Computational study on the metabolic activation mechanism of PeCDD by Cytochrome P450 1A1

Zhu, Ledong; Zhou, Jie; Zhang, Qingzhu; Li, Yanwei; Wang, Wenxing

doi:10.1016/j.jhazmat.2020.124276

Cited by 11 publications

(5 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We should point out here that although the energy barriers of the isomerization of enediol and decarboxylation are somewhat high for the enzymatic reactions, the relative energies of their transition states are not high, and the former steps are exothermal, which may facilitate the subsequent reactions. These results are similar to those in the literature. − …”

Section: Resultssupporting

confidence: 92%

Mechanism of Sugar Ring Contraction and Closure Catalyzed by UDP-d-apiose/UDP-d-xylose Synthase (UAXS)

Wang

Wei

Zhang

et al. 2022

J. Chem. Inf. Model.

View full text Add to dashboard Cite

Uridine diphosphate (UDP)-apiose/UDP-xylose synthase (UAXS) is a member of the short-chain dehydrogenase/reductase superfamily (SDR), which catalyzes the ring contraction and closure of UDP-d-glucuronic acid (UDP-GlcA), affording UDP-apiose and UDP-xylose. UAXS is a special enzyme that integrates ring-opening, decarboxylation, rearrangement, and ring closure/contraction in a single active site. Recently, the ternary complex structure of UAXS was crystallized from Arabidopsis thaliana. In this work, to gain insights into the detailed formation mechanism of UDP-apiose and UDP-xylose, an enzyme–substrate reactant model has been constructed and quantum mechanical/molecular mechanical (QM/MM) calculations have been performed. Our calculation results reveal that the reaction starts from the C4–OH oxidation, which is accompanied by the conformational transformation of the sugar ring from chair type to boat type. The sugar ring-opening is prior to decarboxylation, and the deprotonation of the C2–OH group is the prerequisite for sugar ring-opening. Moreover, the keto–enol tautomerization of the decarboxylated intermediate is a necessary step for ring closure/contraction. Based on our calculation results, more UDP-apiose product was expected, which is in line with the experimental observation. Three titratable residues, Tyr185, Cys100, and Cys140, steer the reaction by proton transfer from or to UDP-GlcA, and Arg182, Glu141, and D337 constitute a proton conduit for sugar C2–OH deprotonation. Although Thr139 and Tyr105 are not directly involved in the enzymatic reaction, they are responsible for promoting the catalysis by forming hydrogen-bonding interactions with GlcA. Our calculations may provide useful information for understanding the catalysis of the SDR family.

show abstract

Section: Resultssupporting

confidence: 92%

Mechanism of Sugar Ring Contraction and Closure Catalyzed by UDP-d-apiose/UDP-d-xylose Synthase (UAXS)

Wang

Wei

Zhang

et al. 2022

J. Chem. Inf. Model.

View full text Add to dashboard Cite

show abstract

“…In another study, SER122, ALA317, ILE386, and LEU496 were found to be the main amino acids that affect the metabolism of dioxin. 37 The reason for the differences in the main amino acids for the metabolism of FQs and dioxin, may be due to differences in the hydrophobicity of the ligands. FQ molecules, containing hydrophilic groups such as piperazine ring and carboxyl, are more soluble in the water.…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

“…75 However, dioxin is a strong hydrophobic material, which is more easily solved in a lipid phase. 37 Thus, the differences in hydrophobic properties of the ligands may lead to various key amino acids that interact with metabolic enzymes. To further analyze the mechanism of interaction between molecules and receptor (4R1Z), the 30 NOR substitutes screened were docked with cytochrome P450 metabolic enzymes (4R1Z), as shown in Table S8 † and Fig.…”

Section: Evaluation Of the Stability And Bidirectional Selectivity Of...mentioning

confidence: 99%

“…Molecular docking, MD simulations and other simulation methods were used to screen natural benzodiazepine-specific receptor inhibitors, 34 identifying the interaction between antiviral drugs and receptors (CCR5 and CXCR4), and revealing the key targets for drug action. 35 In addition, some researchers used MD simulations and DFT to reveal the metabolic transformation path and catalytic reduction mechanism of cytochrome P450 enzyme on polycyclic aromatic hydrocarbons (PAHs), 36 dioxins, 37 DDT 38 and other pollutants. Key factors affecting metabolic processes were also analyzed in previous studies, which provided theoretical support for the analysis of the toxicity mechanism of environmental pollutants and the regulation of environmental risks.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Designing and screening of fluoroquinolone substitutes using combined in silico approaches: biological metabolism–bioconcentration bilateral selection and their mechanism analyses

Han

et al. 2022

Green Chem.

View full text Add to dashboard Cite

show abstract

Computational study on the endocrine-disrupting metabolic activation of Benzophenone-3 catalyzed by cytochrome P450 1A1: A QM/MM approach

Wang,

Zhang,

et al. 2024

Chemosphere

View full text Add to dashboard Cite

Computational study on the metabolic activation mechanism of PeCDD by Cytochrome P450 1A1

Cited by 11 publications

References 54 publications

Mechanism of Sugar Ring Contraction and Closure Catalyzed by UDP-d-apiose/UDP-d-xylose Synthase (UAXS)

Mechanism of Sugar Ring Contraction and Closure Catalyzed by UDP-d-apiose/UDP-d-xylose Synthase (UAXS)

Designing and screening of fluoroquinolone substitutes using combined in silico approaches: biological metabolism–bioconcentration bilateral selection and their mechanism analyses

Computational study on the endocrine-disrupting metabolic activation of Benzophenone-3 catalyzed by cytochrome P450 1A1: A QM/MM approach

Contact Info

Product

Resources

About