Trends in Parasitology
ReviewProtein translation in Plasmodium parasites
Section snippets
Plasmodium translation in the post-genomic era
Since the sequencing of the P. falciparum genome, and the complete or near-complete genome sequencing of a handful of other Plasmodium species, there have been tremendous advances in the characterization of the molecules governing host–pathogen interactions. Less striking has been the pursuit in Plasmodium species of one of the basic processes of life – the translation of RNA into protein. Perhaps the very centrality of this process to biology has made it a less attractive research topic in a
Three compartments, three translation machines?
Plasmodium, as do plants, algae, and the majority of other Apicomplexans, possesses three active compartments of translation: the cytosol, mitochondrion and a relic plastid termed the apicoplast (see Glossary) or apicomplexan plastid. Apicomplexans contain, therefore, a mixture of translation machinery, with eukaryotic components for cytosolic mRNA translation and prokaryotic-like components for mRNA translation in the mitochondria and apicoplast. The apicoplast is non-photosynthetic and
Amino acids
P. falciparum parasites have multiple means of obtaining amino acids for protein synthesis, but the most important for growth in vivo remain unclear. Of the 20 canonical amino acids, Plasmodium possesses biosynthetic pathways for Asn, Gln, Gly, Pro, Asp and Glu [14]. However, very low amounts of these amino acids are incorporated into Plasmodium proteins [15]. This limited capacity for de novo amino acid synthesis means that, during in vitro culture at least, to charge its own tRNAs Plasmodium
tRNA
Of the three Plasmodium genomes, nuclear, apicoplast and mitochondrial, only the first two encode tRNAs 3, 26, 27 and correspond to compartments in which translation has been demonstrated [5]. A total of 46 tRNA genes, coding for 45 tRNA isoacceptors (initiator and elongator tRNAMet are encoded by two different genes), are found in the nuclear genome whereas the apicoplast genome contains 35 genes encoding 26 tRNA isoacceptors. With the exception of the apicoplast initiator tRNAMet,
Control and regulation of translation
A large number of proteomic studies have examined individual life stages of Plasmodium, or compared transitions from one stage to another (reviewed in [65]). Although these studies show shifts in protein composition between stages or treatments, the lack of corresponding transcriptome analyses for the same parasites makes it unclear whether expression regulation takes place at the transcriptional, translational or post-translational levels. The earliest mRNA microarrays indicate that the timing
Drug targets
Translation is a longstanding and major focus for drug development in Plasmodium. The relevant enzymes in the apicoplast and mitochondria in particular are attractive targets for malaria chemotherapy due to their prokaryotic origin. The promise of anti-translation inhibitors as antimalarials is highlighted by the number of inhibitors of protein translation already used for the clinical treatment of malaria (Table 3), of which doxycycline is perhaps the most widely known. Despite its potency and
Unanswered questions
Plasmodium has three translationally active compartments, the nucleus, apicoplast and mitochondrion, each with distinct evolutionary origins. These origins are reflected in differing mechanisms controlling translation, presenting three separate biological stories, and three potential sets of targets for inhibition. Several aspects of these stories remain to be revealed: ribosomal proteins for each compartment are generally poorly annotated, and the recent structural elucidation of ribosomes in
Acknowledgments
The authors are funded by an European Union FP7 Collaborative Project Grant HEALTH-F3-2009-223024 – Mephitis. S.A.R. is funded by Australian Research Council Future fellowship FT0990350. The authors acknowledge and apologize to the authors of many important studies in this field whose findings had to be omitted or referred to only via review papers owing to space constraints.
Glossary
- Apicoplast
- non-photosynthetic plastid with its own circular genome, found in most Apicomplexa. Arose via secondary endosymbiosis.
- Cytosol
- the intracellular fluid found within cells, excluding that within membrane-bound organelles.
- Isoacceptors
- tRNAs that have different anticodons but are charged with the same amino acid.
- Mitochondrion
- endosymbiotic organelle with its own small mitochondrial chromosome. Generally plays a major role in energy conversion.
- Peptide exit tunnel
- the site, formed by proteins
References (95)
Protein synthesis in the plastid of Plasmodium falciparum
Protist
(1999)- et al.
Apicoplast translation, transcription and genome replication: targets for antimalarial antibiotics
Trends Parasitol.
(2008) The 6 kb element of Plasmodium falciparum encodes mitochondrial cytochrome genes
Mol. Biochem. Parasitol.
(1992)- et al.
Transport of the essential nutrient isoleucine in human erythrocytes infected with the malaria parasite Plasmodium falciparum
Blood
(2007) Methionine transport in the malaria parasite Plasmodium falciparum
Int. J. Parasitol.
(2011)Characterization of an eukaryotic peptide deformylase from Plasmodium falciparum
Arch. Biochem. Biophys.
