Leishmania purine salvage

Purine salvage enzymes - The drugs allopurinol (see here) and formycin B inhibit the action of cellular purine salvage enzymes. Thus, these drugs can be used to treat individuals infected by the parasitic protozans, Plasmodium, and Leishmania because these parasites lack the capacity for de novo purine synthesis (i.e., they depend entirely upon cellular purine salvage enzymes and bases provided by the host)... 

Individual enzymes of purine salvage are similar to those of Leishmania. PRTase activities were found for adenine, hypoxanthine, and guanine in the three forms (43). As in Leishmania, there is also a separate xanthine PRTase. Nucleoside kinase activities were found for adenosine, inosine, and guanosine (43), nucleoside hydrolase activities for inosine and guanosine and a nucleoside phosphorylase activity for adenosine. There are both nucleoside hydrolase and phosphorylase activities in epimastigotes (44,45). The adenylosuccinate synthetase and adenylosuccinate lyase are essentially identical to those found in L. donovani (46). 

Leishmania, Toxoplasma has adenine deaminase activity (62), supporting the suggestion that hypoxanthine salvage plays a central role in purine metabolism (61). Consistent with this is the finding that hypoxanthine incorporation is second only to that of adenosine. The majority of adenine, as in Leishmania, is salvaged by deamination to hypoxanthine. 

Figure 1. Purine salvage pathways of Leishmania species. Enzymes 1) phosphoribosyltransferase 2) adenine deaminase 3) guanine deaminase 4) adenosine deaminase 5) nucleoside kinase 6, nucleotidase 7) AMP deaminase 8) adenylosuccinate synthetase 9) adenylosuccinate lyase 10) AMP kinase 11) GMP kinase 12) IMP dehydrogenase 13) GMP synthetase 14) GMP reductase.

Leishnumia have developed an extensive network of salvage enzymes that enable them to interconvert and metabolize any host purine to the nucleotide level. Through a variety of molecular and biochemical studies, the following purine salvage pathway has been proposed in Leishmania. 

Purine Salvage Enzymes as Drug Taigets in Leishmania... 

Figure 3. Compartmentalization of the purine salvage pathway of Leishmania. Abbreviations are as follows AAH, adenine aminohydrolase XPRT, xanthine phosphoribosyltransferase HGPRT, hypoxanthine-guaninephosphoribosyltransferase ADSS, adenylosuccinate synthetase ASL, adenylosuccinate lyase IMPDH, inosine monophosphate dehydrogenase GMPS, gua-nosine monophosphate synthase GDA, guanine deaminase AMPDA, adenosine monophosphate deaminase GMPR, guanosine monophosphate reductase APRT, adenine phosphoribosyltransferase AK, adenosine kinase. Enzymes that have been localized are shown in black and those that are predicted to be in the denoted locations are depicted in gray.

Cui L, Rajasekariah GR, Martin SK. A nonspecific nucleoside hydrolase from Leishmania donovani Implications for purine salvage by the parasite. Gene 2001 280(1-2) 153-162. 

Boitz JM, Ullman B. A conditional mutant deficient in hypoxanthine juanine phosphoribosyliransfeiase and xanthine phosphoribosylttansfetase validates the purine salvage pathway of Leishmania donovani. J Biol Chem 2006 281(23) 16084-9. 

It was previously reported that L. donovani had high levels of nucleoside hydrolase activities toward all the common purine nucleosides except adenosine. It was clear that if the phospho-rylase-kinase pathway was the only route of purine salvage in trichomonas the presence of such hydrolases would be difficult to explain. Figure 3 shows the nucleoside hydrolase levels of leish-mania and trichomonas. With leishmania, the levels are high with... 

Differences in the metabolic sequences for purine metabolism in the various morphological forms of the pathogenic kinetoplastids appears to be only quantitative and not qualitative with the exception of Leishmania. Leishmania amastigotes and promas-tigotes differ with respect to particular enzymes which metabolize adenine and adenosine. Fig. 6.7 shows the major salvage and interconversion pathways of the Kinetoplastida. 

Leishmania species possess the unique salvage etrzyme, purine nucleoside phosphotransferase. This enz5mie phosphorylates allopuritrol riboside to form the corresponding nucleotide, which interferes with puritre and nucleic acid metabolism. The answer is (B). 

It therefore appears that the Lxishmania parasites possess multiple routes for salvaging purines and all the purine bases are interconvertible with an apparent branch point at IMP. Hence, the Leishmania species, unlike some other protozoa, when cultured in vitro, do not require any particular purine base for growth. 

LaFon SW, Nelson DJ, Berens RL et al. Purine and pyrimidine salvage pathways in Leishmania donovani. Biochem Pharmacol 1982 31(2) 231-238. 

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