Giardiasis is an enteric infection widely disseminated in the United States and the international community. Therapeutic agents are few and somewhat limited due to questions of toxicity or potential carcinogenicity. We intend to investigate purine metabolism in Giardia lamblia for the purpose of developing a nonbsorbable purine analogue for the treatment of giardiasis. This study will be done by incubating the organism in a medium which is defined with respect to its purine content. Radio-labeled purines or precursors will be added in order to trace the metabolic sequences. Analysis of cell extracts will be done by high performance liquid chromatography and the kinetics of flow through the metabolic pathways will be investigated using a computer model which calculates the rate of flux through a particular enzymatic step. These studies will be done with all natural purine bases and ribonucleosides to compare the metabolism of these compounds, including the kinetics in vivo, and specific enzymatic reactions which may be important in chemotherapy. When the general metabolic sequences are determined, purine analogues known to affect these steps will be studied. Our preliminary investigation has shown that there is no de novo synthesis of purines and that there is no interchange between the adenine and guanine nucleotide pools. This is a most interesting finding and potentially the most useful for chemotherapy. It suggests that interdiction of either adenine or guanine metabolism should be sufficient to kill the organism.
| Baum, K F; Berens, R L; Marr, J J (1993) Purine nucleoside and nucleobase cell membrane transport in Giardia lamblia. J Eukaryot Microbiol 40:643-9 |
| Baum, K F; Berens, R L; Marr, J J et al. (1989) Purine deoxynucleoside salvage in Giardia lamblia. J Biol Chem 264:21087-90 |
| Berens, R L; Marr, J J (1986) Adenosine analog metabolism in Giardia lamblia. Implications for chemotherapy. Biochem Pharmacol 35:4191-7 |
