Current projects

We are broadly interested in understanding the functions and mechanisms of enzymes that are relevant to human health. In particular, we currently study enzymes, especially metalloenzymes, in natural product biosynthesis, bacterial and human cofactor biosynthesis, and fungal cell wall biosynthesi s. For these diverse projects, we use a combination of approaches in organic chemistry, biochemistry, molecular biology, and spectroscopy (see Experimental Techniques for details).

(1) Metallo-enzymology

One of our foci is the functions and mechanisms of redox-active metalloenzymes. Our primary focus is a group of enzymes called radical S-adenosylmethionine (SAM) enzymes. These enzymes form one of the largest groups of enzymes with > 700,000 functional domains. They 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. We also study O2-activating non-heme Fe enzymes. Studying these two different types of enzymes gives us a unique perspective on both O2-dependent and independent radical chemistry in enzyme catalysis. See the project page for details.

(2) Natural product and cofactor biosynthesis

i. Natural products

Natural products are secondary metabolites of any organisms, but mostly bacteria, fungi, and plants, although other higher eukaryotes, including humans, produce them. These molecules are the single largest source of drug leads and biomedical research probes. They are also important communication mediators among different organisms. My group studies the biosynthesis of such metabolites, mostly from bacteria, to (1) elucidate novel enzyme functions and (2) apply the knowledge to discover or develop novel bioactive agents (antifungal, antibacterial, and anticancer).

Natural products biosynthesized by radical-mediated mechanisms.

ii. Cofactors (molybdenum cofactor)

We also study enzyme cofactor biosynthesis focusing on molybdenum cofactor (Moco), which is 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. Consequently, moco biosynthesis 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 incurable disease. In bacteria, Moco plays a crucial role in virulence. Therefore, a fundamental understanding of Moco biosynthesis is critical. We are studying the Moco biosynthesis in both humans and bacteria with the eventual goal of solving the aforementioned human health problems. See the project description page for details.

(3) Antifungal antibiotics and fungal cell wall biosynthesis.

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.

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.