Abstract
BackgroundThe 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.ResultsSequence 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.ConclusionsThis study highlighted significant structural peculiarities, corresponding to functionally relevant sequence divergence in LiMTAP, making of it a potential drug target against Leishmania.
Highlights
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
The V233 was replaced by an alanine in both Leishmania infantum MTAP (LiMTAP) and Trypanosoma brucei MTAP (TbMTAP) (A236 and A240, respectively) and by K254 in the human purine nucleoside phosphorylase (huPNP)
The L237 was conserved in the huPNP (L261) but replaced by T240 in LiMTAP and R244 in TbMTAP
Summary
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. Neglected Tropical Diseases (NTDs) correspond to multiple transmissible pathologies that mainly occur in tropical and sub-tropical regions. They affect populations living in poverty with more than a billion people in 149 countries worldwide [1]. Mainstay therapy is based on the use of toxic pentavalent antimonials in long treatment courses [4]. Their prolonged use is increasingly inducing parasite drug resistance [5]. Second line drugs, such as pentamidine, miltefosine, and amphotericin B are toxic, costly or have adverse effects [6]. The need for new targets and new drugs is increasingly important, and constitutes research priority
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