Understanding the Catalytic Machinery of Chondroitinase ABC I in Processing Dermatan Sulfate

In recent studies related to injury to the central nervous system, researchers have found that galactosaminoglycans can serve as inhibitors to neuron regeneration. The chondroitinase enzyme family is comprised of several bacterial lyases known to dissolve galactosaminoglycans in the extracellular matrix. Although several studies have shown the benefit of using chondroitinase enzymes for treatment, there is much to learn about its enzyme-substrate complex. For the purpose of this research, we focus on the processing of two key galactosaminoglycan substrates, chondroitin-6-sulfate and dermatan sulfate. Through a systematic approach, we investigate the active site of chondroitinase ABC I with biological and structural studies. We demonstrate that calcium, a divalent ion, potentially increases the activity of chondroitinase ABC I when processing dermatan sulfate. From this we gain insight into the structural make-up of the chondroitinase ABC I enzyme, allowing us to optimize our approach for targeting inhibitory substrates that prevent regeneration in the central nervous system. Thesis Supervisor: Ram Sasisekharan Title: Professor of Biological Engineering & HST