Divergent biosynthesis of monoterpene indole alkaloids from geissoschizine
Mohamed O. Kamileen, Benke Hong, Klaus Gase, Maritta Kunert, Lorenzo Caputi, Benjamin R Lichman, Sarah E. O’connor
bioRxiv October 25, 2024 preprint DOI: 10.1101/2024.10.22.619577 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Basic science (in vitro enzymology and plant gene silencing study) |
|---|---|
| Population | The medicinal plant Catharanthus roseus and its biosynthetic enzymes |
| Key points | Three cytochrome P450 enzymes in Catharanthus roseus convert 19E-geissoschizine into four distinct alkaloid scaffolds (strychnos, sarpagan, akuammiline-type, and mavacurane-type). The authors argue that minimal active-site mutations among these similar enzymes modulate product specificity, and that substrate reactivity and enzyme mutations work together to generate chemical diversity. |
Abstract
Plants can generate structural diversity by enzymatic rearrangement of a central intermediate. 19 E -geisssochizine 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 19 E -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 19 E -geisssochzine 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.