Promiscuous CYP87A enzyme activity initiates cardenolide biosynthesis in plants.

Cardenolides are specialized, steroidal metabolites produced in a wide array of plant families. Cardenolides play protective roles in plants, but these molecules, including digoxin from foxglove (Digitalis spp.), are better known for treatment of congenital heart failure, atrial arrhythmia, various cancers and other chronic diseases.

Directed Evolution of Piperazic Acid Incorporation by a Nonribosomal Peptide Synthetase.

Engineering of biosynthetic enzymes is increasingly employed to synthesize structural analogues of antibiotics. Of special interest are nonribosomal peptide synthetases (NRPSs) responsible for the production of important antimicrobial peptides. Here, directed evolution of an adenylation domain of a Pro-specific NRPS module completely switched substrate specificity to the non-standard amino acid piperazic acid (Piz) bearing a labile N-N bond.

Beyond the semi-synthetic artemisinin: metabolic engineering of plant-derived anti-cancer drugs.

The discovery and supply of plant-derived anti-cancer compounds remain challenging given their low bioavailability and structural complexity. Reconstituting the pathways of these compounds in heterologous hosts is a promising solution; however, requires the complete elucidation of the biosynthetic genes involved and extensive metabolic engineering to optimise enzyme activity and metabolic flux. This review describes the current strategies and recent advancements in the production of these valuable therapeutic compounds, and highlights plant-derived immunomodulators as an emerging class of anti-cancer agents.

Sarpagan bridge enzyme has substrate-controlled cyclization and aromatization modes.

Cyclization reactions that create complex polycyclic scaffolds are hallmarks of alkaloid biosynthetic pathways. We present the discovery of three homologous cytochrome P450s from three monoterpene indole alkaloid-producing plants (Rauwolfia serpentina, Gelsemium sempervirens and Catharanthus roseus) that provide entry into two distinct alkaloid classes, the sarpagans and the β-carbolines. Our results highlight how a common enzymatic mechanism, guided by related but structurally distinct substrates, leads to either cyclization or aromatization.