The purpose of this investigation is to develop a purine analogue which will interrupt purine synthesis in Giardial lamblia and thereby act as a chemotherapeutic agent. The objectives are to understand purine transport and metabolism in this parasite and utilize this knowledge to manipulate the structures of purine bases or nucleosides so they will serve as inhibitors of particular enzymatic reactions or transport processes. It is known that this organism has two pathways for the incorporation of adenine and guanine into its nucleotide pools; there is no interconversion between the pathways. Of particular importance are recent observations which suggest that there is a requirement for exogenous deoxyribonucleosides. If this is the case, then there are several avenues available for experimental development which are especially inviting as far as chemotherapy is concerned. These include the lack of interconversion between ribonucleotides, the transport of nucleoside analogues, and the requirement for deoxyribonucleosides. This investigation will pursue these opportunities by determining if the organism can synthesize deoxyribonucleotides, it will characterize the enzyme which phoosphorylates these compounds, compare the structure- activity relationships of the phosphorylating enzymes for the ribo- and deoxyribonucleosides, study the sterochemical requirements for transport of nucleosides, and explore the possibility of using mutagenesis to separate transport processes from phosphorylation mechanisms in order to study each without interference from the other.
| 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 |
