AUTHOR=Nguyen Tuan-Anh M. , Grzech Dagny , Chung Khoa , Xia Zhicheng , Nguyen Trinh-Don , Dang Thu-Thuy T. 

TITLE=Discovery of a cytochrome P450 enzyme catalyzing the formation of spirooxindole alkaloid scaffold

JOURNAL=Frontiers in Plant Science

VOLUME=Volume 14 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/plant-science/articles/10.3389/fpls.2023.1125158

DOI=10.3389/fpls.2023.1125158

ISSN=1664-462X

ABSTRACT=<p>Spirooxindole alkaloids feature a unique scaffold of an oxindole ring sharing an atom with a heterocyclic moiety. These compounds display an extensive range of biological activities such as anticancer, antibiotics, and anti-hypertension. Despite their structural and functional significance, the establishment and rationale of the spirooxindole scaffold biosynthesis are yet to be elucidated. Herein, we report the discovery and characterization of a cytochrome P450 enzyme from kratom (<italic>Mitragyna speciosa</italic>) responsible for the formation of the spirooxindole alkaloids 3-<italic>epi</italic>-corynoxeine (3<italic>R</italic>, 7<italic>R</italic>) and isocorynoxeine (3<italic>S</italic>, 7<italic>S</italic>) from the corynanthe-type (3<italic>R</italic>)-secoyohimbane precursors. Expression of the newly discovered enzyme in <italic>Saccharomyces cerevisiae</italic> yeast allows for the efficient <italic>in vivo</italic> and <italic>in vitro</italic> production of spirooxindoles. This discovery highlights the versatility of plant cytochrome P450 enzymes in building unusual alkaloid scaffolds and opens a gateway to access the prestigious spirooxindole pharmacophore and its derivatives.</p>