Xanthine phosphoribosyltransferase

Mbewe, B., Chibale, K., and McIntosh, D. B. (2007). Purification of human malaria parasite hypoxanthine guanine xanthine phosphoribosyltransferase (HGXPRT) using immobilized Reactive Red 120. Protein Expr. Purif. 52,153-158. 

Subbayya, I., and Balaram, H. (2000). Evidence for multiple active states of Plasmodium falciparum hypoxanthine-guanine-xanthine phosphoribosyltransferase. Biochem. Biophys. Res. Commun. 279,433-437. 

Another pathway of potential interest is the xanthine phosphoribosyltransferase. This enzyme is present in leishmania yet absent in humans. This raises the possibility that xanthine analogs could serve as specific chemotherapeutic agents since they would be activated by an enzyme not found in the host and incorporated into nucleotides by the parasite. In addition, xanthine analogs are likely to be oxidized by xanthine oxidase in the host and excreted, thus eliminating potential problems of toxicity. 

Another approach followed by Wang et al. led to an inhibitor of Tritrichomonas foetus hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT). The X-ray structure of this enzyme is available and it was used in a search for novel scaffolds. The Available Chemicals Directory (ACD) was screened with the program DOCK. Isatin and phthalic anhydride were capable of mimicking the substrate purine base and acting as competitive inhibitors. A virtual library of substituted... 

I. D. and Wang, C. (2000) Rational design of selective submicromolar inhibitors of Tritrichomonas foetus hypoxanthine-guanine-xanthine phosphoribosyltransferase. Biochemistry 39 4684-4691. 

Jardim A, Bergeson SE, Shih S et al. Xanthine phosphoribosyltransferase from Leishmania donovani. Molecular cloning, biochemical characterization, and genetic analysis. J Biol Chem 1999 274(48) 34403-34410. 

Somoza JR, Chin MS, Focia PJ et al. Crystal structure of the hypoxanthine-guanine-xanthine phosphoribosyltransferase from the protozoan parasite Tritrichomonas foetus. Biochemistry 1996 35(22) 7032-7040. 

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.

Hazleton KZ, Ho M, Cassera MB, Clinch K, Crump DR, Rosario I, Merino EF, Almo SC, Tyler PC, Schramm VL (2012) Acyclic immucillin phosphonates second-generation inhibitors of plasmodium falciparum hypoxanthine-guanine-xanthine phosphoribosyltransferase. Chem Biol 19 721-730... 

Purine salvage enzyme Hypoxanthine-guanine-xanthine phosphoribosyltransferase... 

A separate xanthine phosphoribosyltransferase has been shown to be present in Salmonella typhimitrium (34, 4 ) uud in L. casei (36). Krenitsky et al. (36) have also recently demonstrated that in Escherichia ccli there is a separate hypoxanthine phosphoribosyltransferase, and that guanine and xanthine phosphoribosyltransferase activities are present in a sii e enz3rme. 

---