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The crystal structure and activity of a putative trypanosomal nucleoside phosphorylase reveal it to be a homodimeric uridine phosphorylase.

Larson ET, Mudeppa DG, Gillespie JR, Mueller N, Napuli AJ, Arif JA, Ross J, Arakaki TL, Lauricella A, Detitta G, Luft J, Zucker F, Verlinde CL, Fan E, Van Voorhis WC, Buckner FS, Rathod PK, Hol WG, Merritt EA
J Mol Biol 396 1244-59 (2010)
Cited: 14 times
EuropePMC logo PMID: 20070944

Abstract

Purine nucleoside phosphorylases (PNPs) and uridine phosphorylases (UPs) are closely related enzymes involved in purine and pyrimidine salvage, respectively, which catalyze the removal of the ribosyl moiety from nucleosides so that the nucleotide base may be recycled. Parasitic protozoa generally are incapable of de novo purine biosynthesis; hence, the purine salvage pathway is of potential therapeutic interest. Information about pyrimidine biosynthesis in these organisms is much more limited. Though all seem to carry at least a subset of enzymes from each pathway, the dependency on de novo pyrimidine synthesis versus salvage varies from organism to organism and even from one growth stage to another. We have structurally and biochemically characterized a putative nucleoside phosphorylase (NP) from the pathogenic protozoan Trypanosoma brucei and find that it is a homodimeric UP. This is the first characterization of a UP from a trypanosomal source despite this activity being observed decades ago. Although this gene was broadly annotated as a putative NP, it was widely inferred to be a purine nucleoside phosphorylase. Our characterization of this trypanosomal enzyme shows that it is possible to distinguish between PNP and UP activity at the sequence level based on the absence or presence of a characteristic UP-specificity insert. We suggest that this recognizable feature may aid in proper annotation of the substrate specificity of enzymes in the NP family.

Reviews - 3bje mentioned but not cited (1)

  1. The Potential of Secondary Metabolites from Plants as Drugs or Leads against Protozoan Neglected Diseases-Part III: In-Silico Molecular Docking Investigations. Ogungbe IV, Setzer WN. Molecules 21 (2016)

Articles - 3bje mentioned but not cited (3)

  1. The crystal structure and activity of a putative trypanosomal nucleoside phosphorylase reveal it to be a homodimeric uridine phosphorylase. Larson ET, Mudeppa DG, Gillespie JR, Mueller N, Napuli AJ, Arif JA, Ross J, Arakaki TL, Lauricella A, Detitta G, Luft J, Zucker F, Verlinde CL, Fan E, Van Voorhis WC, Buckner FS, Rathod PK, Hol WG, Merritt EA. J. Mol. Biol. 396 1244-1259 (2010)
  2. Prediction of Long Loops with Embedded Secondary Structure using the Protein Local Optimization Program. Miller EB, Murrett CS, Zhu K, Zhao S, Goldfeld DA, Bylund JH, Friesner RA. J Chem Theory Comput 9 1846-4864 (2013)
  3. Structural and catalytic analysis of two diverse uridine phosphorylases in Phytophthora capsici. Yang C, Li J, Huang Z, Zhang X, Gao X, Zhu C, Morris PF, Zhang X. Sci Rep 10 9051 (2020)


Reviews citing this publication (3)

  1. Pyrimidine metabolism in schistosomes: A comparison with other parasites and the search for potential chemotherapeutic targets. El Kouni MH. Comp. Biochem. Physiol. B, Biochem. Mol. Biol. 213 55-80 (2017)
  2. Fresh insights into the pyrimidine metabolism in the trypanosomatids. Tiwari K, Dubey VK. Parasit Vectors 11 87 (2018)
  3. Targeting the nucleotide metabolism of Trypanosoma brucei and other trypanosomatids. Hofer A. FEMS Microbiol Rev 47 fuad020 (2023)

Articles citing this publication (7)

  1. Pyrimidine salvage in Trypanosoma brucei bloodstream forms and the trypanocidal action of halogenated pyrimidines. Ali JA, Creek DJ, Burgess K, Allison HC, Field MC, Mäser P, De Koning HP. Mol. Pharmacol. 83 439-453 (2013)
  2. Pyrimidine biosynthesis is not an essential function for Trypanosoma brucei bloodstream forms. Ali JA, Tagoe DN, Munday JC, Donachie A, Morrison LJ, de Koning HP. PLoS ONE 8 e58034 (2013)
  3. A novel structural mechanism for redox regulation of uridine phosphorylase 2 activity. Roosild TP, Castronovo S, Villoso A, Ziemba A, Pizzorno G. J. Struct. Biol. 176 229-237 (2011)
  4. Pyrimidine Salvage Enzymes Are Essential for De Novo Biosynthesis of Deoxypyrimidine Nucleotides in Trypanosoma brucei. Leija C, Rijo-Ferreira F, Kinch LN, Grishin NV, Nischan N, Kohler JJ, Hu Z, Phillips MA. PLoS Pathog. 12 e1006010 (2016)
  5. Transition-state analysis of Trypanosoma cruzi uridine phosphorylase-catalyzed arsenolysis of uridine. Silva RG, Vetticatt MJ, Merino EF, Cassera MB, Schramm VL. J. Am. Chem. Soc. 133 9923-9931 (2011)
  6. Active site conformational dynamics in human uridine phosphorylase 1. Roosild TP, Castronovo S. PLoS ONE 5 e12741 (2010)
  7. Constrained bonding environment in the Michaelis complex of Trypanosoma cruzi uridine phosphorylase. Silva RG, Kipp DR, Schramm VL. Biochemistry 51 6715-6717 (2012)


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