Plants and microbes produce an enormous number of complex molecules called natural products or specialized metabolites. These compounds play varied and rich roles in the environment. Moreover, many of these compounds have life-saving properties and are used in both traditional and modern medicine. We are developing approaches to elucidate and engineer specialized plant metabolism to understand the fundamental chemical, biological and evolutionary processes that underlie the biosynthesis of these complex molecules. Additionally, we develop platforms that allow fast and inexpensive production of these compounds, as well as platforms to produce unnatural variants of these products.
Discovery of new plant biosynthetic genes
Many of the metabolic pathways that produce specialized metabolites in plants have not been characterized at the gene level. We are using modern sequencing and bioinformatics approaches to rapidly characterize these pathways by identifying new biosynthetic genes in plants. The figure shows a self organizing map that identifies co-expressed clusters of metabolic genes in the medicinal plant Catharanthus roseus.
To use our self organizing map developed by Marc Jones in Payne et al. (2017) Nature Plants, go to this link:
Alkaloids are nitrogen containing compounds that have varied and rich biological activities. The monoterpene indole alkaloids, which include the pharmaceutically important compounds vincristine, quinine and strychnine, are derived from a central intermediate strictosidine, shown in red in the figure. Our group discovers and studies biosynthetic enzymes that create the chemical diversity found in this class of specialized metabolites. Monoterpene indole alkaloids are found across five plant families and we are currently working with a number of these producer species. See for our sequence databases for some of these alkaloid producing plants.
Iridoids are a specialized class of monoterpenes best known for mediating plant-insect interactions. Our group has discovered some of the important enzymes of iridoid biosynthesis; the figure shows the recently reported crystal structure of iridoid synthase, an enzyme that we discovered in 2012. We are using these newly discovered enzymes to understand how iridoid pathways evolved. Some of our sequence databases for iridoid producing plants are found at
Metabolic engineering/synthetic biology of plant pathways
We create transgenic plant tissue capable of producing unnatural or “new-to-nature” products. This reprogramming of biosynthetic pathways to produce unnatural products may lead to the development of molecules with new biological activities. Reconstitution of plant pathways in more tractable host organisms such as yeast or E. coli - often called synthetic biology - is an exciting opportunity to facilitate the production of otherwise difficult to obtain plant molecules. 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.
Mechanistic enzymology of biosynthetic enzymes
Many of the biochemical transformations that occur in specialized metabolism are poorly understood. Our group has discovered a number of unprecedented enzymatic transformations from plant specialized metabolism, which we then study using structural biology approaches. The figure shows the structure of heteroyohimbine synthase, a biosynthetic enzyme from the monoterpene indole alkaloid biosynthetic pathway that we reported in 2016. Our mechanistic studies enable us to understand, and sometimes engineer, the substrate specificity of biosynthetic enzymes for use in metabolic engineering efforts. Moreover, understanding the mechanism of an enzyme allows us to speculate about the evolutionary origin of specialized metabolic pathways.