Erythrocytic Casein Kinase II Regulates Cytoadherence of Plasmodium falciparum-infected Red Blood Cells

Hora, Rachna; Bridges, Daniel J.; Craig, Alister G.; Sharma, Amit

doi:10.1074/jbc.m809756200

Cited by 40 publications

(35 citation statements)

References 37 publications

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“…These include cell surface receptors, nucleosome assembly factors, fatty acid binders and kinases [48][49][50][51]. The malaria parasite tRNA synthetase family drives protein translation in the three cellular compartments of mitochondria, apicoplast and Fig.…”

Section: Discussionmentioning

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: Discussionmentioning

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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“…The Plasmodium falciparum 3D7 strain was cultured in 96-well plates and synchronized at the ring stage using sorbitol. At ϳ1% parasitemia and 2% hematocrit levels, the compounds were incubated for 48 h with parasite cultures, and the mixtures were assayed by the SYBR green I DNA staining method, as described previously (36,37). After 48 h, 100 l SYBR green dye at 1ϫ concentration in lysis buffer supplemented with 0.1% saponin was added to each well.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of Protein Synthesis and Malaria Parasite Development by Drug Targeting of Methionyl-tRNA Synthetases

Hussain

Yogavel

Sharma

2015

Antimicrob Agents Chemother

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Aminoacyl-tRNA synthetases (aaRSs) are housekeeping enzymes that couple cognate tRNAs with amino acids to transmit genomic information for protein translation. The Plasmodium falciparum nuclear genome encodes two P. falciparum methionyl-tRNA synthetases (PfMRS), termed PfMRS cyt and PfMRS api . Phylogenetic analyses revealed that the two proteins are of primitive origin and are related to heterokonts (PfMRS cyt ) or proteobacteria/primitive bacteria (PfMRS api ). We show that PfMRS cyt localizes in parasite cytoplasm, while PfMRS api localizes to apicoplasts in asexual stages of malaria parasites. Two known bacterial MRS inhibitors, REP3123 and REP8839, hampered Plasmodium growth very effectively in the early and late stages of parasite development. Small-molecule drug-like libraries were screened against modeled PfMRS structures, and several "hit" compounds showed significant effects on parasite growth. We then tested the effects of the hit compounds on protein translation by labeling nascent proteins with 35 S-labeled cysteine and methionine. Three of the tested compounds reduced protein synthesis and also blocked parasite growth progression from the ring stage to the trophozoite stage. Drug docking studies suggested distinct modes of binding for the three compounds, compared with the enzyme product methionyl adenylate. Therefore, this study provides new targets (PfMRSs) and hit compounds that can be explored for development as antimalarial drugs. P lasmodium falciparum is the most virulent form of Plasmodium and a causative agent of malaria. The World Health Organization (WHO) estimates that there are ϳ0.62 million deaths due to malaria per year (1). The P. falciparum genome is AT-rich (81%) and codes for ϳ5,300 proteins, with unusual distributions of several residues (2). Almost 60% of encoded proteins appear to be unique to the parasite, reflecting great evolutionary distance between the parasite and the genomes of known eukaryotes (3). The malaria parasite (and the related apicomplexan Toxoplasma gondii) has three translationally active compartments, i.e., cytoplasm, apicoplasts, and mitochondria (4-8). All malaria parasite proteins involved in the protein synthesis machinery are encoded by the nuclear genome. Either these proteins are transported to target organelles or their modified/activated substrates are transported across the organelles to perform required functions (4-9). The primary enzymes responsible for translating genetic code into polypeptide chains are aminoacyl-tRNA synthetases (aaRSs). The canonical function of aaRSs is to ligate a specific amino acid to its cognate tRNA, which is then employed in protein synthesis. The aaRSs are an ancient class of essential enzymes, and their catalytic domains are conserved in all kingdoms (bacteria, archaebacteria, and eukaryotes). On the basis of catalytic domain architecture, aaRSs are classified into two categories, with each class containing ϳ10 aaRSs (10). Although aaRSs perform the basic function of charging tRNA molecules for protein synthesis, a...

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“…[112][113][114][115][116] In particular, the erythrocytic casein kinase II has been associated with the regulation of plasmodium falciparum infected red blood cells cytoadherence. 117,118 6. PK CK2 activity is associated with the proliferative status of several tumor cells.…”

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confidence: 99%

How druggable is protein kinase CK2?

2009

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CK2 is a pleiotropic, ubiquitous, and constitutively active protein kinase (PK), with both cytosolic and nuclear localization in most mammalian cells. The holoenzyme is generally composed of two catalytic (alpha and/or alpha') and two regulatory (beta) subunits, but the free alpha/alpha' subunits are catalytically active by themselves and can be present in cells under some circumstances. CK2 catalyzes the phosphorylation of more than 300 substrates characterized by multiple acidic residues surrounding the phosphor-acceptor amino acid, and, consequently, it plays a key role in several physiological and pathological processes. But how can one kinase orchestrate all these tasks faithfully? How is it possible that one kinase can, despite all pleiotropic characteristics of PKs in general, be involved in so many different biochemical events? Is CK2 a druggable target? Several questions are still to be clearly answered, and this review is an occasion for a fruitful discussion.

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Erythrocytic Casein Kinase II Regulates Cytoadherence of Plasmodium falciparum-infected Red Blood Cells

Cited by 40 publications

References 37 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

Inhibition of Protein Synthesis and Malaria Parasite Development by Drug Targeting of Methionyl-tRNA Synthetases

How druggable is protein kinase CK2?

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