Abstract
Monoterpene indole alkaloids comprise a diverse family of over 2000 plant-produced natural products. This pathway provides an outstanding example of how nature creates chemical diversity from a single precursor, in this case from the intermediate strictosidine. The enzymes that elicit these seemingly disparate products from strictosidine have hitherto been elusive. Here we show that the concerted action of two enzymes commonly involved in natural product metabolism—an alcohol dehydrogenase and a cytochrome P450—produces unexpected rearrangements in strictosidine when assayed simultaneously. The tetrahydro-β-carboline of strictosidine aglycone is converted into akuammicine, a Strychnos alkaloid, an elusive biosynthetic transformation that has been investigated for decades. Importantly, akuammicine arises from deformylation of preakuammicine, which is the central biosynthetic precursor for the anti-cancer agents vinblastine and vincristine, as well as other biologically active compounds. This discovery of how these enzymes can function in combination opens a gateway into a rich family of natural products.
Highlights
Monoterpene indole alkaloids comprise a diverse family of over 2000 plant-produced natural products
We use a transcriptomic database for the medicinal plant Catharanthus roseus to identify two enzymes, an alcohol dehydrogenase (GS) and a cytochrome P450 (GO), that act in tandem on 4,21-dehydrogeissoschizine to yield akuammicine, a Strychnos alkaloid
Gene candidates identified were initially screened in C. roseus by virus-induced gene silencing (VIGS), a transient silencing system in which qualitative perturbations in the metabolic profile between silenced and control tissue provide clues to the metabolic function of the gene of interest
Summary
Monoterpene indole alkaloids comprise a diverse family of over 2000 plant-produced natural products. Akuammicine arises from deformylation of preakuammicine, which is the central biosynthetic precursor for the anti-cancer agents vinblastine and vincristine, as well as other biologically active compounds This discovery of how these enzymes can function in combination opens a gateway into a rich family of natural products. Akuammicine is known to arise from deformylation of preakuammicine[8, 10,11,12], which is the central biosynthetic precursor for the anti-cancer agents vinblastine and vincristine, as well as hundreds of other biologically active compounds These enzymes open a gateway into a rich family of natural products, and will facilitate metabolic engineering efforts to make high-value monoterpene indole alkaloids
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