(2001)Localization of organellar proteins in Plasmodium falciparum using a novel set of transfection vectors and a new immunofluorescence fixation method
Mol. Biochem. Parasitol.
(2004)Mitochondrial DNA of the human malarial parasite Plasmodium falciparum
Mol. Biochem. Parasitol.
(1988)Diversity and similarity in the tRNA world: overall view and case study on malaria-related tRNAs
FEBS Lett.
(2010)Low complexity regions behave as tRNA sponges to help co-translational folding of plasmodial proteins
FEBS Lett.
(2010)
Aminoacyl-tRNA synthetases: potential markers of genetic code development
Trends Biochem. Sci.
Mitochondrial tRNA import in Toxoplasma gondii
J. Biol. Chem.
Identification of nuclear encoded precursor tRNAs within the mitochondrion of Trypanosoma brucei
J. Biol. Chem.
Metabolism of D-aminoacyl-tRNAs in Escherichia coli and Saccharomyces cerevisiae cells
J. Biol. Chem.
D-Tyrosyl RNA: formation, hydrolysis and utilization for protein synthesis
J. Mol. Biol.
Ligand-bound structures provide atomic snapshots for the catalytic mechanism of D-amino acid deacylase
J. Biol. Chem.
The cytoplasmic ribosomal RNAs of Plasmodium spp
Parasitol. Today
Species-specific regulation and switching of transcription between stage-specific ribosomal RNA genes in Plasmodium berghei
J. Biol. Chem.
Functional equivalence of structurally distinct ribosomes in the malaria parasite, Plasmodium berghei
J. Biol. Chem.
Have malaria parasites three genomes?
Parasitol. Today
The Plasmodium falciparum 6 kb element is polycistronically transcribed
Mol. Biochem. Parasitol.
Characterization of human malaria parasite Plasmodium falciparum eIF4E homologue and mRNA 5’ cap status
Mol. Biochem. Parasitol.
Isolation and functional characterization of eIF4F components and poly(A)-binding protein from Plasmodium falciparum
Parasitol. Int.
Modification of eukaryotic initiation factor 5A from Plasmodium vivax by a truncated deoxyhypusine synthase from Plasmodium falciparum: An enzyme with dual enzymatic properties
Bioorg. Med. Chem.
Translation initiation factor eIF-5A from Plasmodium falciparum
Mol. Biochem. Parasitol.
Interaction of apicoplast-encoded elongation factor (EF) EF-Tu with nuclear-encoded EF-Ts mediates translation in the Plasmodium falciparum plastid
Int. J. Parasitol.
Analysis of the role of the Shine–Dalgarno sequence and mRNA secondary structure on the efficiency of translational initiation in the Euglena gracilis chloroplast atpH mRNA
J. Biol. Chem.
Proteomes and transcriptomes of the Apicomplexa – where's the message?
Int. J. Parasitol.
The effects of anti-bacterials on the malaria parasite Plasmodium falciparum
Mol. Biochem. Parasitol.
Antibiotic inhibitors of organellar protein synthesis in Plasmodium falciparum
Protist
Activity of fusidic acid against Plasmodium falciparum in vitro
Lancet
Thiostrepton binds to malarial plastid rRNA
FEBS Lett.
In vitro efficacy, resistance selection, and structural modeling studies implicate the malarial parasite apicoplast as the target of azithromycin
J. Biol. Chem.
The sensitivity of Plasmodium protein synthesis to prokaryotic ribosomal inhibitors
Mol. Biochem. Parasitol.
Inhibition of mitochondrial and plastid activity of Plasmodium falciparum by minocycline
FEBS Lett.
Tropical infectious diseases: metabolic maps and functions of the Plasmodium falciparum apicoplast
Nat. Rev. Microbiol.
Mitochondrial evolution and functions in malaria parasites
Annu. Rev. Microbiol.
Genome sequence of the human malaria parasite Plasmodium falciparum
Nature
Nuclear-encoded proteins target to the plastid in Toxoplasma gondii and Plasmodium falciparum
Proc. Natl. Acad. Sci. U.S.A.
The apicoplast of Plasmodium falciparum is translationally active
Mol. Microbiol.
Targeting the transcriptional and translational machinery of the endosymbiotic organelle in apicomplexans
Curr. Drug Targets
Identification of additional rRNA fragments encoded by the Plasmodium falciparum 6 kb element
Nucl. Acids Res.
Plasmodium chabaudi chabaudi malaria parasites can develop stable resistance to atovaquone with a mutation in the cytochrome b gene
Malariol. J.
Specific role of mitochondrial electron transport in blood-stage Plasmodium falciparum
Nature
Ultrastructure and function of mitochondria in gametocytic stage of Plasmodium falciparum
Parasite
Retention and loss of amino acid biosynthetic pathways based on analysis of whole-genome sequences
Eukaryot. Cell
Carbon dioxide fixation in malaria (Plasmodium iophurae)
Nature
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These authors contributed equally to this work.