A highly selective, high-affinity transporter for uracil in Trypanosoma brucei brucei: evidence for proton-dependent transport

1998 ◽  
Vol 76 (5) ◽  
pp. 853-858 ◽  
Author(s):  
Harry P. de Koning ◽  
Simon M. Jarvis
Keyword(s):  
Trypanosoma Brucei ◽  
Trypanosoma Brucei Brucei ◽  
High Affinity ◽  
Dependent Transport

A highly selective, high-affinity transporter for uracil in Trypanosoma brucei brucei: evidence for proton-dependent transport

1998 ◽  
Vol 76 (5) ◽  
pp. 853-858 ◽  
Author(s):  
Harry P de Koning ◽  
Simon M Jarvis
Keyword(s):  
Trypanosoma Brucei ◽  
Protozoan Parasite ◽  
Trypanosoma Brucei Brucei ◽  
Uptake Mechanism ◽  
Pyrimidine Nucleosides ◽  
High Affinity ◽  
Carbonyl Cyanide ◽  
Dependent Transport ◽  
Extracellular Sodium ◽  
Sodium And Potassium

The presence of an uptake mechanism for uracil in procyclic forms of the protozoan parasite Trypanosoma brucei brucei was investigated. Uptake of [3H]uracil at 22°C was rapid and saturable and appeared to be mediated by a single high-affinity transporter, designated U1, with an apparent Km of 0.46 ± 0.09 µM and a Vmax of 0.65 ± 0.08 pmol·(107 cells)-1·s-1. [3H]Uracil uptake was not inhibited by a broad range of purine and pyrimidine nucleosides and nucleobases (concentrations up to 1 mM), with the exception of uridine, which acted as an apparent weak inhibitor (Ki value of 48 ± 15 µM). Similarly, most chemical analogues of uracil, such as 5-chlorouracil, 3-deazauracil, and 2-thiouracil, had little or no affinity for the U1 carrier. Only 5-fluorouracil was found to be a relatively potent inhibitor of uracil uptake (Ki = 3.2 ± 0.4 µM). Transport of uracil was independent of extracellular sodium and potassium gradients, as replacement of NaCl in the assay buffer by N-methyl-D-glucamine, KCl, LiCl, CsCl, or RbCl did not affect initial rates of transport. However, the proton ionophore carbonyl cyanide chlorophenylhydrazone inhibited up to 70% of [3H]uracil flux. These data show that uracil uptake in T. b. brucei procyclics is mediated by a single high-affinity transporter with high substrate selectivity and are consistent with a nucleobase-H+-symporter model for this carrier.Key words: uracil, trypanosome, proton-nucleobase cotransport, nucleobase transport.

Effects of n-hexane and ethylacetate fractions of Terminalia catappa leaf extract in experimental Trypanosoma brucei brucei infection in Wistar rats

2021 ◽  
Author(s):  
Folashade Sarah Ojeleye ◽  
Helen Ileigo Inabo ◽  
Clement Myah Zaman Whong ◽  
Bolanle Olufunke Priscilla Musa ◽  
Ochuko Orakpoghenor
Keyword(s):  
Trypanosoma Brucei ◽  
Wistar Rats ◽  
Leaf Extract ◽  
Trypanosoma Brucei Brucei ◽  
Terminalia Catappa

Modulation of Early Immune Responses and Suppression of Trypanosoma brucei brucei Infections by Surgical Denervation of the Spleen

2000 ◽  
Vol 8 (1) ◽  
pp. 31-38 ◽  
Author(s):  
Yajuan Liu ◽  
Manal Mustafa ◽  
Hu-Lun Li ◽  
Lauri Nuortio ◽  
Amged Mustafa ◽  
...  
Keyword(s):  
Immune Responses ◽  
Trypanosoma Brucei ◽  
Trypanosoma Brucei Brucei

Biochemical properties of histone-like proteins of procyclic Trypanosoma brucei brucei

Acta Tropica ◽  
1991 ◽  
Vol 50 (2) ◽  
pp. 169-183 ◽  
Author(s):  
Klaus Bender ◽  
Bruno Betschart ◽  
Johann Schaller ◽  
Urs Kämpfer ◽  
Hermann Hecker
Keyword(s):  
Trypanosoma Brucei ◽  
Biochemical Properties ◽  
Trypanosoma Brucei Brucei

scholarly journals Cross-Resistance to Nitro Drugs and Implications for Treatment of Human African Trypanosomiasis

2010 ◽  
Vol 54 (7) ◽  
pp. 2893-2900 ◽  
Author(s):  
Antoaneta Y. Sokolova ◽  
Susan Wyllie ◽  
Stephen Patterson ◽  
Sandra L. Oza ◽  
Kevin D. Read ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
Human African Trypanosomiasis ◽  
Parent Drug ◽  
Cross Resistance ◽  
Pharmacokinetic Studies ◽  
African Trypanosomiasis ◽  
Trypanosoma Brucei Brucei ◽  
Resistant Lines

ABSTRACT The success of nifurtimox-eflornithine combination therapy (NECT) for the treatment of human African trypanosomiasis (HAT) has renewed interest in the potential of nitro drugs as chemotherapeutics. In order to study the implications of the more widespread use of nitro drugs against these parasites, we examined the in vivo and in vitro resistance potentials of nifurtimox and fexinidazole and its metabolites. Following selection in vitro by exposure to increasing concentrations of nifurtimox, Trypanosoma brucei brucei nifurtimox-resistant clones designated NfxR1 and NfxR2 were generated. Both cell lines were found to be 8-fold less sensitive to nifurtimox than parental cells and demonstrated cross-resistance to a number of other nitro drugs, most notably the clinical trial candidate fexinidazole (∼27-fold more resistant than parental cells). Studies of mice confirmed that the generation of nifurtimox resistance in these parasites did not compromise virulence, and NfxR1 remained resistant to both nifurtimox and fexinidazole in vivo. In the case of fexinidazole, drug metabolism and pharmacokinetic studies indicate that the parent drug is rapidly metabolized to the sulfoxide and sulfone form of this compound. These metabolites retained trypanocidal activity but were less effective in nifurtimox-resistant lines. Significantly, trypanosomes selected for resistance to fexinidazole were 10-fold more resistant to nifurtimox than parental cells. This reciprocal cross-resistance has important implications for the therapeutic use of nifurtimox in a clinical setting and highlights a potential danger in the use of fexinidazole as a monotherapy.

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