Deciphering apicoplast targeting signals – feature extraction from nuclear-encoded precursors of Plasmodium falciparum apicoplast proteins

Zuegge, Jochen; Ralph, Stuart A.; Schmuker, Michael; McFadden, Geoffrey I.; Schneider, Gisbert

doi:10.1016/s0378-1119(01)00776-4

Cited by 207 publications

(175 citation statements)

References 28 publications

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“…Apicoplast targeting signals are characterized by a plastid transit peptide next to the SP. An algorithm developed to predict apicoplast targeting proteins based on the SP and an adjacent transit peptide (the PATs program 51 ) correctly predicts the plastid localizations of AZI1 family members and CAH1. How this targeting system works at the molecular level in higher plants will be an interesting topic for future work.…”

Section: Resultsmentioning

confidence: 99%

Arabidopsis AZI1 family proteins mediate signal mobilization for systemic defence priming

et al. 2015

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Priming is a major mechanism behind the immunological 'memory' observed during two key plant systemic defences: systemic acquired resistance (SAR) and induced systemic resistance (ISR). Lipid-derived azelaic acid (AZA) is a mobile priming signal. Here, we show that the lipid transfer protein (LTP)-like AZI1 and its closest paralog EARLI1 are necessary for SAR, ISR and the systemic movement and uptake of AZA in Arabidopsis. Imaging and fractionation studies indicate that AZI1 and EARLI1 localize to expected places for lipid exchange/movement to occur. These are the ER/plasmodesmata, chloroplast outer envelopes and membrane contact sites between them. Furthermore, these LTP-like proteins form complexes and act at the site of SAR establishment. The plastid targeting of AZI1 and AZI1 paralogs occurs through a mechanism that may enable/facilitate their roles in signal mobilization.

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Section: Resultsmentioning

confidence: 99%

Arabidopsis AZI1 family proteins mediate signal mobilization for systemic defence priming

et al. 2015

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“…In addition to a number of insertions that are distributed throughout the sequence, PFL1210w also carries an N-terminal extension that encodes a predicted signal peptide and a transmembrane domain. The PATS prediction program gives a high likelihood of apicoplast-targeting with a score of 0.996 (15). PFL1210w appears to be expressed at low levels in erythrocytic stages: mass spectrometry detected only one peptide of the large protein (16), and we could not detect fluorescence upon expressing the gene with a C-terminal GFP tag using the native promoter.…”

Section: Two Plasmodium Irss Localize To Distinct Compartments In Thementioning

confidence: 88%

Validation of isoleucine utilization targets in Plasmodium falciparum

Istvan

Dharia

Bopp

et al. 2011

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

126

141

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Intraerythrocytic malaria parasites can obtain nearly their entire amino acid requirement by degrading host cell hemoglobin. The sole exception is isoleucine, which is not present in adult human hemoglobin and must be obtained exogenously. We evaluated two compounds for their potential to interfere with isoleucine utilization. Mupirocin, a clinically used antibacterial, kills Plasmodium falciparum parasites at nanomolar concentrations. Thiaisoleucine, an isoleucine analog, also has antimalarial activity. To identify targets of the two compounds, we selected parasites resistant to either mupirocin or thiaisoleucine. Mutants were analyzed by genome-wide high-density tiling microarrays, DNA sequencing, and copy number variation analysis. The genomes of three independent mupirocin-resistant parasite clones had all acquired either amplifications encompassing or SNPs within the chromosomally encoded organellar (apicoplast) isoleucyl-tRNA synthetase. Thiaisoleucine-resistant parasites had a mutation in the cytoplasmic isoleucyl-tRNA synthetase. The role of this mutation in thiaisoleucine resistance was confirmed by allelic replacement. This approach is generally useful for elucidation of new targets in P. falciparum . Our study shows that isoleucine utilization is an essential pathway that can be targeted for antimalarial drug development.

