Grant: CIHR Fellowship

The eukaryotic cell surface is covered with an array of sugar coated molecules. These provide a key structural determinant, playing a role in physiological and pathological events such as adhesion, motility, immunity and tumor metastasis. The major goal of this project is to elucidate the three dimensional structure of selected polysialyltransferase enzymes, which represent one of the key points of targeted intervention in the polysialic acid (PSA) pathway. PSA is a unique carbohydrate that is added in a protein specific manner to the neural cell adhesion molecule (NCAM) in the vertebrate neural system. Changes in PSA expression have been linked with neurological disorders such as Alzheimer's and schizophrenia. Of utmost relevance, the malignant potential of numerous tumors including neuroendocrine tumors, Wilms tumor, neuroblastoma, colon cancer and pancreatic cancer has been linked to PSA-NCAM. A compound affecting polysialyltransferase enzyme expression has been implicated in down-regulation of the metastatic capacity in a wide range of tumors, suggesting these as promising drug targets. Thus, from a health perspective there is a pressing need to elucidate the biosynthetic pathway of PSA expression. Biochemical progress has been made to this effect in recent years but critically, structural data of any of the polysialyltransferases is lacking. Structural information will aid the discovery of novel drugs targeting this pathway and therefore has the potential to impact treatments for neurological diseases and cancer.