BACKGROUND The 5'-methylthioadenosine phosphorylase (MTAP), an enzyme involved in purine and polyamine metabolism and in the methionine salvage pathway, is considered as a potential drug target against cancer and trypanosomiasis. In fact, Trypanosoma and Leishmania parasites lack de novo purine pathways and rely on purine salvage pathways to meet their requirements. Herein, we propose the first comprehensive bioinformatic and structural characterization of the putative Leishmania infantum MTAP (LiMTAP), using a comparative computational approach. RESULTS Sequence analysis showed that LiMTAP shared higher identity rates with the Trypanosoma brucei (TbMTAP) and the human (huMTAP) homologs as compared to the human purine nucleoside phosphorylase (huPNP). Motifs search using MEME identified more common patterns and higher relatedness of the parasite proteins to the huMTAP than to the huPNP. The 3D structures of LiMTAP and TbMTAP were predicted by homology modeling and compared to the crystal structure of the huMTAP. These models presented conserved secondary structures compared to the huMTAP, with a similar topology corresponding to the Rossmann fold. This confirmed that both LiMTAP and TbMTAP are members of the NP-I family. In comparison to the huMTAP, the 3D model of LiMTAP showed an additional α-helix, at the C terminal extremity. One peptide located in this specific region was used to generate a specific antibody to LiMTAP. In comparison with the active site (AS) of huMTAP, the parasite ASs presented significant differences in the shape and the electrostatic potentials (EPs). Molecular docking of 5'-methylthioadenosine (MTA) and 5'-hydroxyethylthio-adenosine (HETA) on the ASs on the three proteins predicted differential binding modes and interactions when comparing the parasite proteins to the human orthologue. CONCLUSIONS This study highlighted significant structural peculiarities, corresponding to functionally relevant sequence divergence in LiMTAP, making of it a potential drug target against Leishmania.

中文翻译：

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婴儿利什曼原虫5'-甲基硫代腺苷磷酸化酶表现出相关的结构差异，以构成潜在的药物靶标。

背景技术5'-甲基硫代腺苷磷酸化酶（MTAP）是一种参与嘌呤和多胺代谢以及蛋氨酸抢救途径的酶，被认为是对抗癌症和锥虫病的潜在药物靶标。实际上，锥虫和利什曼原虫寄生虫缺乏从头嘌呤途径，而依靠嘌呤挽救途径来满足其需求。在这里，我们建议使用比较计算方法对假定的婴儿利什曼原虫MTAP（LiMTAP）进行首次全面的生物信息学和结构表征。结果序列分析表明，与人嘌呤核苷磷酸化酶（huPNP）相比，LiMTAP与布鲁氏锥虫（TbMTAP）和人（huMTAP）同源物具有更高的同一性。使用MEME进行的基序搜索发现，与huPNP相比，寄生虫蛋白与huMTAP更为常见，并且相关性更高。通过同源性建模预测了LiMTAP和TbMTAP的3D结构，并将其与huMTAP的晶体结构进行了比较。与huMTAP相比，这些模型呈现出保守的二级结构，并具有对应于Rossmann折叠的相似拓扑。这证实了LiMTAP和TbMTAP都是NP-I家族的成员。与huMTAP相比，LiMTAP的3D模型在C末端末端显示了一个附加的α螺旋。位于该特定区域的一种肽用于产生针对LiMTAP的特异性抗体。与huMTAP的活性位点（AS）相比，寄生虫的AS的形状和静电势（EP）表现出显着差异。5'-甲硫基腺苷（MTA）和5'-羟乙硫基腺苷（HETA）在三种蛋白质的AS上的分子对接预测了将寄生虫蛋白质与人类直系同源物进行比较时的差异结合方式和相互作用。结论本研究强调了显着的结构特点，与LiMTAP中功能相关的序列差异相对应，使其成为对抗利什曼原虫的潜在药物靶标。