Plasmodium Apicoplast Gln-tRNAGln Biosynthesis Utilizes a Unique GatAB Amidotransferase Essential for Erythrocytic Stage Parasites

Mailu, Boniface M.; Li, Ling; Arthur, Jen; Nelson, Todd M.; Ramasamy, Gowthaman; Fritz‐Wolf, Karin; Becker, Katja; Gardner, Malcolm J.

doi:10.1074/jbc.m115.655100

Cited by 17 publications

(10 citation statements)

References 85 publications

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“…The presence of a plastidial version of Gln-tRNA synthetase in Euglena spp. is noteworthy, because plastids of different plant and algal groups lack this enzyme and instead rely on an alternative two-step process of Gln-tRNA synthesis inherited from the cyanobacterial progenitor of the plastid and mediated by Glu-tRNA synthetase and Glu-tRNA amidotransferase 35 , 36 . However, putative plastid-targeted glutaminyl-tRNA synthetases were recently found in diatoms and the cryptophyte Guillardia theta 37 , so plastids may be more diverse in their mechanism of Gln-tRNA synthesis than previously thought.…”

Section: Resultsmentioning

confidence: 99%

Peculiar features of the plastids of the colourless alga Euglena longa and photosynthetic euglenophytes unveiled by transcriptome analyses

Záhonová

Füssy

Birčák

et al. 2018

Sci Rep

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Euglenophytes are a familiar algal group with green alga-derived secondary plastids, but the knowledge of euglenophyte plastid function and evolution is still highly incomplete. With this in mind we sequenced and analysed the transcriptome of the non-photosynthetic species Euglena longa. The transcriptomic data confirmed the absence of genes for the photosynthetic machinery, but provided candidate plastid-localised proteins bearing N-terminal bipartite topogenic signals (BTSs) of the characteristic euglenophyte type. Further comparative analyses including transcriptome assemblies available for photosynthetic euglenophytes enabled us to unveil salient aspects of the basic euglenophyte plastid infrastructure, such as plastidial targeting of several proteins as C-terminal translational fusions with other BTS-bearing proteins or replacement of the conventional eubacteria-derived plastidial ribosomal protein L24 by homologs of archaeo-eukaryotic origin. Strikingly, no homologs of any key component of the TOC/TIC system and the plastid division apparatus are discernible in euglenophytes, and the machinery for intraplastidial protein targeting has been simplified by the loss of the cpSRP/cpFtsY system and the SEC2 translocon. Lastly, euglenophytes proved to encode a plastid-targeted homolog of the termination factor Rho horizontally acquired from a Lambdaproteobacteria-related donor. Our study thus further documents a substantial remodelling of the euglenophyte plastid compared to its green algal progenitor.

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Section: Resultsmentioning

confidence: 99%

Peculiar features of the plastids of the colourless alga Euglena longa and photosynthetic euglenophytes unveiled by transcriptome analyses

Záhonová

Füssy

Birčák

et al. 2018

Sci Rep

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“…A design involving intricate organization of the two domains enables allosteric activation of the GATase domain, coordination of the catalytic events and ammonia tunnelling in all GATs. The reactions catalysed by GATs are indispensable for various cellular functions, and hence, many GATs are being pursued as drug targets against cancer, infectious pathogens and towards development of herbicides [9][10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Helices on interdomain interface couple catalysis in the ATPPase domain with allostery inPlasmodium falciparumGMP synthetase

Shivakumaraswamy

Pandey

Ballut

et al. 2019

Preprint

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AbstractGMP synthetase catalyzes the substitution of the C2 oxo-group of the purine base in XMP with an amino-group generating GMP, the last step in the biosynthesis of GMP. This reaction involves a series of catalytic events that include hydrolysis of Gln generating ammonia in the glutamine amidotransferase (GATase) domain, activation of XMP to adenyl-XMP intermediate in the ATP pyrophosphatase (ATPPase) domain and reaction of ammonia with the intermediate to generate GMP. Inherent to the functioning of GMP synthetases is bidirectional domain crosstalk, which leads to allosteric activation of the GATase domain by substrates binding to the ATPPase domain, synchronization of the two catalytic events and tunnelling of ammonia from the GATase to the ATPPase domain. Herein, we have taken recourse to the analysis of structures of GMP synthetases, site-directed mutagenesis and, steady-state and transient kinetic assays on the Plasmodium falciparum enzyme to decipher the molecular basis of catalysis in the ATPPase domain and domain crosstalk. The results map the residues critical for catalysis in the ATPPase domain to the helices α11 and α12 that are located at the interdomain interface, and the lid-loop that follows α11. This apart, perturbing interdomain interactions involving residues on α11 and α12 impairs GATase activation. These results imply that this arrangement of helices at the domain interface with residues that play roles in ATPPase catalysis as well as domain crosstalk enables coupling ATPPase catalysis with GATase activation. Overall, the study enhances our understanding of GMP synthetases, which are drug targets in many infectious pathogens.

