Haoran Pang, 2016 Matriculant
Haoran Pang, 2016 Matriculant
In joining the biochemistry department, Haoran Pang combined his undergraduate degree in chemistry with his interest in biology. He eventually joined Dr. Kenichi Yokoyama’s Lab, where they characterize the biosynthetic pathways of natural products and mechanisms of critical enzymes for the development of novel therapeutics. Haoran is researching a radical SAM enzyme, MoaA, which is essential in molybdenum cofactor (Moco) biosynthesis.
Moco is found in almost all organisms and plays a central role in various metabolic and catabolic pathways. In humans, it’s necessary in various detoxification pathways and perturbation or genetic mutations in its biosynthetic pathway causes the fatal and currently incurable Moco deficiency disease (MoCD). Despite Moco’s significance, the current enzymological understanding of its biosynthesis is limited, which has hampered therapeutic development.
MoaA, a Moco biosynthetic enzyme in bacteria, attracts research interests for two reasons: first, more than 50% of MoCD patients have a mutation in human homolog of MoaA, and second, it’s a mechanistically interesting enzyme that belongs to a radical S-adenosyl-L-methionine (SAM) superfamily, actually one of the largest enzyme superfamilies, with over 113,000 members that catalyze free radical-mediated reactions and form a unique paradigm in enzymology. The Yokoyama Lab was the first to confirm the structure of the product of MoaA which helped define its function of catalyzing a chemically challenging cyclization reaction. However, how the enzyme catalyzes the reaction and how mutations inactivate the enzyme that leads to MoCD is still up for interpretation.
More specifically, Haoran is researching the mechanisms of MoaA and the disease-related mutations to provide both insights into the enzymology of the radical SAM superfamily, as well as determining a basic knowledge for developing novel therapies to combat human MoCD. He’s used multidisciplinary approaches, including small molecule probes, enzyme kinetics, electron paramagnetic resonance spectroscopy, and theoretical chemistry. After 3 years of research, he determined the kinetic rate of the key radical cyclization step during MoaA catalysis and discovered that the enzyme accelerates this step by 6~9 orders of magnitude compared to when there is no enzymatic support. Haoran was also the first to provide evidence of the functional role of a critical MoCD-associated mutation spot, called Arginine 17. His first manuscript was recently accepted by the Journal of the American Chemical Society.
Haoran believes that understanding a biological target is essential to developing new medicines, and as a basic scientist, his research will help solve this problem. So in the next phase of his PhD, Haoran wants to understand the functions of other MoCD-associated mutation spots and how they affect the enzyme’s activity, which should provide a more detailed picture of MoaA catalysis. Although there is a long way to go before drugs or novel strategies can be developed for MoCD, he is very encouraged by his results.