Cell surface oligosaccharides play essential roles in the cell-cell recognition events associated with bacterial and viral infection, tumor cell metastasis and leukocyte adhesion at sites of inflammation. These important biological functions obviate importance of studying the enzymes that modulate oligosaccharide structures. We have developed a multidisciplinary program aimed at the study of two oligosaccharide-processing enzymes: carbohydrate sulfotransferases and proximal glycanases. The sulfotransferases have been implicated in the regulation of leukocyte adhesion to endothelium at sites of inflammation, but have not yet been identified at the molecular level. The proximal glycanases liberate N-linked oligosaccharides fromglycoproteins, yet their biological functions remain undefined. Our goals are to identify the mechanisms and biological functions of these enzymes using organic chemistry as a tool. We are synthesizing inhibitors of both classes of enzymes, which will be used to observe the effects of enzyme inhibition on the cellular expression of glycoconjugates. In the case of the sulfotransferases, the inhibitors we synthesize may have anti-inflammatory activity and serve as leads for a new generation of anti-inflammatory drugs. Our synthetic targets comprise complex glycoconjugates related to cell-associated glycoproteins. These molecules are among the most difficult to synthesize and characterize. Mass spectrometry willbe an essential tool for the characterization of our synthetic compounds due to their high molecular weight, their structural complexity and their chemical liability. The UCSF Mass Spectrometry Facility is the only facility in the area with state-of-the-art instrumentation and a staff with expertise in glycoconjugate characterization, both of which will be necessary to these projects.
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