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“…These shared motifs show that these two proteins have a high sequence identity and may explain why plasmodium apicoplast GluRS mischarges glutamine specific tRNA with glutamate. In this case, glutamate is then changed to glutamine a reaction catalysed by glutamyl-tRNA amidotransferase enzyme [110,111].…”

Section: Resultsmentioning

confidence: 99%

Aminoacyl tRNA Synthetases as Malarial Drug Targets: A Comparative Bioinformatics Study

Nyamai

Bishop

2018

Preprint

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10Treatment of parasitic diseases has been challenging due to the development of drug 11 resistance by parasites, and thus there is need to identify new class of drugs and drug targets. 12 Protein translation is important for survival of plasmodium and the pathway is present in all 13 the life cycle stages of the plasmodium parasite. Aminoacyl tRNA synthetases are primary 14 enzymes in protein translation as they catalyse the first reaction where an amino acid is added 15 to the cognate tRNA. Currently, there is limited research on comparative studies of 16 aminoacyl tRNA synthetases as potential drug targets. The aim of this study is to understand 17 differences between plasmodium and human aminoacyl tRNA synthetases through 18 bioinformatics analysis. Plasmodium falciparum, P. fragile, P. vivax, P. ovale, P. knowlesi, 19 P. bergei, P. malariae and human aminoacyl tRNA synthetase sequences were retrieved from 20 UniProt database and grouped into 20 families based on amino acid specificity. Despite 21 functional and structural conservation, multiple sequence analysis, motif discovery, pairwise 22 sequence identity calculations and molecular phylogenetic analysis showed striking 23 differences between parasite and human proteins. Prediction of alternate binding sites 24 revealed potential druggable sites in PfArgRS, PfMetRS and PfProRS at regions that were 25 weakly conserved when compared to the human homologues. These differences provide a 26 basis for further exploration of plasmodium aminoacyl tRNA synthetases as potential drug 27 targets. 28 Keywords 29 Aminoacyl tRNA synthetases; motif analysis; phylogenetic tree calculations, homology 30 modelling 31 Abbreviations 32 aaRS, aminoacyl tRNA synthetases; RF, rossmann fold; CPI, connective peptide I; MSA, 33 multiple sequence alignment; CD, catalytic domain; ABD, anticodon binding domain 34 Introduction 35 Parasitic diseases like trypanosomiasis, malaria, leishmaniasis and filariasis affect millions of 36 people in the world yearly [1-4]. These diseases cause a remarkable burden in economic 37 development and health of affected countries and thus the need to come up with control and 38 prevention strategies. Currently, the main mode of prevention and treatment of these parasitic 39 diseases is by use of drugs as there are no approved vaccines in the market [5] . However, 40 most parasites have developed resistance against conventional drugs leading to the drugs 41 being ineffective [6,7]. Thus, there is need to develop new classes of drugs and to identify 42 drug targets to solve the shortcoming of drug resistance. Targeting housekeeping pathways 43 such as protein translation may help deal with drug resistance as they are important for the 44 survival of most parasites [8-10]. 45Plasmodium parasite causes malaria disease, which is a major public concern due to its high 46 mortality and morbidity rates [10,11]. There are five plasmodium species that cause malaria 47 in human, and these are Plasmodium falciparum (P. falciparum), Plasmodium vivax (P. 48 vivax), Pl...

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Plasmodium Apicoplast Gln-tRNAGln Biosynthesis Utilizes a Unique GatAB Amidotransferase Essential for Erythrocytic Stage Parasites

Cited by 17 publications

References 85 publications

Peculiar features of the plastids of the colourless alga Euglena longa and photosynthetic euglenophytes unveiled by transcriptome analyses

Peculiar features of the plastids of the colourless alga Euglena longa and photosynthetic euglenophytes unveiled by transcriptome analyses

Helices on interdomain interface couple catalysis in the ATPPase domain with allostery inPlasmodium falciparumGMP synthetase

Aminoacyl tRNA Synthetases as Malarial Drug Targets: A Comparative Bioinformatics Study

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