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Biotransformation of Bisphenol by Human Cytochrome P450 2C9 Enzymes: A Density Functional Theory Study.
Hermano Sampaio Dias, Artur; Yadav, Rolly; Mokkawes, Thirakorn; Kumar, Asheesh; Skaf, Munir S; Sastri, Chivukula V; Kumar, Devesh; de Visser, Sam P.
Afiliación
  • Hermano Sampaio Dias A; Manchester Institute of Biotechnology and Department of Chemical Engineering, The University of Manchester, 131 Princess Street, ManchesterM1 7DN, United Kingdom.
  • Yadav R; Center for Computing in Engineering & Sciences, University of Campinas, Rua Josué de Castro, s/n, Campinas13083-861, Brazil.
  • Mokkawes T; Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati, Assam781039, India.
  • Kumar A; Manchester Institute of Biotechnology and Department of Chemical Engineering, The University of Manchester, 131 Princess Street, ManchesterM1 7DN, United Kingdom.
  • Skaf MS; Department of Physics, Babasaheb Bhimrao Ambedkar University, Lucknow, Uttar Pradesh (U.P.)226025, India.
  • Sastri CV; Center for Computing in Engineering & Sciences, University of Campinas, Rua Josué de Castro, s/n, Campinas13083-861, Brazil.
  • Kumar D; Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati, Assam781039, India.
  • de Visser SP; Department of Physics, Siddharth University, Kapilvastu, Siddharthnagar272202, India.
Inorg Chem ; 62(5): 2244-2256, 2023 Feb 06.
Article en En | MEDLINE | ID: mdl-36651185
Bisphenol A (BPA, 2,2-bis-(4-hydroxyphenyl)propane) is used as a precursor in the synthesis of polycarbonate and epoxy plastics; however, its availability in the environment is causing toxicity as an endocrine-disrupting chemical. Metabolism of BPA and their analogues (substitutes) is generally performed by liver cytochrome P450 enzymes and often leads to a mixture of products, and some of those are toxic. To understand the product distributions of P450 activation of BPA, we have performed a computational study into the mechanisms and reactivities using large model structures of a human P450 isozyme (P450 2C9) with BPA bound. Density functional theory (DFT) calculations on mechanisms of BPA activation by a P450 compound I model were investigated, leading to a number of possible products. The substrate-binding pocket is tight, and as a consequence, aliphatic hydroxylation is not feasible as the methyl substituents of BPA cannot reach compound I well due to constraints of the substrate-binding pocket. Instead, we find low-energy pathways that are initiated with phenol hydrogen atom abstraction followed by OH rebound to the phenolic ortho- or para-position. The barriers of para-rebound are well lower in energy than those for ortho-rebound, and consequently, our P450 2C9 model predicts dominant hydroxycumyl alcohol products. The reactions proceed through two-state reactivity on competing doublet and quartet spin state surfaces. The calculations show fast and efficient substrate activation on a doublet spin state surface with a rate-determining electrophilic addition step, while the quartet spin state surface has multiple high-energy barriers that can also lead to various side products including C4-aromatic hydroxylation. This work shows that product formation is more feasible on the low spin state, while the physicochemical properties of the substrate govern barrier heights of the rate-determining step of the reaction. Finally, the importance of the second-coordination sphere is highlighted that determines the product distributions and guides the bifurcation pathways.
Asunto(s)

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Fenoles / Sistema Enzimático del Citocromo P-450 Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Inorg Chem Año: 2023 Tipo del documento: Article País de afiliación: Reino Unido

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Fenoles / Sistema Enzimático del Citocromo P-450 Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Inorg Chem Año: 2023 Tipo del documento: Article País de afiliación: Reino Unido