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

摘要: 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 designated LmU1. This displayed degree of specificity, as it had virtually no cytosine, thymine or nucleobases, nor did pyrimidine nucleosides. Highest was 5-fluorouracil. The results show that the permeant binding site LmU1 interacts strongly keto groups uracil, shown by low 2-thio- and 4-thiouracil. appears further bind through weak hydrogen bond N(1)H ring addition stronger H-bond N(3)H. Substrate selectivity were strikingly similar U1 related kinetoplastid Trypanosoma brucei. Uracil analogues likely be transported also screened antileishmanial activity, 5-fluorouracil displaying strong activity against promastigotes intracellular amastigotes. Overall, that, like nucleobase transport, function very L. T. brucei insect forms.