Biosynthesis of benzylisoquinoline alkaloids and its evolution in plants

Benzylisoquinoline alkaloids (BIAs) represent a large class of plant specialized metabolites that enhance plant resistance to biotic and abiotic stresses while also exhibiting diverse pharmacological activities, such as the analgesic effects of morphine and the antibacterial properties of berberine. We systematically review the biosynthetic pathways of diverse BIA scaffolds and the key enzymes involved. These enzymes, including methyltransferases, cytochrome P450 monooxygenases, berberine bridge enzymes, demethylases, and acyltransferases, collectively mediate structural diversification of BIAs through reactions such as methylation, oxidation, ring formation, demethylation, and acetylation. Additionally, we discuss how lineage-specific gene duplication events, neofunctionalization, and/or the assembly of biosynthetic gene clusters have driven structural diversification and adaptive evolution across taxa. Despite significant progress, challenges remain in fully characterizing pathway gaps, enzyme promiscuity, and regulatory networks. We recommend that integrating multi-omics data with protein engineering and synthetic biology offers promising avenues for sustainable production of high-value BIAs and the discovery of novel bioactive compounds.