We study the biochemical mechanisms of multisubunit proteins, particularly those involved in nitrogen metabolism. Binding of ligands to these proteins typically causes changes in tertiary structure and subunit interactions that mediate and regulate their biological activity. We study these structural changes and their relationship to function by X-ray crystallography, computer modeling and a variety of physical biochemicaland enzymological approaches. Current research focuses on enzymes of the urea cycle in humans and in the arginine biosynthetic pathway in plants and micro-organisms. A long term goal is to develop new treatments for diseases of nitrogen metabolism. In collaboration with Dr. Mendel Tuchman at Children’s National Medical Center in Washington, DC, we carried studies of human ornithine transcarbamylase (OTCase) through to determining high resolution crystal structures. These structures define the catalytic mechanism of OTCase and explain why mutations cause OTCD disease. OTCD elevates levels of ammonia in the blood, causing neurological damage. More recently, in collaboration withDr. Tuchman and colleagues, we have identified the N-acetylglutamate synthase (NAGS) gene, cloned and characterized NAGS from humans and several micro-organisms, and determined the high resolution crystal structure of N. gonorrhoeae NAGS. Related studies led to the elucidationof alternate pathways of arginine biosynthesis in certain classes of microorganisms.
