Deciphering the biotransformation mechanism of dialkylresorcinols by CYP4F11

[Display omitted] •The human P450 CYP4F11 can oxidize two dialkylresorcinol natural products.•Oxidation occurs exclusively at the ω-position of the C-5 alkyl chains.•Homology modeling shows H-bonding to both phenolic OHs controls regiospecificity.•The closely-related CYP4F12 cannot oxidize, as the b...

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Published in:Bioorganic chemistry 2023-02, Vol.131, p.106330-106330, Article 106330
Main Authors: Shi, Yue, Wolf, Clemens A., Lotfy, Rowaa, Sharma, Sangeeta S., Tesfa, Abel Fekadu, Wolber, Gerhard, Bureik, Matthias, Clark, Benjamin R.
Format: Article
Language:English
Subjects:
Anti-Bacterial Agents - metabolism
Biotransformation
Cytochrome P-450 Enzyme System - metabolism
Cytochrome P450
Dialkylresorcinols
Fission yeast
Homology modeling
Humans
Natural products
Oxidation-Reduction
Recombinant expression
Resorcinols - metabolism
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Summary:[Display omitted] •The human P450 CYP4F11 can oxidize two dialkylresorcinol natural products.•Oxidation occurs exclusively at the ω-position of the C-5 alkyl chains.•Homology modeling shows H-bonding to both phenolic OHs controls regiospecificity.•The closely-related CYP4F12 cannot oxidize, as the binding pocket is blocked by Arg126.•Addition of polar groups to C-5 alkyl chain drastically reduces antimicrobial activity. Cytochrome P450 enzymes (CYPs) are one of the most important classes of oxidative enzymes in the human body, carrying out metabolism of various exogenous and endogenous substrates. In order to expand the knowledge of these enzymes’ specificity and to obtain new natural product derivatives, CYP4F11, a cytochrome P450 monooxygenase, was used in the biotransformation of dialkylresorcinols 1 and 2, a pair of antibiotic microbial natural products. This investigation resulted in four biotransformation products including two oxidative products: a hydroxylated derivative (3) and a carboxylic acid derivative (4). In addition, acetylated (5) and esterified products (6) were isolated, formed by further metabolism by endogenous yeast enzymes. Oxidative transformations were highly regioselective, and took place exclusively at the ω-position of the C-5 alkyl chain. Homology modeling studies revealed that optimal hydrogen bonding between 2 and the enzyme can only be established with the C-5 alkyl chain pointing towards the heme. The closely-related CYP4F12 was not capable of oxidizing the dialkylresorcinol 2. Modeling experiments rationalize these differences by the different shapes of the binding pockets with respect to the non-oxidized alkyl chain. Antimicrobial testing indicated that the presence of polar groups on the side-chains reduces the antibiotic activity of the dialkylresorcinols.
ISSN:0045-2068
1090-2120
DOI:10.1016/j.bioorg.2022.106330