Research

Current projects

We are broadly interested in understanding the functions and mechanisms of enzymes that are relevant to human health. In particular, we currently focus on enzymes involved in antifungal natural product biosynthesis, fungal cell wall biosynthesis, and bacterial and human cofactor biosynthesis.  Another scientific interest of ours is the functions and mechanisms of metalloenzymes, such as radical SAM enzymes.  For these diverse projects, we use a combination of approaches from organic chemistry, biochemistry, molecular biology, and spectroscopy (see Experimental Techniques for details).

(1)  Radical SAM enzymology

One of our foci is the functions and mechanisms of a group of enzymes called radical S-adenosylmethionine (SAM) enzymes, one of the largest groups of enzymes with > 113,000 functional domains. These enzymes catalyze the reductive cleavage of S-adenosyl-L-methionine (SAM) to generate transient 5’-deoxyadenosyl radical, which is subsequently used to catalyze various free radical-mediated reactions (see Figure below). Many of these enzymes are found in biological processes closely associated with human diseases.  Also, these enzymes catalyze free radical-mediated reactions, which until recently, were considered rare in enzyme catalysis.  Thus, their functions and mechanisms form the foundation of a novel paradigm in enzymology.  See the project page for details.

Reductive cleavage of SAM by radical SAM enzymes.

Natural products biosynthesized by radical-mediated mechanisms.

(2)  Molybdenum cofactor biosynthesis

Molybdenum cofactor (Moco) is an enzyme cofactor found in almost all organisms from all kingdoms of life and plays a central role in various metabolic and catabolic pathways. Moco cannot be acquired from the environment and hence, must be biosynthesized de novo through a conserved pathway. Moco biosynthesis plays essential roles in various scientific contexts and is associated with multiple medical and environmental problems. For example, in humans, Moco is essential across multiple detoxification pathways, and perturbation in its biosynthesis causes a fatal and currently incurable disease. In bacteria, Moco plays a crucial role in virulence. Therefore, a fundamental understanding of Moco biosynthesis is critical. We have recently discovered a novel biosynthetic intermediate. This finding provided a breakthrough approach for us to study the mechanism of constructing the pyranopterin backbone structure of Moco. We are now studying the mechanisms of this transformation by taking a multidisciplinary approach by combining enzymology, organic chemistry, NMR, EPR, and X-ray crystallography.  See the project description page for details.
Moco

(3)  Antifungal antibiotics.

Fungal infection is increasing in the past decade, but our current treatment option is limited due to the toxic side effects of the existing molecules and growing drug resistance.  Inhibitors of fungal cell wall biosynthesis have been found in Nature and exhibit highly potent and selective antifungal activities. While some of these antifungal molecules have been successful in clinics, many others have not been clinically exploited.  With the long-term goal of providing novel and clinically useful antifungal agents, we are studying (i) the biosynthesis of antifungal natural products and (ii) the biosynthesis of the fungal cell wall and its inhibition by antifungals.
Antifungal

Techniques

To address our biochemical questions described above, we take diverse approaches.  Each student/postdoc in the lab will learn multiple of these techniques in excellent depth and combine them to address their scientific questions.  Therefore, our studies are highly interdisciplinarity in nature.  The skills and knowledge obtained from these studies are translatable to many other systems, providing an outstanding training opportunity for students and postdocs.  See Experimental Techniques for details.