| Autor: |
ABID, H., HARIGUA-SOUIAI, E., MEJRI, T., BARHOUMI, M., GUIZANI, I. |
| Předmět: |
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| Zdroj: |
Archives de l'Institut Pasteur de Tunis; 2020, Vol. 97 Issue 1-4, p34-34, 1p |
| Abstrakt: |
Introduction and Objectives: 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. Material and Methods: Primary Sequence Analysis of LiMTAP, Trypanosoma brucei MTAP (TbMTAP) and the human MTAP (huMTAP) and purine nucleoside phosphorylase (huPNP) homologs was assessed under T-Coffee using the clustalw_msa method. Motifs search was performed using MEME. The 3D structure modeling of LiMTAP and TbMTAP was performed through I-TASSER server Molecular docking of 5'-methylthioadenosine (MTA) and 5'-hydroxyethylthio-adenosine (HETA) on the active site (AS) of the three MTAPs was performed using Autodockvina 1.1.2. Specificity of the produced polyclonal LiMTAP antibody was assessed by western blot. Results: Sequence analysis showed that LiMTAP shared higher identity rates with the TbMTAP and the huMTAP homolog as compared to the huPNP. Motifs search identified more common patterns and higher relatedness of the parasite proteins to the huMTAP than to the huPNP. The 3D structures of the predicted LiMTAP and TbMTAP 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 a-helix, at the C terminal extremity. One peptide located in this specific region was used to generate a specific LiMTAP antibody. 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 MTA and HETA on the ASs on the three proteins predicted differential binding modes and interactions when comparing the parasite proteins to the human orthologue. Conclusion: This study highlighted significant structural peculiarities, corresponding to functionally relevant sequence divergence in LiMTAP, making of it a potential drug target against Leishmania. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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