Enzyme-Mediated Two-Step Regio- and Stereoselective Synthesis of Potential Rapid-Acting Antidepressant (2S,6S)‑Hydroxynorketamine

Recently, the anesthetic (S)-ketamine has been approved as a rapid-acting and long-lasting antidepressant. Its metabolite, (2S,6S)-hydroxynorketamine, has been found to have a similar antidepressant effect but with less undesirable side effects, which make this compound an interesting target for syn...

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Bibliographic Details
Published inACS catalysis Vol. 10; no. 7; pp. 4151 - 4159
Main Authors Bokel, Ansgar, Rühlmann, Ansgar, Hutter, Michael C, Urlacher, Vlada B
Format Journal Article
LanguageEnglish
Published American Chemical Society 03.04.2020
Subjects
regioselectivity
protein engineering
stereoselectivity
ketamine
hydroxylation
N-demethylation
cytochrome P450
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Summary:Recently, the anesthetic (S)-ketamine has been approved as a rapid-acting and long-lasting antidepressant. Its metabolite, (2S,6S)-hydroxynorketamine, has been found to have a similar antidepressant effect but with less undesirable side effects, which make this compound an interesting target for synthesis. Using the first-sphere mutagenesis of the cytochrome P450 154E1 from Thermobifida fusca YX, we constructed a triple mutant that enables the effective production of (2S,6S)-hydroxynorketamine from (S)-ketamine. This engineered P450 monooxygenase catalyzes the consecutive oxidative N-demethylation and highly regio- and stereoselective C6-hydroxylation reactions leading directly to the desired product with 85% product selectivity. The integration of this selective monooxygenase into an Escherichia coli whole-cell biocatalyst allowed the production of (2S,6S)-hydroxynorketamine at a semipreparative scale. The metabolite was purified and its structure was confirmed by NMR spectroscopy.
ISSN:2155-5435
2155-5435
DOI:10.1021/acscatal.9b05384