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Enzyme-Mediated Two-Step Regio- and Stereoselective Synthesis of Potential Rapid-Acting Antidepressant (2S,6S)‑Hydroxynorketamine
journal contribution
posted on 2020-03-18, 17:37 authored by Ansgar Bokel, Ansgar Rühlmann, Michael C. Hutter, Vlada B. UrlacherRecently,
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.
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semipreparative scaleStereoselective SynthesisThermobifida fusca YXketamineP 450 monooxygenase catalyzesoxidative N-demethylationantidepressant effectEscherichia coli whole-cell biocatalysthydroxynorketaminestereoselective C 6-hydroxylation reactionsNMR spectroscopymetabolitefirst-sphere mutagenesiscytochrome P 450 154 E 1side effectsEnzyme-Mediated Two-Step Regio
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