Emerging logic in monoterpene indole alkaloid biosynthesis: a perspective

The importance of plant natural products as a source of structurally diverse small molecules for drug discovery has long been established. Among these, monoterpene indole alkaloids (MIAs) represent one of the most chemically and pharmacologically rich classes of plant specialized metabolites, encompassing FDA-approved chemotherapeutics including vinblastine, vincristine, and the camptothecin-derived drugs irinotecan and topotecan. These highly complex molecules possess dense stereochemistry and intricately fused ring systems that plants assemble with remarkable precision and efficiency, often surpassing the reach of current synthetic chemistry. Synthetic biology offers a promising alternative to reliance on plant extraction for MIA production; however, progress is constrained by the extensive diversification of MIA biosynthetic pathways, in which only early steps are broadly conserved, and many downstream transformations are lineage or species-specific. Consequently, elucidating these pathways and identifying the underlying genes require extensive genomic, metabolic, and molecular resources. Identifying shared biosynthetic logic across divergent pathways is therefore critical for developing informed hypotheses and enabling targeted approaches to gene mining and pathway reconstruction. This perspective highlights recent advances that have uncovered, revised, and broadened the conceptual framework underlying MIA biosynthesis and diversification. Together, these advances update foundational assumptions and established archetypes that shape hypotheses in MIA pathway discovery. They also provide new guiding principles for metabolic engineering and synthetic biology efforts aimed at expanding access to bioactive MIAs from non-model medicinal plant species.