| Full text | |
| Author(s): |
Dias, Artur Hermano Sampaio
;
Yadav, Rolly
;
Mokkawes, Thirakorn
;
Kumar, Asheesh
;
Skaf, Munir S.
;
Sastri, Chivukula, V
;
Kumar, Devesh
;
de Visser, Sam P.
Total Authors: 8
|
| Document type: | Journal article |
| Source: | Inorganic Chemistry; v. N/A, p. 13-pg., 2023-01-18. |
| Abstract | |
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. (AU) | |
| FAPESP's process: | 21/10472-3 - Molecular modeling of GcoA enzyme activity on lignin |
| Grantee: | Artur Hermano Sampaio Dias |
| Support Opportunities: | Scholarships abroad - Research Internship - Doctorate |
| FAPESP's process: | 13/08293-7 - CCES - Center for Computational Engineering and Sciences |
| Grantee: | Munir Salomao Skaf |
| Support Opportunities: | Research Grants - Research, Innovation and Dissemination Centers - RIDC |