The Oxidation of Oxygen and Sulfur-Containing Heterocycles by Cytochrome P450 Enzymes

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dc.contributor.authorPodgorski, M.N.
dc.contributor.authorKeto, A.B.
dc.contributor.authorColeman, T.
dc.contributor.authorBruning, J.B.
dc.contributor.authorDe Voss, J.J.
dc.contributor.authorKrenske, E.H.
dc.contributor.authorBell, S.G.
dc.date.issued2023
dc.descriptionVersion of record online: August 2, 2023
dc.description.abstractThe 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.statementofresponsibilityMatthew N. Podgorski, Angus B. Keto, Tom Coleman, John B. Bruning, James J. De Voss, Elizabeth H. Krenske, and Stephen G. Bell
dc.identifier.citationChemistry: A European Journal, 2023; 29(50):e202301371-1-e202301371-15
dc.identifier.doi10.1002/chem.202301371
dc.identifier.issn0947-6539
dc.identifier.issn1521-3765
dc.identifier.orcidPodgorski, M.N. [0000-0003-3238-8735]
dc.identifier.orcidBruning, J.B. [0000-0002-6919-1824]
dc.identifier.orcidBell, S.G. [0000-0002-7457-9727]
dc.identifier.urihttps://hdl.handle.net/2440/140445
dc.language.isoen
dc.publisherWiley-VCH GmbH
dc.relation.granthttp://purl.org/au-research/grants/arc/DP180103047
dc.relation.granthttp://purl.org/au-research/grants/arc/DP140103229
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.urihttps://doi.org/10.1002/chem.202301371
dc.subjectcytochrome P450 enzymes
dc.subjectenzyme mechanism
dc.subjectHeterocycles
dc.subjectmetalloenzymes
dc.subjectX-ray crystallography
dc.subject.meshOxides
dc.subject.meshBenzoic Acid
dc.subject.meshThiophenes
dc.subject.meshCytochrome P-450 Enzyme System
dc.subject.meshOxidation-Reduction
dc.titleThe Oxidation of Oxygen and Sulfur-Containing Heterocycles by Cytochrome P450 Enzymes
dc.typeJournal article
pubs.publication-statusPublished

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