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Lignin Biodegradation by a Cytochrome P450 Enzyme: A?Computational Study into Syringol Activation by GcoA.

ABSTRACT: A recently characterized cytochrome P450 isozyme GcoA activates lignin components through a selective O-demethylation or alternatively an acetal formation reaction. These are important reactions in biotechnology and, because lignin is readily available; it being the main component in plant cell walls. In this work we present a density functional theory study on a large active site model of GcoA to investigate syringol activation by an iron(IV)-oxo heme cation radical oxidant (Compound?I) leading to hemiacetal and acetal products. Several substrate-binding positions were tested and full energy landscapes calculated. The study shows that substrate positioning determines the product distributions. Thus, with the phenol group pointing away from the heme, an O-demethylation is predicted, whereas an initial hydrogen-atom abstraction of the weak phenolic O-H group would trigger a pathway leading to ring-closure to form acetal products. Predictions on how to engineer P450 GcoA to get more selective product distributions are given.

SUBMITTER: Ali HS

PROVIDER: S-EPMC7590115 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Lignin Biodegradation by a Cytochrome P450 Enzyme: A Computational Study into Syringol Activation by GcoA.

Ali Hafiz Saqib HS Ali Hafiz Saqib HS Henchman Richard H RH de Visser Sam P SP

Chemistry (Weinheim an der Bergstrasse, Germany) 20200916 57

A recently characterized cytochrome P450 isozyme GcoA activates lignin components through a selective O-demethylation or alternatively an acetal formation reaction. These are important reactions in biotechnology and, because lignin is readily available; it being the main component in plant cell walls. In this work we present a density functional theory study on a large active site model of GcoA to investigate syringol activation by an iron(IV)-oxo heme cation radical oxidant (Compound I) leading ...[more]

PMID: 32613677

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Project description:BackgroundCytochrome P450s (CYPs) are important heme-containing proteins, well known for their monooxygenase reaction. The human cytochrome P450 4X1 (CYP4X1) is categorized as "orphan" CYP because of its unknown function. In recent studies it is found that this enzyme is expressed in neurovascular functions of the brain. Also, various studies have found the expression and activity of orphan human cytochrome P450 4X1 in cancer. It is found to be a potential drug target for cancer therapy. However, three-dimensional structure, the active site topology and substrate specificity of CYP4X1 remain unclear.MethodsIn the present study, the three-dimensional structure of orphan human cytochrome P450 4X1 was generated by homology modeling using Modeller 9v8. The generated structure was accessed for geometrical errors and energy stability using PROCHECK, VERFIY 3D and PROSA. A molecular docking analysis was carried out against substrates arachidonic acid and anandamide and the docked substrates were predicted for drug-likeness, ADME-Tox parameters and biological spectrum activity.ResultsThe three-dimensional model of orphan human cytochrome P450 4X1 was generated and assessed with various structural validation programmes. Docking of orphan human cytochrome P450 4X1 with arachidonic acid revealed that TYR 112, ALA 126, ILE 222, ILE 223, THR 312, LEU 315, ALA 316, ASP 319, THR 320, PHE 491 and ILE 492 residues were actively participating in the interaction, while docking of CYP4X1 with anandamide showed that TYR 112, GLN 114, PRO 118, ALA 126, ILE 222, ILE 223, SER 251, LEU 315, ALA 316 and PHE 491 key residues were involved in strong interaction.ConclusionFrom this study, several key residues were identified to be responsible for the binding of arachidonic acid and anandamide with orphan human cytochrome P450 4X1. Both substrates obeyed Lipinski rule of five in drug-likeness test and biological spectrum prediction showed anticarcinogenic activity. Compared to anandamide, arachidonic acid showed strong interaction with cytochrome P450 4X1 and also less health effect in certain human system in ADME-Tox prediction. These findings provide useful information on the biological role and structure-based drug design of orphan human cytochrome P450 4X1.

Dataset Information

Lignin Biodegradation by a Cytochrome P450 Enzyme: A?Computational Study into Syringol Activation by GcoA.

Publications

Lignin Biodegradation by a Cytochrome P450 Enzyme: A Computational Study into Syringol Activation by GcoA.

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