“…In addition to targeting the apicoplast, thiostrepton has also been shown to act on the cytosolic proteasome [80] and has detectable effects on mitochondrial translation [81]. Thiostrepton is also able to partially lock P. falciparum mitochondrial EF-G onto surrogate E. coli ribosomes, an effect not observed with apicoplast EF-G [14]. Figure 4.Predicted interaction of thiostrepton with LSU rRNA and L11 of ribosomes of the P. falciparum apicoplast ( a ) and mitochondrion ( b ).…”
Apicomplexan protists such as Plasmodium and Toxoplasma contain a mitochondrion and a relic plastid (apicoplast) that are sites of protein translation. Although there is emerging interest in the partitioning and function of translation factors that participate in apicoplast and mitochondrial peptide synthesis, the composition of organellar ribosomes remains to be elucidated. We carried out an analysis of the complement of core ribosomal protein subunits that are encoded by either the parasite organellar or nuclear genomes, accompanied by a survey of ribosome assembly factors for the apicoplast and mitochondrion. A cross-species comparison with other apicomplexan, algal and diatom species revealed compositional differences in apicomplexan organelle ribosomes and identified considerable reduction and divergence with ribosomes of bacteria or characterized organelle ribosomes from other organisms. We assembled structural models of sections of Plasmodium falciparum organellar ribosomes and predicted interactions with translation inhibitory antibiotics. Differences in predicted drug–ribosome interactions with some of the modelled structures suggested specificity of inhibition between the apicoplast and mitochondrion. Our results indicate that Plasmodium and Toxoplasma organellar ribosomes have a unique composition, resulting from the loss of several large and small subunit proteins accompanied by significant sequence and size divergences in parasite orthologues of ribosomal proteins.
“…In addition to targeting the apicoplast, thiostrepton has also been shown to act on the cytosolic proteasome [80] and has detectable effects on mitochondrial translation [81]. Thiostrepton is also able to partially lock P. falciparum mitochondrial EF-G onto surrogate E. coli ribosomes, an effect not observed with apicoplast EF-G [14]. Figure 4.Predicted interaction of thiostrepton with LSU rRNA and L11 of ribosomes of the P. falciparum apicoplast ( a ) and mitochondrion ( b ).…”
Apicomplexan protists such as Plasmodium and Toxoplasma contain a mitochondrion and a relic plastid (apicoplast) that are sites of protein translation. Although there is emerging interest in the partitioning and function of translation factors that participate in apicoplast and mitochondrial peptide synthesis, the composition of organellar ribosomes remains to be elucidated. We carried out an analysis of the complement of core ribosomal protein subunits that are encoded by either the parasite organellar or nuclear genomes, accompanied by a survey of ribosome assembly factors for the apicoplast and mitochondrion. A cross-species comparison with other apicomplexan, algal and diatom species revealed compositional differences in apicomplexan organelle ribosomes and identified considerable reduction and divergence with ribosomes of bacteria or characterized organelle ribosomes from other organisms. We assembled structural models of sections of Plasmodium falciparum organellar ribosomes and predicted interactions with translation inhibitory antibiotics. Differences in predicted drug–ribosome interactions with some of the modelled structures suggested specificity of inhibition between the apicoplast and mitochondrion. Our results indicate that Plasmodium and Toxoplasma organellar ribosomes have a unique composition, resulting from the loss of several large and small subunit proteins accompanied by significant sequence and size divergences in parasite orthologues of ribosomal proteins.
