Leishmania infantum 5'-Methylthioadenosine Phosphorylase presents relevant structural divergence to constitute a potential drug target.
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.
['Abid|Hela|H|', 'Harigua-Souiai|Emna|E|', 'Mejri|Thouraya|T|', 'Barhoumi|Mourad|M|', 'Guizani|Ikram|I|http://orcid.org/0000-0003-2763-8963']
D000241:Adenosine D020816:Amino Acid Motifs D000595:Amino Acid Sequence D000906:Antibodies D001666:Binding Sites, Antibody D020134:Catalytic Domain D003839:Deoxyadenosines D006801:Humans D018314:Leishmania infantum D062105:Molecular Docking Simulation D010446:Peptide Fragments D011485:Protein Binding D011487:Protein Conformation D011683:Purine-Nucleoside Phosphorylase D017422:Sequence Analysis, DNA D017385:Sequence Homology D055672:Static Electricity D013379:Substrate Specificity D013872:Thionucleosides D014346:Trypanosoma brucei brucei
Leishmania MTAP Homology modeling Antibody Molecular docking