Benzylisoquinoline alkaloid production: Moving from crop farming to chemical and biosynthesis

Benzylisoquinoline alkaloids (BIAs) are a diverse group of plant secondary metabolites that play a key role as analgesics, anti-cancer, and anti-microbial medication. BIAs are currently exclusively produced through crop farming which adversely affects the supply chain resilience of BIA-based medication because availability is limited by low accumulation in plants and harvest seasons. Also, yields fluctuate due to annual weather changes and decrease overall due to global climate change impact on agriculture. Here we review the potential of chemical synthesis, synthetic microbial pathways and genetically engineered plants (cell- and tissue culture) as alternative BIA production approaches. The challenges and opportunities to achieve economically viable BIA titers in the gram per liter range are highlighted. Chemical BIA synthesis is robust and predictable, but yields are often <30% due to the complex chemical structures and the necessary asymmetric synthesis. Synthetic microbial pathways can be engineered into heterologous production hosts like Escherichia coli and Saccharomyces cerevisiae. Whereas the former produces amino acid precursors at high titers, it fails to provide active cytochrome P450 enzymes necessary for BIA synthesis. Yeasts enable the expression of full biosynthetic pathways but struggle with relevant product titers (often <10 mg L^-1). Alternatively, genetic engineering can activate the endogenous BIA pathway for a given alkaloid in the native host plant or cell cultures thereof, but currently lacks selectivity of activation and scalability of the processes. Overcoming current barriers to competitiveness will require future research to build upon the works summarized in this review.