 69 publications

Cysteine Radical and Glutamate Collaboratively Enable C–H Bond Activation and C–N Bond Cleavage in a Glycyl Radical Enzyme HplG

Cysteine Radical and Glutamate Collaboratively Enable C–H Bond Activation and C–N Bond Cleavage in a Glycyl Radical Enzyme HplG

Computational Insight into Biotransformation Profiles of Organophosphorus Flame Retardants to Their Diester Metabolites by Cytochrome P450

Integrated toxicology, metabolomics, and transcriptomics analyses reveal the biodegradation and adaptation mechanisms to BDE-47 in Pseudomonas plecoglossicida

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