Microbial Cell Factories for Tetrahydroisoquinoline Alkaloid Production

Abstract

For decades, plants have represented an inexhaustible source of natural products used in various sectors such as health and industry. However, one recurring problem is the low accumulation of these compounds in planta and, therefore, their production costs and supply. In recent years, unprecedented hope has been brought by the metabolic engineering of microorganisms, which opens up prospects for supply of these molecules at lower cost with high added value. However, many of these productions remained at a laboratory scale. In a recent article published in Nature Communication, Vincent J. J. Martin's team has developed an optimized yeast strain capable of synthesizing not only a huge amount of (S)‐reticuline, a major precursor of the plant tetrahydroisoquinoline alkaloid series, but also a whole range of new‐to‐nature compounds from this prominent family of natural products. This synthesis, reaching industrial scales, thus paves the way to efficient production in microbial cell factories.

Optimization of Tabersonine Methoxylation to Increase Vindoline Precursor Synthesis in Yeast Cell Factories

“…Therefore, the tight control of the metabolic flux in yeast constitutes a main concern for an optimal production of vindoline through tabersonine bioconversion with reduced accumulation of intermediates and limited vindorosine synthesis. A similar rationale has been already pointed out for benzylisoquinoline [29][30][31][32] and tetrahydroisoquinoline [33,34] alkaloids.…”

“…Among the potential heterologous hosts, yeast is considered as one of the most suitable organisms for metabolic engineering due to its fast growth, easy genetic manipulation, and available genome sequence [22]. Following the seminal heterologous productions of artemisinin [23], hydrocortisone [24], and progesterone [25], several plant alkaloids have been more recently biosynthesized by recombinant yeast, such as MIAs [26][27][28] but also benzylisoquinoline [29][30][31][32] and tetrahydroisoquinoline [33,34] alkaloids. However, heterologous biosynthesis of MIAs remains challenging due to the high complexity of the pathway and the elaborate cellular and subcellular compartmentalization of enzymes [35][36][37].…”

Engineered Microbes for Producing Anticholinergics

“…Because industrial‐scale productions of specialized metabolites using yeast as a host are now becoming routine, we could reasonably anticipate that a 1–2 year effort would be required to reach such production scale [14,15] . In the context of a future decrease in global cultivable surfaces, authors estimate that a yeast fermentation‐based process sourcing sugar from sugarcane would require at least ten times less land than the existing Duboisia farming‐based approach (Figure 2).…”

“…Because industrial-scale productions of specialized metabolites using yeast as a host are now becoming routine, we could reasonably anticipate that a 1-2 year effort would be required to reach such production scale. [14,15] In the context of a future decrease in global cultivable surfaces, authors estimate that a yeast fermentation-based process sourcing sugar from sugarcane would require at least ten times less land than the existing Duboisia farming-based approach (Figure 2). It must be highlighted that this study also provides a solid proof of concept that reconfiguring intracellular trafficking of littorine synthase and related enzymes from various source plants is a promising strategy to expand the diversity of natural product biosynthesis in yeast cells.…”

Implementation of a MS/MS database for isoquinoline alkaloids and other annonaceous metabolites

“…These advances in THIQ metabolite production guided Courdavault et al . to identify this family of compounds as holding “an eminent biosynthetic potential in the field of drug discovery” 6 .…”