Biosynthesis of Securinega alkaloids via a cyanogenic glucoside-like pathway

Abstract

The elucidation of biosynthetic pathways towards bioactive compounds in plants is essential for building biotechnological platforms for their scalable synthesis. Securinine and allosecurinine form part of the complement of Securinega alkaloids in Flueggea suffruticosa, a fundamental herb of Chinese medicine. Despite their potent biological activities and a growing interest in derivatives as pharmaceutical leads, key steps in their biosynthesis remain obscure. Here we report the discovery and reconstitution of the pathway to the core Securinega alkaloid precursor menisdaurilide. Using transcriptomics, Nicotiana benthamiana transient expression, in vitro assays, and pathway reconstitution in Saccharomyces cerevisiae, we reveal that three cytochrome P450s and a reductase are required for the biosynthesis of menisdaurilide from L-tyrosine via the cyano-metabolite menisdaurigenin, revealing a surprising convergence with the biosynthesis of cyanogenic glucosides such as dhurrin. The de novo biosynthesis of allosecurinine in N. benthamiana highlights the potential for preparative-scale heterologous production of Securinega alkaloids.