Structural and functional attributes of malaria parasite diadenosine tetraphosphate hydrolase

Sharma, Amit; Yogavel, Manickam

doi:10.1038/srep19981

Cited by 13 publications

(15 citation statements)

References 57 publications

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“…The positions of our metals match those found in structural homologs Ap4A and RppH, which have been crystallized with four [ 21 , 25 ] and three [ 22 , 26 ] Mg 2+ ions in their active site ( Fig 2E ). M1-M3 is represented in all three structures; RppH does not have a modeled metal ion in position of our M4, the metal ion that does not come in contact with protein residues.…”

Section: Resultssupporting

confidence: 68%

Metal ion coordination in the E. coli Nudix hydrolase dihydroneopterin triphosphate pyrophosphatase: New clues into catalytic mechanism

Hill¹,

Nguyen²,

Ukachukwu³

et al. 2017

PLoS ONE

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Dihydroneopterin triphosphate pyrophosphatase (DHNTPase), a member of the Mg2+ dependent Nudix hydrolase superfamily, is the recently-discovered enzyme that functions in the second step of the pterin branch of the folate biosynthetic pathway in E. coli. DHNTPase is of interest because inhibition of enzymes in bacterial folate biosynthetic pathways is a strategy for antibiotic development. We determined crystal structures of DHNTPase with and without activating, Mg2+-mimicking metals Co2+ and Ni2+. Four metal ions, identified by anomalous scattering, and stoichiometrically confirmed in solution by isothermal titration calorimetry, are held in place by Glu56 and Glu60 within the Nudix sequence motif, Glu117, waters, and a sulfate ion, of which the latter is further stabilized by a salt bridge with Lys7. In silico docking of the DHNTP substrate reveals a binding mode in which the pterin ring moiety is nestled in a largely hydrophobic pocket, the β-phosphate activated for nucleophilic attack overlays with the crystallographic sulfate and is in line with an activated water molecule, and remaining phosphate groups are stabilized by all four identified metal ions. The structures and binding data provide new details regarding DHNTPase metal requirements, mechanism, and suggest a strategy for efficient inhibition.

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Section: Resultssupporting

confidence: 68%

Metal ion coordination in the E. coli Nudix hydrolase dihydroneopterin triphosphate pyrophosphatase: New clues into catalytic mechanism

Hill¹,

Nguyen²,

Ukachukwu³

et al. 2017

PLoS ONE

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“…Plasmodium falciparum tyrosyl-tRNA synthetases (PfTyrRS), for instance, have cytokine-like functions, while eukaryotic methionyl-tRNA synthetases (MetRS) have glutathione-S-transferase domains that play a key role in protein–protein interactions [26, 27]. Plasmodium falciparum lysyl-tRNA synthetase (PfLysRS) synthesizes diadenosine polyphosphate, a signaling molecule that plays a role in gene expression, DNA replication and regulation of ion channels of the parasite [28, 29].…”

Section: Introductionmentioning

confidence: 99%

Aminoacyl tRNA synthetases as malarial drug targets: a comparative bioinformatics study

Nyamai

Bishop

2019

Malar J

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BackgroundTreatment of parasitic diseases has been challenging due to evolution of drug resistant parasites, and thus there is need to identify new class of drugs and drug targets. Protein translation is important for survival of malarial parasite, Plasmodium, and the pathway is present in all of its life cycle stages. Aminoacyl tRNA synthetases are primary enzymes in protein translation as they catalyse amino acid addition to the cognate tRNA. This study sought to understand differences between Plasmodium and human aminoacyl tRNA synthetases through bioinformatics analysis.MethodsPlasmodium berghei, Plasmodium falciparum, Plasmodium fragile, Plasmodium knowlesi, Plasmodium malariae, Plasmodium ovale, Plasmodium vivax, Plasmodium yoelii and human aminoacyl tRNA synthetase sequences were retrieved from UniProt database and grouped into 20 families based on amino acid specificity. These families were further divided into two classes. Both families and classes were analysed. Motif discovery was carried out using the MEME software, sequence identity calculation was done using an in-house Python script, multiple sequence alignments were performed using PROMALS3D and TCOFFEE tools, and phylogenetic tree calculations were performed using MEGA vs 7.0 tool. Possible alternative binding sites were predicted using FTMap webserver and SiteMap tool.ResultsMotif discovery revealed Plasmodium-specific motifs while phylogenetic tree calculations showed that Plasmodium proteins have different evolutionary history to the human homologues. Human aaRSs sequences showed low sequence identity (below 40%) compared to Plasmodium sequences. Prediction of alternative binding sites revealed potential druggable sites in PfArgRS, PfMetRS and PfProRS at regions that are weakly conserved when compared to the human homologues. Multiple sequence analysis, motif discovery, pairwise sequence identity calculations and phylogenetic tree analysis showed significant differences between parasite and human aaRSs proteins despite functional and structural conservation. These differences may provide a basis for further exploration of Plasmodium aminoacyl tRNA synthetases as potential drug targets.ConclusionThis study showed that, despite, functional and structural conservation, Plasmodium aaRSs have key differences from the human homologues. These differences in Plasmodium aaRSs can be targeted to develop anti-malarial drugs with less toxicity to the host.Electronic supplementary materialThe online version of this article (10.1186/s12936-019-2665-6) contains supplementary material, which is available to authorized users.

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“…Suramin was also proven to bind to recombinant falcipain-2 and to inhibit its cysteine protease activity, a key step in the hydrolysis of hemoglobin by this parasite during the erythrocytic stage of its life cycle [ 88 ]. Finally, suramin was shown to weakly inhibit P. falciparum diadenosine tetraphosphate hydrolase [ 89 ]. However, its nonspecific interactions and consequent toxicity hinder its use as an anti-plasmodial compound.…”

Section: Targeting the Liver Stage Of Plasmodium mentioning

confidence: 99%

Repurposing Drugs to Fight Hepatic Malaria Parasites

2020

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Malaria remains one of the most prevalent infectious diseases worldwide, primarily affecting some of the most vulnerable populations around the globe. Despite achievements in the treatment of this devastating disease, there is still an urgent need for the discovery of new drugs that tackle infection by Plasmodium parasites. However, de novo drug development is a costly and time-consuming process. An alternative strategy is to evaluate the anti-plasmodial activity of compounds that are already approved for other purposes, an approach known as drug repurposing. Here, we will review efforts to assess the anti-plasmodial activity of existing drugs, with an emphasis on the obligatory and clinically silent liver stage of infection. We will also review the current knowledge on the classes of compounds that might be therapeutically relevant against Plasmodium in the context of other communicable diseases that are prevalent in regions where malaria is endemic. Repositioning existing compounds may constitute a faster solution to the current gap of prophylactic and therapeutic drugs that act on Plasmodium parasites, overall contributing to the global effort of malaria eradication.

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Structural and functional attributes of malaria parasite diadenosine tetraphosphate hydrolase

Cited by 13 publications

References 57 publications

Metal ion coordination in the E. coli Nudix hydrolase dihydroneopterin triphosphate pyrophosphatase: New clues into catalytic mechanism

Metal ion coordination in the E. coli Nudix hydrolase dihydroneopterin triphosphate pyrophosphatase: New clues into catalytic mechanism

Aminoacyl tRNA synthetases as malarial drug targets: a comparative bioinformatics study

Repurposing Drugs to Fight Hepatic Malaria Parasites

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