Aminoacylation of Plasmodium falciparum tRNAAsn and Insights in the Synthesis of Asparagine Repeats

Filisetti, Denis; Théobald-Dietrich, Anne; Mahmoudi, Nassira; Rudinger-Thirion, Joëlle; Candolfi, Ermanno; Frugier, Magali

doi:10.1074/jbc.m113.522896

Cited by 26 publications

(29 citation statements)

References 58 publications

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“…Aminoacyl-tRNA synthetases (aaRSs) are ubiquitous enzymes that attach amino acids onto cognate tRNAs that eventually feed into protein translation [1]. The structure-function attributes of parasitic aaRSs have been under intense investigation lately [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17], and of 36 Plasmodium falciparum aaRSs several have been proposed as drug targets [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17]. The present enzyme in discussion-V. Jain Á A. Sharma Á M. Yogavel (&) Structural and Computational Biology Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi 110067, India e-mail: myogavel@yahoo.com prolyl-tRNA synthetase (PRS) is the latest in this regard [17,18].…”

Section: Introductionmentioning

confidence: 99%

Structural and functional analysis of the anti-malarial drug target prolyl-tRNA synthetase

Jain

Kikuchi

Oshima

et al. 2014

J Struct Funct Genomics

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Aminoacyl-tRNA synthetases (aaRSs) drive protein translation in cells and hence these are essential enzymes across life. Inhibition of these enzymes can halt growth of an organism by stalling protein translation. Therefore, small molecule targeting of aaRS active sites is an attractive avenue from the perspective of developing anti-infectives. Febrifugine and its derivatives like halofuginone (HF) are known to inhibit prolyl-tRNA synthetase of malaria parasite Plasmodium falciparum. Here, we present functional and crystallographic data on P. falciparum prolyl-tRNA synthetase (PfPRS). Using immunofluorescence data, we show that PfPRS is exclusively resident in the parasite cytoplasm within asexual blood stage parasites. The inhibitor HF interacts strongly with PfPRS in a non-competitive binding mode in presence or absence of ATP analog. Intriguingly, the two monomers that constitute dimeric PfPRS display significantly different conformations in their active site regions. The structural analyses presented here provide a framework for development of febrifugine derivatives that can seed development of new anti-malarials.

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Section: Introductionmentioning

confidence: 99%

Structural and functional analysis of the anti-malarial drug target prolyl-tRNA synthetase

Jain

Kikuchi

Oshima

et al. 2014

J Struct Funct Genomics

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“…This single-gene feature is an exception among eukaryotes, where tRNA genes are usually present in multiple copies. Discrepancies between codon use and expression levels of corresponding tRNAs were also observed in Plasmodium falciparum blood stages (2). These considerations raise the possibility that, under at least some conditions, the parasite may need an additional source of tRNAs and possibly rely on the import of exogenous tRNAs.…”

mentioning

confidence: 96%

Apicomplexa -specific tRip facilitates import of exogenous tRNAs into malaria parasites

Bour

Mahmoudi

Kapps

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The malaria-causing Plasmodium parasites are transmitted to vertebrates by mosquitoes. To support their growth and replication, these intracellular parasites, which belong to the phylum Apicomplexa, have developed mechanisms to exploit their hosts. These mechanisms include expropriation of small metabolites from infected host cells, such as purine nucleotides and amino acids. Heretofore, no evidence suggested that transfer RNAs (tRNAs) could also be exploited. We identified an unusual gene in Apicomplexa with a coding sequence for membrane-docking and structurespecific tRNA binding. This Apicomplexa protein-designated tRip (tRNA import protein)-is anchored to the parasite plasma membrane and directs import of exogenous tRNAs. In the absence of tRip, the fitness of the parasite stage that multiplies in the blood is significantly reduced, indicating that the parasite may need host tRNAs to sustain its own translation and/or as regulatory RNAs. Plasmodium is thus the first example, to our knowledge, of a cell importing exogenous tRNAs, suggesting a remarkable adaptation of this parasite to extend its reach into host cell biology.tRNA | Plasmodium | trafficking

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“…8A). These poly-KN tracks are often found in Plasmodium proteins and reflect the AT-rich genome of the parasite (48,49).…”

Section: Plasmodium Ankyrin-containing Acbd6 Protein Stimulates Pfnmtmentioning

confidence: 99%

ACBD6 protein controls acyl chain availability and specificity of the N-myristoylation modification of proteins

Soupène¹,

Kuypers²

2019

Journal of Lipid Research

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of pathogens such as parasitic protozoa, fungi, and viruses (5-12). N-Myristoylation is a multistep process initiated by the binding of myristoyl-CoA to the N-terminal domain of apo-NMT, covalent linkage of the myristoyl chain to the glycine residue, and release of CoA, followed by the final release of the acyl peptide. In retinal photoreceptor cells, C 14:1 and C 14:2 rather than C 14:0 are the fatty acids used to modify proteins such as the -subunit of the G-protein photoreceptor (13-15). While the 14-carbon chain is the preferred substrate, NMT proteins lack binding specificity for C 14-CoA. This renders NMT incapable of preventing the unwarranted occupation of the site by acyl-CoA species other than C 14-CoA (4-6, 10, 13). Because the transfer rate of acyl chains with a length other than C 14 is extremely slow, binding of the "wrong" acyl-CoA blocks the myristoyltransferase cycle for NMT enzymes. In the cell, the greater abundance of acyl-CoAs such as C 16-CoA compared with C 14-CoA would therefore prevent protein myristoylation. It follows that mechanisms that prevent binding or trigger the release of these nontransferable competitors from the myristoyl-CoA binding site are essential in supporting NMT enzyme activity. Acyl-CoA binding domain-containing (ACBD) proteins are involved in the maintenance of diverse cellular functions. They interact with a multitude of proteins and can be located in the cytosol, organelles, or nucleus; bound to membranes; or secreted (16, 17). This protein family regulates processes as diverse as neural stem-cell self-renewal, protein and lipid acylation, lipid homeostasis, intracellular vesicle trafficking, organelle formation, viral replication, and apoptotic response (18-35). Plant ACBD proteins are also implicated in essential functions such as embryogenesis and resistance to various stresses (36-38). Acyl-CoAs

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Aminoacylation of Plasmodium falciparum tRNAAsn and Insights in the Synthesis of Asparagine Repeats

Cited by 26 publications

References 58 publications

Structural and functional analysis of the anti-malarial drug target prolyl-tRNA synthetase

Structural and functional analysis of the anti-malarial drug target prolyl-tRNA synthetase

Apicomplexa -specific tRip facilitates import of exogenous tRNAs into malaria parasites

ACBD6 protein controls acyl chain availability and specificity of the N-myristoylation modification of proteins

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