Biosynthesis of an Anti-Addiction Agent from the Iboga Plant

Abstract

Ibogaine and (-)-voacangine are plant derived psychoactives that show promise as effective treatments for opioid addiction. However, these compounds are produced by hard to source plants making these chemicals difficult for broad-scale use. Here we report the complete biosynthesis of (-)-voacangine, and de-esterified voacangine, which is converted to (-)-ibogaine 15 by heating. This discovery will enable production of these compounds by synthetic biology methods. Notably, (-)-ibogaine and (-)-voacangine are of the opposite enantiomeric configuration compared to the other major alkaloids found in this natural product class. Discovery of these biosynthetic enzymes therefore demonstrates how nature generates both enantiomeric series of this medically important alkaloid scaffold using closely related enzymes, 20 including those that catalyze enantioselective formal Diels-Alder reactions.One Sentence Summary: Biosynthesis of iboga alkaloids with anti-addiction promise reveals enantioselectivity of enzymatic Diels-Alder reactions.Main Text: (up to ~2500 words including references, notes and captions) Treatment of opiate addiction remains challenging, with over 45-thousand people in the 25 United States dying in 2017 and a 500% increase in yearly opioid overdose deaths since the year 2000 (1). (-)-Ibogaine (1) (Fig. 1A), a plant-derived iboga-type alkaloid, has anti-addictive properties that were discovered accidentally by Howard Lotsof in 1962 when he noticed that ingesting this compound mitigated heroin cravings and acute opiate withdrawal symptomatology (2, 3). Although the toxicity of (-)-ibogaine (1) has slowed its formal approval for addiction 30 treatment in many countries, increased knowledge of its mode of action, side-effects and the discovery of (-)-ibogaine (1) analogs clearly indicate its potential as an anti-addictive agent (2-4). The plant that synthesizes (-)-ibogaine (1), Tabernanthe iboga (Iboga), is difficult to cultivate, prompting interest in developing biocatalytic methods for (-)-ibogaine (1) production. While the biosynthesis of the (+)-iboga type alkaloid scaffold has been recently elucidated (5), 35 biosynthesis of the antipodal (-)-ibogaine (1) remained uncertain. Here we show that (-)ibogaine (1) biosynthesis uses the same starting substrate as observed in (+)-iboga biosynthesis, but the key cyclization step proceeds via a distinct mechanism to generate the reduced iboga alkaloid (-)-coronaridine (2) (Fig. 1A). We further demonstrate that enzymatically generated (-)coronaridine (2) can be 10-hydroxylated and 10-O-methylated (6) to form (-)-voacangine (3), 40 and treatment of (-)-voacangine (3) with a T. iboga esterase reported here, followed by heating,

Molecules from nature: Reconciling biodiversity conservation and global healthcare imperatives for sustainable use of medicinal plants and fungi

“…Recent elucidation of the vinblastine pathway (Caputi et al., 2018; Qu et al., 2018; Tatsis et al., 2017) resulted in a paradigm shift in understanding specialized metabolism. Based on this example, the metabolic pathways of other indole alkaloids have been elucidated, including ibogaine (Farrow et al., 2018, 2019) from iboga ( Tabernanthe iboga Baill. ), which has been studied for its effects on drug addiction (Dauncey & Howes, 2020), and the antiarrhythmic ajmaline (Dang et al., 2018; Dang, Franke, Tatsis, & O'Connor, 2017) from snakeroot ( Rauvolfia serpentina (L.) Benth.…”