Giardia duodenalis (syn. G. lamblia, G. intestinahs) is a pathogenic protozoan parasite, and worldwide is a leading cause of intestinal disease in waterbome outbreaks, nursery or day-care facilities, and homosexuals. Fecal-oral transmission of the disease occurs when viable cysts are ingested, and excystation occurs in the upper small intestine with the emergence of two trophozoites. Trophozoites colonize the small intestine where, at least in part stimulated by bile, they form new cysts (encystment) which are shed in the feces. During encystment, Giardia trophozoites synthesize a filamentous cyst wall that is composed, in large part, of N-acetylgalactosarnine (GaINAc), which is undetectable in non-encysting trophozoites. In order to accomplish this, Giardia trophozoites use a synthetic pathway of inducible enzymes to convert endogenous glucose to GaINAc. This pathway is not only paramount in their cytodifferentiation from trophozoite to cyst, but represents a potential point of chemotherapeutic attack against Giardia. Little is known of the regulation or genetic control of the enzymes that comprise the inducible GaINAc synthetic pathway in Giardia, nor of a previously undescribed enzyme activity, tentatively referred to as """"""""cyst wall synthetase"""""""", which appears to fix GaINAc into the insoluble filaments that compose the outer cyst wall of Giardia. The current project continues studying this pathway by 1) purifying, characterizing and localizing the inducible, particulate """"""""cyst wall synthetase""""""""; and 2) determining the chemical nature of its uncharacterized product, which is likely to be a major component of the Giardia cyst wall. The detailed information generated here will provide important information about a key metabolic pathway vital to Giardia encystment and transmission (and perhaps in other cyst-producing protozoa). Several drugs are currently being used to treat giardiasis and many have unpleasant side effects. Some, including the most frequently used drug, metronidazole, are at risk of becoming obsolete. While resistance to metronidazole has not yet become a problem in practice, in vivo and in vitro resistance has been demonstrated and thus a potential problem exists.
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