Oxidative Rearrangements of the Alkaloid Intermediate Geissoschizine

TY - JOUR

T1 - Oxidative Rearrangements of the Alkaloid Intermediate Geissoschizine

AU - Kamileen, Mohamed O.

AU - Hong, Benke

AU - Gase, Klaus

AU - Kunert, Maritta

AU - Caputi, Lorenzo

AU - Lichman, Benjamin R.

AU - O'Connor, Sarah E.

N1 - Publisher Copyright: © 2025 The Author(s). Angewandte Chemie International Edition published by Wiley-VCH GmbH.

PY - 2025/6/7

Y1 - 2025/6/7

N2 - Plants can generate structural diversity by enzymatic rearrangement of a central intermediate. 19E-geissoschizine is one such chemically versatile intermediate that plays a central role in the biosynthesis of monoterpene indole alkaloids such as strychnine, ibogaine, and vinblastine. Here we report how 19E-geissoschizine undergoes oxidative transformations to generate four distinct alkaloid scaffolds through the action of three biosynthetic enzymes. Using in vitro enzymatic assays and gene silencing, we demonstrate how these three cytochrome P450 enzymes in the medicinal plant Catharanthus roseus transform 19E-geissoschizine into strychnos, sarpagan, akuammiline-type, and mavacurane-type alkaloids. We use mutational analysis to show how minimal changes to the active site of these similar enzymes modulate product specificity. This work highlights how substrate reactivity and enzyme mutations work synergistically to generate chemical diversity.

AB - Plants can generate structural diversity by enzymatic rearrangement of a central intermediate. 19E-geissoschizine is one such chemically versatile intermediate that plays a central role in the biosynthesis of monoterpene indole alkaloids such as strychnine, ibogaine, and vinblastine. Here we report how 19E-geissoschizine undergoes oxidative transformations to generate four distinct alkaloid scaffolds through the action of three biosynthetic enzymes. Using in vitro enzymatic assays and gene silencing, we demonstrate how these three cytochrome P450 enzymes in the medicinal plant Catharanthus roseus transform 19E-geissoschizine into strychnos, sarpagan, akuammiline-type, and mavacurane-type alkaloids. We use mutational analysis to show how minimal changes to the active site of these similar enzymes modulate product specificity. This work highlights how substrate reactivity and enzyme mutations work synergistically to generate chemical diversity.

KW - Biosynthesis

KW - Enzymes

KW - Geissoschizine

KW - Natural products

KW - Plant P450s

UR - https://www.scopus.com/pages/publications/105005168044

U2 - 10.1002/anie.202501323

DO - 10.1002/anie.202501323

M3 - Article

C2 - 40202182

AN - SCOPUS:105005168044

SN - 1433-7851

VL - 64

JO - Angewandte Chemie - International Edition

JF - Angewandte Chemie - International Edition

IS - 24

M1 - e202501323

ER -