“…These factors interact with the reduced and divergent ribosomes (Gupta et al ., ) of the parasite organelles. Initiation factors IF1 and IF3, elongation factors EF‐Tu, EF‐Ts and EF‐G and ribosome recycling factor RRF1 functioning in the apicoplast have been characterized recently and IF2, IF3, EF‐Tu, EF‐G and RRF2 have been identified for parasite mitochondrial translation (Biswas et al ., ; Jackson et al ., ; Johnson et al ., ; Gupta et al ., ; Haider et al ., ). Our results identify release factors that are critical for correct termination of organellar DNA‐encoded proteins in Plasmodium .…”
Section: Discussionmentioning
confidence: 99%
“…Investigations in the recent past have focused on nuclear‐encoded factors involved in the steps of translation initiation, elongation and ribosome recycling in Plasmodium organelles (Biswas et al ., ; Jackson et al ., ; Gupta et al ., ; Haider et al ., ). Intriguing features such as absence of a mitochondrial EF‐Ts (Biswas et al ., ), import of amino‐acylated tRNA by the mitochondrion (Pino et al ., ), comparable affinity of mitochondrial IF2 for Met‐RNA and fMet‐tRNA (Haider et al ., ), have been revealed in P. falciparum .…”
Correct termination of protein synthesis would be a critical step in translation of organellar open reading frames (ORFs) of the apicoplast and mitochondrion of the malaria parasite. We identify release factors (RFs) responsible for recognition of the UAA and UGA stop-codons of apicoplast ORFs and the sole UAA stop-codon that terminates translation from the three mitochondrial ORFs. A single nuclear-encoded canonical RF2, PfRF2Api , localizes to the apicoplast. It has a conserved tripeptide motif (SPF) for stop-codon recognition and is sufficient for peptidyl-tRNA hydrolysis (PTH) from both UAA and UGA. Two RF family proteins are targeted to the parasite mitochondrion; a canonical RF1, PfRF1Mit , with a variant codon-recognition motif (PxN instead of the conserved RF1 PxT) is the major peptidyl-hydrolase with specific recognition of the UAA codon relevant to mitochondrial ORFs. Mutation of the N residue of the PfRF1Mit PxN motif and two other conserved residues of the codon recognition domain lowers PTH activity from pre-termination ribosomes indicating their role in codon-recognition. The second RF imported by the mitochondrion is the non-canonical PfICT1 that functions as a dimer and mediates codon nonspecific peptide release. Our results help delineate a critical step in organellar translation in Plasmodium, which is an important target for anti-malarials.
“…Its displayed an in vitro anti-malarial activity against P. falciparum parasites at concentrations achievable by oral administration [109]. Two studies showed the effect of the elongation factor-G (EF-G) inhibitor on the translation apparatus of two malaria parasite organelles (the mitochondrion and the apicoplast) [110, 111]. Fusidic acid stalls the EF-G/GDP complex by binding to this complex immediately after GTP hydrolysis and by inhibiting a conformational change required for the release of the factor from the ribosome.…”
Section: Fusidic Acidmentioning
confidence: 99%
“…However, thiostrepton showed effects on mitochondrial protein synthesis [119]. Thiostrepton exerted action on mitochondrial EF-G [110]. This drug could be a candidate against malaria in the future; thus, its mechanism of action needs to be better documented.…”
Section: Thiopeptides: Thiostrepton and Nocathiacinmentioning
Malaria, a parasite vector-borne disease, is one of the most significant health threats in tropical regions, despite the availability of individual chemoprophylaxis. Malaria chemoprophylaxis and chemotherapy remain a major area of research, and new drug molecules are constantly being developed before drug-resistant parasites strains emerge. The use of anti-malarial drugs is challenged by contra-indications, the level of resistance of Plasmodium falciparum in endemic areas, clinical tolerance and financial cost. New therapeutic approaches are currently needed to fight against this disease. Some antibiotics that have shown potential effects on malaria parasite have been recently studied in vitro or in vivo intensively. Two families, tetracyclines and macrolides and their derivatives have been particularly studied in recent years. However, other less well-known have been tested or are being used for malaria treatment. Some of these belong to older families, such as quinolones, co-trimoxazole or fusidic acid, while others are new drug molecules such as tigecycline. These emerging antibiotics could be used to prevent malaria in the future. In this review, the authors overview the use of antibiotics for malaria treatment.
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