Purine salvage in Leishmania: complex or simple by design?

Abstract

Purine nucleotides function in a variety of vital cellular and metabolic processes including energy production, cell signaling, synthesis of vitamin-derived cofactors and nucleic acids, and as determinants of cell fate. Unlike their mammalian and insect hosts, Leishmania cannot synthesize the purine ring de novo and are absolutely dependent upon them to meet their purine requirements. The obligatory nature of purine salvage in these parasites, therefore, offers an attractive paradigm for drug targeting and, consequently, the delineation of the pathway has been under scientific investigation for over 30 years. Here, we review recent developments that reveal how purines flux in Leishmania and offer a potential 'Achilles' heel' for future validation.

Figure 1

Predicted purine salvage pathway of Leishmania. The purine salvage and interconversion enzymes that have been identified in L. donovani are depicted. Abbreviations: APRT, adenine phosphoribosyltransferase; HGPRT, hypoxanthine-guanine phosphoribosyltransferase; XPRT, xanthine phosphoribosyltransferase; AK, adenosine kinase; AAH, adenine aminohydrolase; GDA, guanine deaminase; ADSS, adenylosuccinate synthetase; ASL, adenylosuccinate lyase; AMPDA, AMP deaminase; IMPDH, inosine monophosphate dehydrogenase; GMPS, GMP synthase; GMPR, GMP reductase; NH, nucleoside hydrolase; ADO, adenosine; ADE, adenine; INO, inosine; HYP, hypoxanthine; GUO, guanosine; GUA, guanine; XAO, xanthosine; XAN, xanthine.

Figure 2

Metabolic flux through the purine salvage pathway in L. donovani. Heavy blue arrows highlight the major flux of substrates through the purine salvage pathway as deduced from genetic and biochemical experiments. The minor activities are represented by black arrows, and the dashed line indicates that the phosphoribosylation of guanine most likely does not occur under physiological conditions in Leishmania. Abbreviations: APRT, adenine phosphoribosyltransferase; HGPRT, hypoxanthine-guanine phosphoribosyltransferase; XPRT, xanthine phosphoribosyltransferase; AK, adenosine kinase; AAH, adenine aminohydrolase; GDA, guanine deaminase; ADSS, adenylosuccinate synthetase; ASL, adenylosuccinate lyase; AMPDA, AMP deaminase; IMPDH, inosine monophosphate dehydrogenase; GMPS, GMP synthase; GMPR, GMP reductase; NH, nucleoside hydrolase; ADO, adenosine; ADE, adenine; INO, inosine; HYP, hypoxanthine; GUO, guanosine; GUA, guanine; XAO, xanthosine; XAN, xanthine.

Figure I

Predicted compartmentalization of the Leishmania purine salvage pathway. The gray shaded circle represents the glycosomal membrane and the cytosolic environment is located outside of the circle. Enzymes within the purine salvage pathway that have been experimentally determined to be in the cytosol or the glycosome are shown in red and those that are based on their in silico predictions are shown in blue. Abbreviations: HGPRT, hypoxanthine-guanine phosphoribosyltransferase; XPRT, xanthine phosphoribosyltransferase; IMPDH, inosine monophosphate dehydrogenase; GMPR, GMP reductase; GMPS, GMP synthase; APRT, adenine phosphoribosyltransferase; AAH, adenine aminohydrolase; AK, adenosine kinase; ADSS, adenylosuccinate synthetase; ASL, adenylosuccinate lyase; AMPDA, AMP deaminase; GDA, guanine deaminase; NH, nucleoside hydrolase.