Emerging trends in production of plant natural products and new-to-nature biopharmaceuticals in yeast.

Natural products represent an inestimable source of valuable compounds for human health. Notably, those produced by plants remain challenging to access due to their low production. Potential shortages of plant-derived biopharmaceuticals caused by climate change or pandemics also regularly tense the market trends. Thus, biotechnological alternatives of supply based on synthetic biology have emerged. These innovative strategies mostly rely on the use of engineered microbial systems for compound synthesis. In this regard, yeasts remain the easiest-tractable eukaryotic models and a convenient chassis for reconstructing whole biosynthetic routes for the heterologous production of plant-derived metabolites. Here, we highlight the recent discoveries dedicated to the bioproduction of new-to-nature compounds in yeasts and provide an overview of emerging strategies for optimising bioproduction.

The Rauvolfia tetraphylla genome suggests multiple distinct biosynthetic routes for yohimbane monoterpene indole alkaloids.

Monoterpene indole alkaloids (MIAs) are a structurally diverse family of specialized metabolites mainly produced in Gentianales to cope with environmental challenges. Due to their pharmacological properties, the biosynthetic modalities of several MIA types have been elucidated but not that of the yohimbanes. Here, we combine metabolomics, proteomics, transcriptomics and genome sequencing of Rauvolfia tetraphylla with machine learning to discover the unexpected multiple actors of this natural product synthesis. We identify a medium chain dehydrogenase/reductase (MDR) that produces a mixture of four diastereomers of yohimbanes including the well-known yohimbine and rauwolscine. In addition to this multifunctional yohimbane synthase (YOS), an MDR synthesizing mainly heteroyohimbanes and the short chain dehydrogenase vitrosamine synthase also display a yohimbane synthase side activity. Lastly, we establish that the combination of geissoschizine synthase with at least three other MDRs also produces a yohimbane mixture thus shedding light on the complex mechanisms evolved for the synthesis of these plant bioactives.