Identification of the first pyrimidine nucleobase transporter in Leishmania: similarities with the Trypanosoma brucei U1 transporter and antileishmanial activity of uracil analogues

Papageorgiou, I. G., Yakob, L., Al Salabi, M. I., Diallinas, G., Soteriadou, K. P. and De Koning, H. P. (2005) Identification of the first pyrimidine nucleobase transporter in Leishmania: similarities with the Trypanosoma brucei U1 transporter and antileishmanial activity of uracil analogues. Parasitology, 130 3: 275-283. doi:10.1017/S0031182004006626


Author Papageorgiou, I. G.
Yakob, L.
Al Salabi, M. I.
Diallinas, G.
Soteriadou, K. P.
De Koning, H. P.
Title Identification of the first pyrimidine nucleobase transporter in Leishmania: similarities with the Trypanosoma brucei U1 transporter and antileishmanial activity of uracil analogues
Formatted title
Identification of the first pyrimidine nucleobase transporter in Leishmania: similarities with the Trypanosoma brucei U1 transporter and antileishmanial activity of uracil analogues
Journal name Parasitology   Check publisher's open access policy
ISSN 0031-1820
1469-8161
Publication date 2005-03
Sub-type Article (original research)
DOI 10.1017/S0031182004006626
Volume 130
Issue 3
Start page 275
End page 283
Total pages 9
Place of publication Cambridge, United Kingdom
Publisher Cambridge University Press
Language eng
Formatted 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 μM) 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.
Keyword Leishmania major
Trypanosoma brucei
Pyrimidine transporters
Purine transporters
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: ERA 2012 Admin Only
School of Biological Sciences Publications
 
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Created: Thu, 19 Jan 2012, 10:52:05 EST by Dr Laith Yakob on behalf of School of Biological Sciences