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https://hdl.handle.net/2440/140445
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Type: | Journal article |
Title: | The Oxidation of Oxygen and Sulfur-Containing Heterocycles by Cytochrome P450 Enzymes |
Author: | Podgorski, M.N. Keto, A.B. Coleman, T. Bruning, J.B. De Voss, J.J. Krenske, E.H. Bell, S.G. |
Citation: | Chemistry: A European Journal, 2023; 29(50):e202301371-1-e202301371-15 |
Publisher: | Wiley-VCH GmbH |
Issue Date: | 2023 |
ISSN: | 0947-6539 1521-3765 |
Statement of Responsibility: | Matthew N. Podgorski, Angus B. Keto, Tom Coleman, John B. Bruning, James J. De Voss, Elizabeth H. Krenske, and Stephen G. Bell |
Abstract: | The cytochrome P450 (CYP) superfamily of monooxygenase enzymes play important roles in the metabolism of molecules which contain heterocyclic, aromatic functional groups. Here we study how oxygen- and sulfur-containing heterocyclic groups interact with and are oxidized using the bacterial enzyme CYP199A4. This enzyme oxidized both 4-(thiophen-2-yl)benzoic acid and 4-(thiophen-3-yl)benzoic acid almost exclusively via sulfoxidation. The thiophene oxides produced were activated towards Diels-Alder dimerization after sulfoxidation, forming dimeric metabolites. Despite X-ray crystal structures demonstrating that the aromatic carbon atoms of the thiophene ring were located closer to the heme than the sulfur, sulfoxidation was still favoured with 4-(thiophen-3-yl)benzoic acid. These results highlight a preference of this cytochrome P450 enzyme for sulfoxidation over aromatic hydroxylation. Calculations predict a strong preference for homodimerization of the enantiomers of the thiophene oxides and the formation of a single major product, in broad agreement with the experimental data. 4-(Furan-2-yl)benzoic acid was oxidized to 4-(4'-hydroxybutanoyl)benzoic acid using a whole-cell system. This reaction proceeded via a g-keto-α,β-unsaturated aldehyde species which could be trapped in vitro using semicarbazide to generate a pyridazine species. The combination of the enzyme structures, the biochemical data and theoretical calculations provides detailed insight into the formation of the metabolites formed from these heterocyclic compounds. |
Keywords: | cytochrome P450 enzymes enzyme mechanism Heterocycles metalloenzymes X-ray crystallography |
Description: | Version of record online: August 2, 2023 |
Rights: | © 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. |
DOI: | 10.1002/chem.202301371 |
Grant ID: | http://purl.org/au-research/grants/arc/DP180103047 http://purl.org/au-research/grants/arc/DP140103229 |
Published version: | http://dx.doi.org/10.1002/chem.202301371 |
Appears in Collections: | Chemistry publications Molecular and Biomedical Science publications |
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hdl_140445.pdf | Published version | 7.69 MB | Adobe PDF | View/Open |
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