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bioRxiv · 10.1101/2024.12.13.628308

Enzymatic epimerization of monoterpene indole alkaloids in Kratom

McDonald, A.·Nakamura, Y.·Schotte, C.·Lau, K.·Alam, R.·Lopes, A. A.·Buell, C. R.·O'Connor, S. E.
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Abstract

Monoterpene indole alkaloids (MIAs) are a large, structurally diverse class of bioactive natural products. These compounds are biosynthetically derived from a stereoselective Pictet-Spengler condensation that generates a tetrahydro-{beta}-carboline scaffold characterized by a 3S stereocenter. However, a subset of MIAs contain a non-canonical 3R stereocenter. Herein, we report the basis for 3R-MIA biosynthesis in Mitragyna speciosa (Kratom). We discover the presence of the iminium species, 20S-3-dehydrocorynantheidine, which led us to hypothesize that isomerization of 3S to 3R occurs by oxidation and stereoselective reduction downstream of the initial Pictet-Spengler condensation. Isotopologue feeding experiments implicated young leaves and stems as the sites for pathway biosynthesis, facilitating the identification of an oxidase/reductase pair that catalyzes this epimerization. This enzyme pair has broad substrate specificity, suggesting that the oxidase and reductase may be responsible for the formation of many 3R-MIAs and downstream spirooxindole alkaloids in Kratom. These enzymes allow biocatalytic access to a range of previously inaccessible pharmacologically active compounds.

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McDonald, A., Nakamura, Y., Schotte, C., Lau, K., Alam, R., Lopes, A. A., Buell, C. R., O'Connor, S. E.. 2024-12-13. Enzymatic epimerization of monoterpene indole alkaloids in Kratom. https://doi.org/10.1101/2024.12.13.628308

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