简介

We study the functional mechanisms and role in health and disease of multisubunit proteins involved in nitrogen metabolism. Binding of ligands typically causes changes in tertiary structure and subunit interactions that mediate and regulate their biological activity. We use X-ray crystallography, computer modeling and genetic, physical biochemical and enzymological approaches to understand the relationship between structure and function and to determine how naturally mutations alter function and cause disease. Current research focuses on enzymes of the urea cycle in humans and arginine biosynthesis in micro-organisms and plants. Mutations in these enzymes often cause clinical hyperammonemia resulting in neurological symptoms or even death. In collaboration with Dr. Mendel Tuchman and his colleagues at Children’s National Medical Center in Washington, DC, we have focused on ornithine transcarbamlyase (OTCase) and N-acetyl-L-glutamate synthase (NAGS). We also discovered novel biochemical pathways for arginine biosynthesis in bacteria and characterized the enzymes involved both biochemically and structurally. Current research focuses on the mechanism by which NAGS acts as a master regulator of the urea cycle and the development of new treatments for treating disorders of the urea cycle.