Structural Biology, Chemical Biology and Enzymology of Metabolic Pathways and Protein Complexes
We take a highly interdisciplinary approach to study the structure, function and control of enzymes and enzyme complexes involved in cellular metabolism. We are particularly interested in understanding how multi-protein macromolecular machines provide spatial and temporal control over metabolic pathways in cells. Our long term goal is to characterize the structure, functions and control mechanisms of these protein assemblies and to exploit this information to develop novel treatments for cancer and inflammatory diseases such as rheumatoid arthritis. To this end, we employ a variety of techniques including X-ray crystallography, mechanistic enzymology, microscopy and chemical biology.
Characterization of multifunctional proteins involved in purine and pyrimidine biosyn
thesis in eukaryotes
Many enzymes in humans and other eukaryotes catalyze multiple steps in metabolic pathways. These multi-domain enzymes are usually very difficult to characterize due to their inherent flexibility and large size. Often these proteins undergo significant conformational changes in response to ligand binding, post-translational modification or when interacting with other proteins. Understanding the structure of such multi-domain enzymes provides a significant opportunity for drug development. Enzymes involved in purine and pyrimidine biosynthesis are of particular interest as this metabolic pathway has been validated as an anti-cancer target (greater than 20% of all clinically approved cancer treatments are purine or pyrimidine anti-metabolites).
Structure and control of the purinosome
Recently, a multi-enzyme metabolic machine involved in purine biosynthesis was discovered. This dynamic and reversible protein complex, called the purinosome, forms when cells are depleted of purines and has been demonstrated to be a potential target for anti-cancer chemotherapeutics. We are investigating the structure and assembly process of this protein agglomerate and hope to use this information to understand how such phenomena may help control metabolism in cells. We are also interested in how such complexes may influence metabolic reprogramming in cancer cells.
One of the long term goals of our research is to use our knowledge of the structure and fun ction of enzymes and protein complexes to develop drugs to treat human disease. Using novel assays, we employ both conventional high-throughput methodologies as well as structure-guided approaches to identify, characterize and optimize lead compounds.