Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/113563
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Type: Journal article
Title: Cytochrome P450 CYP199A4 from Rhodopseudomonas palustris catalyses heteroatom dealkylations, sulfoxidation and amide and cyclic hemiacetal formation
Author: Coleman, T.
Wong, S.
Podgorski, M.
Bruning, J.
De Voss, J.
Bell, S.
Citation: ACS Catalysis, 2018; 8(7):5915-5927
Publisher: American Chemical Society
Issue Date: 2018
ISSN: 2155-5435
2155-5435
Statement of
Responsibility: 
Tom Coleman, Siew Hoon Wong, Matthew N. Podgorski, John B. Bruning, James J. De Voss, and Stephen G. Bell
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.
Keywords: Biocatalysis; cytochrome P450 enzymes; dealkylation; heteroatom oxidation; crystal structures; C−H bond oxidation; enzyme mechanism
Description: Published: May 17, 2018
Rights: © 2018 American Chemical Society
RMID: 0030090564
DOI: 10.1021/acscatal.8b00909
Grant ID: http://purl.org/au-research/grants/arc/DP140103229
http://purl.org/au-research/grants/arc/FT140100355
Appears in Collections:Molecular and Biomedical Science publications

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