Projects

Given our broad interest in (di)terpenoid metabolism, we developed a modular metabolic engineering system that enables facile assembly of diterpenoid biosynthetic pathways in E.

The observed diversification of (di)terpenoids in plants suggests that these natural products play important roles in such organisms.

Given our interest in labdane-related diterpenoid biosynthesis, we were intrigued by the report that the important human pathogen Mycobacterium tuberculosis encoded a class II diterpene cyclase, particularly with separately reported genetic evidence that this enzyme was involved in the ability of the pathogen to suppress acidification of the phagosome into which the bacterium is enveloped by macrophages.  Building on the additional evidence indicating a similar role for the neighboring gene, we demonstrated that the encoded enzyme will react with the halimadienyl diphosphate p

Recognizing that rice produced numerous labdane-related diterpenoid natural products, and the opportunity presented by the publication of the rice genome sequence, we began by carrying out a functional genomics based investigation of the rice diterpene synthases.  Given the relative paucity of characterized diterpene synthases at that time, this effort more than doubled the number of molecularly identified functionally distinct such enzymes.  Strikingly, we further uncovered a functionally distinct pair of alleles for one of the rice class I diterpene synthases, which led to isola

The class II diterpene cyclases catalyze protonation-initiated (bi)cyclization reactions that characterize labdane-related diterpenoid biosynthesis. In collaboration with Prof. David Christianson (Univ. Penn), we have provided the first crystal structures for class II diterpene cyclases.  From these we have generated significant insights into the underlying determinants of enzymatic catalysis, including the generation of enzymes wherein single residue changes have led to novel product outcome.