Please use this identifier to cite or link to this item:
https://hdl.handle.net/2440/113563
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dc.contributor.author | Coleman, T. | - |
dc.contributor.author | Wong, S. | - |
dc.contributor.author | Podgorski, M. | - |
dc.contributor.author | Bruning, J. | - |
dc.contributor.author | De Voss, J. | - |
dc.contributor.author | Bell, S. | - |
dc.date.issued | 2018 | - |
dc.identifier.citation | ACS Catalysis, 2018; 8(7):5915-5927 | - |
dc.identifier.issn | 2155-5435 | - |
dc.identifier.issn | 2155-5435 | - |
dc.identifier.uri | http://hdl.handle.net/2440/113563 | - |
dc.description | Published: May 17, 2018 | - |
dc.description.abstract | The cytochrome P450 enzymes execute a range of selective oxidative biotransformations across many biological systems. The bacterial enzyme CYP199A4 catalyzes the oxidative demethylation of 4-methoxybenzoic acid. The benzoic acid moiety of the molecule binds in the active site of the enzyme such that the functional group at the para-position is held close to the heme iron. Therefore, CYP199A4 has the potential to catalyze alternative monooxygenase reactions with different para-substituted benzoic acid substrates such as thioethers and alkylamines. The oxidation of 4-methyl- and 4-ethyl-thiobenzoic acids by CYP199A4 resulted in sulfur oxidation. 4-Ethylthiobenzoic acid sulfoxidation and 4-ethylbenzoic acid hydroxylation by CYP199A4 occurred with high enantioselectivity (>74% enantiomeric excess). By way of contrast, CYP199A4 catalyzed exclusive oxidative N-demethylation over N-oxide formation with 4-methyl- and 4-dimethylaminobenzoic acids. Unexpectedly acetamide formation by CYP199A4 competes with dealkylation in the turnover of 4-ethyl- and diethyl-aminobenzoic acids. No oxidative dealkylation was observed with 3,4-ethylenedioxybenzoic with only hydroxylation to form a cyclic hemiacetal being detected. The X-ray crystal structures of four substrate-bound forms of the enzyme were solved and revealed subtle changes in the location of the para substituent which, when combined with the reactivity of the substituents, provided a basis for understanding the changes in selectivity. Furthermore, in the 4-ethylthiobenzoic acid-bound structure, the active site residue Phe298 moves to accommodate the substituent which points away from the heme iron. As such, the CYP199A4 enzyme provides ready access to a combination of structural, binding, and activity data with which to study a variety of reactions which are catalyzed by the P450 superfamily of enzymes. | - |
dc.description.statementofresponsibility | Tom Coleman, Siew Hoon Wong, Matthew N. Podgorski, John B. Bruning, James J. De Voss, and Stephen G. Bell | - |
dc.language.iso | en | - |
dc.publisher | American Chemical Society | - |
dc.rights | © 2018 American Chemical Society | - |
dc.source.uri | http://dx.doi.org/10.1021/acscatal.8b00909 | - |
dc.subject | Biocatalysis; cytochrome P450 enzymes; dealkylation; heteroatom oxidation; crystal structures; C−H bond oxidation; enzyme mechanism | - |
dc.title | Cytochrome P450 CYP199A4 from Rhodopseudomonas palustris catalyses heteroatom dealkylations, sulfoxidation and amide and cyclic hemiacetal formation | - |
dc.type | Journal article | - |
dc.identifier.doi | 10.1021/acscatal.8b00909 | - |
dc.relation.grant | http://purl.org/au-research/grants/arc/DP140103229 | - |
dc.relation.grant | http://purl.org/au-research/grants/arc/FT140100355 | - |
pubs.publication-status | Published | - |
dc.identifier.orcid | Podgorski, M. [0000-0003-3238-8735] | - |
dc.identifier.orcid | Bruning, J. [0000-0002-6919-1824] | - |
dc.identifier.orcid | Bell, S. [0000-0002-7457-9727] | - |
Appears in Collections: | Aurora harvest 3 Molecular and Biomedical Science publications |
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File | Description | Size | Format | |
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hdl_113563.pdf | Accepted version | 3.91 MB | Adobe PDF | View/Open |
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