Identification and biochemical characterization of stereospecific and regiospecific cytochrome P450 monooxygenases for monoterpenoid indole alkaloid biosynthesis
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Date
2025-12
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University of New Brunswick
Abstract
Cytochrome P450 monooxygenases (CYPs) are a superfamily of oxidases vital to detoxification and biosynthesis of specialized metabolites, including pharmaceutically relevant monoterpene indole alkaloids (MIAs). Despite their significance, many CYPs remain uncharacterized. This thesis identifies and characterizes several novel CYPs in MIA biosynthetic pathways.
First, I report the biochemical characterization of a sarpagan bridge enzyme (SBE) from Catharanthus roseus, the in planta function of which was supported via virus-induced gene silencing. With CrSBE and three more SBE orthologs from in the Apocynaceae family, I show that SBEs cyclize geissoschizine to 16R sarpagan scaffold. I further show that downstream deformylase and reductase activities epimerize C16, forming species-specific C16 sarpagan epimers that feed into distinct products, such as the anti-arrhythmic ajmaline.
Second, I identify and biochemically characterize a Tabernaemontana elegans enzyme pair coronaridine 11-hydroxylase (TeC11H) and 11-hydroxycoronaridine O-methyltransferase (TeHCOMT). This transformation primes the indole for coupling reactions that yield anticancer bis-iboga-vobasinyl MIAs.