The tropical flowering plant Madagascar periwinkle produces the anti-cancer drug vinblastine. More than 35 enzymes are dedicated to the synthesis of this compound.
How does a plant synthesize an anti-cancer drug in 35 steps? And why?
Vinblastine does not represent an anomaly: many of the ca. 400,000 species of plants found on earth produce molecules of comparable complexity using lengthy metabolic pathways consisting of enzymes, regulatory factors and transporters. Elucidation of these pathways has historically been challenging since the component genes are typically located in disparate regions of the large plant genome. Over the past 10 years, our research group has led efforts to elucidate complex plant natural product pathways, and use this knowledge to understand the mechanism, evolution and function of these pathways.
Discovery of new plant biosynthetic genes
Many of the metabolic pathways that produce natural products in plants have not been characterized at the gene level.
We use state-of-the-art sequencing and bioinformatics, often in collaboration with the Buell group at the University of Georgia, along with chemical and biochemical approaches to rapidly identify new biosynthetic genes in plants.
The figure shows the recently elucidated vinblastine pathway from the medicinal plant Catharanthus roseus.
To use our self organizing map developed by Marc Jones in Payne et al. (2017) Nature Plants:
Structure and mechanism of biosynthetic enzymes
Alkaloids are nitrogen containing compounds that have varied and rich biological activities. The monoterpene indole alkaloids, are some of the most structurally complex molecules found in nature and include the pharmaceutically important compounds vincristine, quinine and strychnine.
Our group discovers and studies biosynthetic enzymes that create the chemical diversity found in the monoterpene indole alkaloids, which are found in five plant families.
The figure shows the recently elucidated crystal structure of the biosynthetic enzyme catharanthine synthase, which is involved in the biosynthesis of the anti-cancer drugs vinblastine and vincristine.
Evolution of biosynthetic
pathways and enzymes
The pathways that generate complex natural products represent a highly plastic set of responses that enable an organism to interact dynamically with the environment. Thus, the chemistry encoded by specialized metabolic pathways is an excellent system for understanding evolution and the selective pressures that drive evolution. Our mechanistic and structural studies set the foundation for understanding how the molecular evolution of new chemistry occurs.
We also investigate how pathways may have evolved, using both genomic sequencing, as well as approaches such as ancestral sequence reconstruction.
The figure shows the evolution of iridoid synthase from progesterone-b-reductase.
Metabolic engineering/synthetic biology of plant pathways
We create transgenic plant tissue capable of producing “new-to-nature” products. This reprogramming of biosynthetic pathways to produce unnatural products may lead to the development of molecules with new biological activities.
We are exploring ways to efficiently reconstitute individual branches of plant pathways in tractable host organisms, such as Nicotiana benthamiana and yeast, to improve production yields and cost.