My group is interested in medicinally important enzymatic reactions involving radical reactions and/or redox active metallo-center. Currently we are focusing on three targets:
1. Ribonucleotide reductase (RNR) and pyruvate formate lyase (PFL), radical enzymes that play key roles in nucleotide and energy metabolisms. These enzymes are also known as virulence factors in pathogenic bacteria. We are studying the chemical mechanism and regulation of these enzymes to better understand the dynamic change in the nucleotide and energy flux in pathogenic bacteria during infection. RNR is also a proven target for anti-cancer drugs, and thus mechanism of RNR targeting drugs are being investigated.
2. Redox sensing nitro aromatic pro-drugs used against anaerobic infections. We are studying the mechanism of activation of these drugs and their specific targets. Possibility of these drugs to target hypoxic tumor cells is also being investigated.
3. Biosynthesis of the molybdenum cofactor (Moco) and neurologic diseases caused by genetic defect in Moco biosynthetic genes (Moco deficiency). We are studying the molecular mechanism of Moco deficiency by studying the mechanisms of reactions catalyzed by the Moco biosynthetic enzymes and their mutants found in the patients of the disease. The reactions catalyzed by Moco biosynthetic enzymes are unique and thus of mechanistic interest.
To study these targets, we use interdisciplinary approaches that include variety of steady-state and transient kinetic methods combined with biophysical detection methods; organic and enzymatic synthesis, isolation and structural analysis of small molecules; site-specific unnatural amino acid incorporation; and in vitro/vivo protein labeling.