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“…Because Rickettsia is regarded as the present-day species closest to the mitochondrial ancestor and because Synechocystis is closely related to plastid organelles, the result of the analysis suggests a separate origin for these two functionally equivalent proteins. In addition, PfLPD2 has a typical bipartite secretory-apicoplast signal peptide [PATS score 0.94/1.0, Box 1(v)] [16]. Both dihydrolipoamide dehydrogenase isoforms from P. falciparum have recently been characterized, substantiating the existence and functionality of the complexes in which these enzymes participate [17].…”

Section: Origin and Segregation Of Two Dihydrolipoamide Dehydrogenasesmentioning

confidence: 97%

A glycine-cleavage complex as part of the folate one-carbon metabolism of Plasmodium falciparum

Salcedo

Sims

Hyde

2005

Trends in Parasitology

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The glycine-cleavage complex (GCV) and serine hydroxymethyltransferase represent the two systems of one-carbon transfer that are employed in the biosynthesis of active folate cofactors in eukaryotes. Although the understanding of this area of metabolism in Plasmodium falciparum is still at an early stage, we discuss evidence that genes and transcription products of the GCV are present and expressed in this parasite. The potential role of the GCV and its relevance to the life cycle and pathogenesis of the malaria erythrocytic stages are also considered. According to its expression profile, the GCV seems to be particularly active in gametocytes. The GCV enzyme dihydrolipoamide dehydrogenase has two isoforms encoded by two different genes. It has been demonstrated recently that both genes are functional, with one of them identified as being part of a pyruvate dehydrogenase complex that is present exclusively in the apicoplast of Plasmodium species. The other isoform probably forms part of the Plasmodium GCV. The GCV is the first enzyme complex involved in folate metabolism in this parasite that can be assumed, with a good degree of certainty, to be located in the mitochondria. Synthesis and use of the one-carbon unit in folateThe glycine-cleavage complex (GCV) and serine hydroxymethyltransferase [SHMT, also called glycine hydroxymethyltransferase (EC 2.1.2.1)] form part of the folic acid biosynthesis pathway, generating one-carbon units from cleavage of the small amino acids glycine and serine, respectively. These one-carbon units are transferred onto folate coenzymes that carry and donate them, primarily for the synthesis of pyrimidines [e.g. thymidylate (5′-TMP)] and methionine in the malaria parasite [1]. SHMT can reversibly interconvert glycine and serine, and glycine itself is a precursor of the synthesis of glutathione, tryptophan and phospholipids in eukaryotes [2]. The importance of the ubiquitous GCV enzymatic complex is exemplified by its role in essential homeostatic processes. For instance, the synthesis of glutathione to maintain the redox balance of the erythrocyte plasma membrane needs an active but regulated glycine supply [3], the mitochondrial processing of high concentrations of phosphorespiration glycine in plants relies on plant GCVs [4], and a dys-functional GCV in humans caused by specific point mutations is related to an inherited condition known as nonketotic hyperglycinemia or glycine encephalopathy [5].Whereas serine, through the reaction catalysed by SHMT, is the main source of one-carbon units in the cytoplasm, glycine is equally relevant in the mitochondrion, and the GCV . The activation and use of folate depend on covalent linkage to a one-carbon unit -a byproduct of the balanced flux of carbon between serine and glycine -through SHMT and GCV, two independent but functionally related enzyme systems (Figure 1). The de novo production of fully reduced and glutamated (and, hence, functional) folate in Plasmodium falciparum is the result of the actions of six enzymatic activities...

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Deciphering apicoplast targeting signals – feature extraction from nuclear-encoded precursors of Plasmodium falciparum apicoplast proteins

Cited by 207 publications

References 28 publications

Arabidopsis AZI1 family proteins mediate signal mobilization for systemic defence priming

Arabidopsis AZI1 family proteins mediate signal mobilization for systemic defence priming

Validation of isoleucine utilization targets in Plasmodium falciparum

A glycine-cleavage complex as part of the folate one-carbon metabolism of Plasmodium falciparum

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