RT Journal Article
SR Electronic
T1 Enzymatic epimerization of monoterpene indole alkaloids in Kratom
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2024.12.13.628308
DO 10.1101/2024.12.13.628308
A1 McDonald, Allwin
A1 Nakamura, Yoko
A1 Schotte, Carsten
A1 Lau, Kin
A1 Alam, Ryan
A1 Lopes, Adriana A.
A1 Buell, C. Robin
A1 O’Connor, Sarah
YR 2024
UL http://biorxiv.org/content/early/2024/12/13/2024.12.13.628308.abstract
AB 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-β-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.Competing Interest StatementThe authors have declared no competing interest.