Identification of the first pyrimidine nucleobase transporter in Leishmania: similarities with the Trypanosoma brucei U1 transporter and antileishmanial activity of uracil analogues
- PMID: 15796010
- DOI: 10.1017/s0031182004006626
Identification of the first pyrimidine nucleobase transporter in Leishmania: similarities with the Trypanosoma brucei U1 transporter and antileishmanial activity of uracil analogues
Abstract
While purine transport has been widely studied in protozoa, almost nothing is known about their capacity to salvage pyrimidines. Here, we report a Leishmania major transporter with high affinity for uracil (Km=0.32+/-0.07 microM) which we designated LmU1. This transporter displayed a high degree of specificity, as it had virtually no affinity for cytosine, thymine or purine nucleobases, nor did it transport pyrimidine nucleosides. Highest affinity was for 5-fluorouracil. The results show that the permeant binding site of LmU1 interacts strongly with the keto groups of uracil, as shown by a low affinity for 2-thio- and 4-thiouracil. LmU1 appears to further bind uracil through a weak hydrogen bond with N(1)H of the pyrimidine ring in addition to a stronger H-bond with N(3)H. Substrate binding and selectivity were strikingly similar to that of the U1 transporter in the related kinetoplastid Trypanosoma brucei. Uracil analogues likely to be transported by LmU1 were also screened for antileishmanial activity, with 5-fluorouracil displaying strong activity against promastigotes and intracellular amastigotes. Overall, the results show that, like purine nucleobase transport, pyrimidine nucleobase transport function is very similar in L. major and T. brucei insect forms.
Similar articles
-
Trypanosoma brucei: a survey of pyrimidine transport activities.Exp Parasitol. 2006 Oct;114(2):118-25. doi: 10.1016/j.exppara.2006.02.018. Epub 2006 Apr 18. Exp Parasitol. 2006. PMID: 16620810
-
A Leishmania major nucleobase transporter responsible for allopurinol uptake is a functional homolog of the Trypanosoma brucei H2 transporter.Mol Pharmacol. 2003 Apr;63(4):814-20. doi: 10.1124/mol.63.4.814. Mol Pharmacol. 2003. PMID: 12644582
-
A highly selective, high-affinity transporter for uracil in Trypanosoma brucei brucei: evidence for proton-dependent transport.Biochem Cell Biol. 1998;76(5):853-8. doi: 10.1139/bcb-76-5-853. Biochem Cell Biol. 1998. PMID: 10353720
-
Pyrimidine transport activities in trypanosomes.Trends Parasitol. 2007 May;23(5):187-9; discussion 190. doi: 10.1016/j.pt.2007.03.003. Epub 2007 Mar 19. Trends Parasitol. 2007. PMID: 17374509 Review.
-
Purine and pyrimidine transport in pathogenic protozoa: from biology to therapy.FEMS Microbiol Rev. 2005 Nov;29(5):987-1020. doi: 10.1016/j.femsre.2005.03.004. Epub 2005 Jul 1. FEMS Microbiol Rev. 2005. PMID: 16040150 Review.
Cited by
-
Pyrimidine salvage in Toxoplasma gondii as a target for new treatment.Front Cell Infect Microbiol. 2023 Dec 15;13:1320160. doi: 10.3389/fcimb.2023.1320160. eCollection 2023. Front Cell Infect Microbiol. 2023. PMID: 38162577 Free PMC article.
-
The Trypanosoma cruzi TcrNT2 Nucleoside Transporter Is a Conduit for the Uptake of 5-F-2'-Deoxyuridine and Tubercidin Analogues.Molecules. 2022 Nov 19;27(22):0. doi: 10.3390/molecules27228045. Molecules. 2022. PMID: 36432150 Free PMC article.
-
Nucleoside Transport and Nucleobase Uptake Null Mutants in Leishmania mexicana for the Routine Expression and Characterization of Purine and Pyrimidine Transporters.Int J Mol Sci. 2022 Jul 23;23(15):8139. doi: 10.3390/ijms23158139. Int J Mol Sci. 2022. PMID: 35897714 Free PMC article.
-
Comprehensive characterization of purine and pyrimidine transport activities in Trichomonas vaginalis and functional cloning of a trichomonad nucleoside transporter.Mol Microbiol. 2021 Dec;116(6):1489-1511. doi: 10.1111/mmi.14840. Epub 2021 Nov 20. Mol Microbiol. 2021. PMID: 34738285 Free PMC article.
-
Divergent metabolism between Trypanosoma congolense and Trypanosoma brucei results in differential sensitivity to metabolic inhibition.PLoS Pathog. 2021 Jul 26;17(7):e1009734. doi: 10.1371/journal.ppat.1009734. eCollection 2021 Jul. PLoS Pathog. 2021. PMID: 34310651 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources