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Type: Journal article
Title: CYP199A4 catalyses the efficient demethylation and demethenylation of para-substituted benzoic acid derivatives
Author: Coleman, T.
Chao, R.
Bruning, J.
De Voss, J.
Bell, S.
Citation: RSC Advances: an international journal to further the chemical sciences, 2015; 5(64):52007-52018
Publisher: Royal Society of Chemistry
Issue Date: 2015
ISSN: 2046-2069
Statement of
Tom Coleman, Rebecca R. Chao, John B. Bruning, James J. De Voss and Stephen G. Bell
Abstract: The cytochrome P450 enzyme CYP199A4, from Rhodopseudomonas palustris strain HaA2, can efficiently demethylate 4-methoxybenzoic acid via hemiacetal formation and subsequent elimination of formaldehyde. Oxidative demethylation of a methoxy group para to the carboxyl moiety is strongly favoured over reaction at one in the ortho or meta positions. Dimethoxybenzoic acids containing a para-methoxy group were also efficiently demethylated exclusively at the para position. The presence of additional methoxy substituents reduces the substrate binding affinity and the activity compared to 4-methoxybenzoic acid. The addition of the smaller hydroxy group to the ortho or meta positions or of a nitrogen heteroatom in the aromatic ring of the 4-methoxybenzoate skeleton was better tolerated by the enzyme and these analogues were also readily demethylated. There was no evidence of methylenedioxy ring formation with 3-hydroxy-4-methoxybenzoic acid, an activity which is observed with certain plant CYP enzymes with analogous substrates. CYP199A4 is also able to deprotect the methylenedioxy group of 3,4-(methylenedioxy)benzoic acid to yield 3,4-dihydroxybenzoic acid and formic acid. This study defines the substrate range of CYP199A4 and reveals that substrates without a para substituent are not oxidised with any significant activity. Therefore para-substituted benzoic acids are ideal substrate scaffolds for the CYP199A4 enzyme and will aid in the design of optimised probes to investigate the mechanism of this class of enzymes. They also allow an assessment of the potential of CYP199A4 for synthetic biocatalytic processes involving selective oxidative demethylation or demethenylation.
Rights: This journal is © The Royal Society of Chemistry 2015
DOI: 10.1039/c5ra08730a
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