Medicinal plants produce a variety of structurally complex, pharmaceutically important products, but generate relatively few halogenated compounds. Runguphan et al. remedy that omission by introducing the biosynthetic machinery responsible for chlorination in soil bacteria into the genome of the periwinkle, Catharanthus roseus. The prokaryotic halogenases function within the plant cells to generate chlorinated tryptophan, which is then utilized by the monoterpene indole alkaloid metabolic pathways to yield chlorinated alkaloids. Halogen atoms have been observed in several different classes of natural product, but very few halogenated natural products have been isolated from terrestrial plants. These authors show that biosynthetic machinery responsible for chlorination events in bacteria could be introduced into the medicinal plant Catharanthus roseus. Prokaryotic halogenases function within the plant cells to generate chlorinated tryptophan, which is then used by the monoterpene indole alkaloid metabolic pathways to yield chlorinated alkaloids. Halogenation, which was once considered a rare occurrence in nature, has now been observed in many natural product biosynthetic pathways1. However, only a small fraction of halogenated compounds have been isolated from terrestrial plants2. Given the impact that halogenation can have on the biological activity of natural products1, we reasoned that the introduction of halides into medicinal plant metabolism would provide the opportunity to rationally bioengineer a broad variety of novel plant products with altered, and perhaps improved, pharmacological properties. Here we report that chlorination biosynthetic machinery from soil bacteria can be successfully introduced into the medicinal plant Catharanthus roseus (Madagascar periwinkle). These prokaryotic halogenases function within the context of the plant cell to generate chlorinated tryptophan, which is then shuttled into monoterpene indole alkaloid metabolism to yield chlorinated alkaloids. A new functional group—a halide—is thereby introduced into the complex metabolism of C. roseus, and is incorporated in a predictable and regioselective manner onto the plant alkaloid products. Medicinal plants, despite their genetic and developmental complexity, therefore seem to be a viable platform for synthetic biology efforts.

Many natural products contain the hexahydropyrrolo[2, 3-b]indole (HPI) framework. HPI containing chemicals exhibit various biological activities and distinguishable structural arrangement. This structural complexity renders chemical synthesis very challenging. Here, through investigating the biosynthesis of a naturally occurring C³-aryl HPI, naseseazine C (NAS-C), we identify a P450 enzyme (NascB) and reveal that NascB catalyzes a radical cascade reaction to form intramolecular and intermolecular carbon–carbon bonds with both regio- and stereo-specificity. Surprisingly, the limited freedom is allowed in specificity to generate four types of C³-aryl HPI scaffolds, and two of them were not previously observed. By incorporating NascB into an engineered strain of E. coli, we develop a whole-cell biocatalysis system for efficient production of NAS-C and 30 NAS analogs. Interestingly, we find that some of these analogs exhibit potent neuroprotective properties. Thus, our biocatalytic methodology offers an efficient and simple route to generate difficult HPI framework containing chemicals.

Recent research on the biosynthesis of pyrroloindoline-containing natural products, including studies investigating their biosynthetic mechanisms and engineering biosynthetic pathways to produce novel products.