Please use this identifier to cite or link to this item:
https://hdl.handle.net/2440/140445
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DC Field | Value | Language |
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dc.contributor.author | Podgorski, M.N. | - |
dc.contributor.author | Keto, A.B. | - |
dc.contributor.author | Coleman, T. | - |
dc.contributor.author | Bruning, J.B. | - |
dc.contributor.author | De Voss, J.J. | - |
dc.contributor.author | Krenske, E.H. | - |
dc.contributor.author | Bell, S.G. | - |
dc.date.issued | 2023 | - |
dc.identifier.citation | Chemistry: A European Journal, 2023; 29(50):e202301371-1-e202301371-15 | - |
dc.identifier.issn | 0947-6539 | - |
dc.identifier.issn | 1521-3765 | - |
dc.identifier.uri | https://hdl.handle.net/2440/140445 | - |
dc.description | Version of record online: August 2, 2023 | - |
dc.description.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. | - |
dc.description.statementofresponsibility | Matthew N. Podgorski, Angus B. Keto, Tom Coleman, John B. Bruning, James J. De Voss, Elizabeth H. Krenske, and Stephen G. Bell | - |
dc.language.iso | en | - |
dc.publisher | Wiley-VCH GmbH | - |
dc.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. | - |
dc.source.uri | http://dx.doi.org/10.1002/chem.202301371 | - |
dc.subject | cytochrome P450 enzymes | - |
dc.subject | enzyme mechanism | - |
dc.subject | Heterocycles | - |
dc.subject | metalloenzymes | - |
dc.subject | X-ray crystallography | - |
dc.subject.mesh | Oxides | - |
dc.subject.mesh | Benzoic Acid | - |
dc.subject.mesh | Thiophenes | - |
dc.subject.mesh | Cytochrome P-450 Enzyme System | - |
dc.subject.mesh | Oxidation-Reduction | - |
dc.title | The Oxidation of Oxygen and Sulfur-Containing Heterocycles by Cytochrome P450 Enzymes | - |
dc.type | Journal article | - |
dc.identifier.doi | 10.1002/chem.202301371 | - |
dc.relation.grant | http://purl.org/au-research/grants/arc/DP180103047 | - |
dc.relation.grant | http://purl.org/au-research/grants/arc/DP140103229 | - |
pubs.publication-status | Published | - |
dc.identifier.orcid | Podgorski, M.N. [0000-0003-3238-8735] | - |
dc.identifier.orcid | Bruning, J.B. [0000-0002-6919-1824] | - |
dc.identifier.orcid | Bell, S.G. [0000-0002-7457-9727] | - |
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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