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https://hdl.handle.net/2440/138684
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Type: | Journal article |
Title: | Cytochrome P450-catalyzed oxidation of halogen-containing substrates. |
Author: | Coleman, T. Podgorski, M.N. Doyle, M.L. Scaffidi-Muta, J.M. Campbell, E.C. Bruning, J.B. De Voss, J.J. Bell, S.G. |
Citation: | Journal of Inorganic Biochemistry, 2023; 244 |
Publisher: | Elsevier |
Issue Date: | 2023 |
ISSN: | 0162-0134 1873-3344 |
Statement of Responsibility: | Tom Coleman, Matthew N. Podgorski, Maya L. Doyle, Jarred M. Scaffidi-Muta, Eleanor C. Campbell, John B. Bruning, James J. De Voss, Stephen G. Bell |
Abstract: | Cytochrome P450 (CYP) enzymes are heme-thiolate monooxygenases which catalyze the oxidation of aliphatic and aromatic C-H bonds and other reactions. The oxidation of halogens by cytochrome P450 enzymes has also been reported. Here we use CYP199A4, from the bacterium Rhodopseudomonas palustris strain HaA2, with a range of para-substituted benzoic acid ligands, which contain halogens, to assess if this enzyme can oxidize these species or if the presence of these electronegative atoms can alter the outcome of P450-catalyzed reactions. Despite binding to the enzyme, there was no detectable oxidation of any of the 4-halobenzoic acids. CYP199A4 was, however, able to efficiently catalyze the oxidation of both 4-chloromethyl- and 4-bromomethyl-benzoic acid to 4-formylbenzoic acid via hydroxylation of the α‑carbon. The 4-chloromethyl substrate bound in the enzyme active site in a similar manner to 4-ethylbenzoic acid. This places the benzylic α‑carbon hydrogens in an unfavorable position for abstraction indicating a degree of substrate mobility must be possible within the active site. CYP199A4 catalyzed oxidations of 4-(2'-haloethyl)benzoic acids yielding α-hydroxylation and desaturation metabolites. The α-hydroxylation product was the major metabolite. The desaturation pathway is significantly disfavored compared to 4-ethylbenzoic acid. This may be due to the electron-withdrawing halogen atom or a different positioning of the substrate within the active site. The latter was demonstrated by the X-ray crystal structures of CYP199A4 with these substrates. Overall, the presence of a halogen atom positioned close to the heme iron can alter the binding orientation and outcomes of enzyme-catalyzed oxidation. |
Keywords: | Cytochrome P450 monooxygenases Enzyme mechanism Halogens Heme proteins X-ray crystal structures |
Rights: | © 2023 Elsevier Inc. All rights reserved. |
DOI: | 10.1016/j.jinorgbio.2023.112234 |
Grant ID: | http://purl.org/au-research/grants/arc/DP140103229 |
Published version: | http://dx.doi.org/10.1016/j.jinorgbio.2023.112234 |
Appears in Collections: | Physics publications |
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