Dissecting Apicoplast Targeting in the Malaria Parasite
            <i>Plasmodium falciparum</i>

Foth, Bernardo J.; Ralph, Stuart A.; Tonkin, Christopher J.; Struck, Nicole S.; Fraunholz, Martin; Roos, David S.; Cowman, Alan F.; McFadden, Geoffrey I.

doi:10.1126/science.1078599

Cited by 424 publications

(438 citation statements)

References 27 publications

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“…PDC located in the apicoplast [23]. The results indicate that PfLPD2 is the third component (E3 dihydrolipoamide dehydrogenase) of the PDC in Plasmodium species, in which the experimentally determined location of this enzyme in the plastid is also consistent with the bioinformatic analysis [24]. In this respect, Plasmodium seems to differ from other eukaryotes, most of which have PDCs located in mitochondria or, as is the case for plants and algae, in both mitochondria and plastids [18].…”

Section: Box 1 Relevant Linkssupporting

confidence: 67%

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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Section: Box 1 Relevant Linkssupporting

confidence: 67%

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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“…Richly et al, 2003) or sets of rules (Foth et al, 2003). As shown here, by combining different predictors, the reliability of predictions of chloroplast protein targeting can be improved substantially.…”

Section: Discussionmentioning

confidence: 84%

An improved prediction of chloroplast proteins reveals diversities and commonalities in the chloroplast proteomes of Arabidopsis and rice

Richly¹,

Leister²

2004

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164

144

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Proteins that form part of the chloroplast proteome can be identified by computational prediction of the N-terminal presequences (chloroplast transit peptides, cTPs) of their cytoplasmic precursor proteins. The accuracy of four different cTP predictors has been evaluated on a test set of 4500 proteins whose subcellular localization is known, and was found to be substantially lower than previously reported. A combination of cTP prediction programs was superior to any one of the predictors alone. This combination was employed to estimate the size and composition of the chloroplast proteomes of Arabidopsis and rice, and about 2,100 (Arabidopsis thaliana) and 4800 (Oryza sativa) different chloroplast proteins with a cTP are predicted to be encoded by their nuclear genomes. A subset of around 900 chloroplast proteins, predominantly derived from the cyanobacterial endosymbiont and with functions mostly related to metabolism, energy and transcription, is shared by the two species. This points to the existence of both conserved nucleus-encoded chloroplast proteins that are predominantly of prokaryotic origin, and a large fraction of taxon-specific chloroplast-targeted proteins, in flowering plants. D

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“…This organelle, similar to the mitochondrion, contains its own genome and is required for parasite survival (Fichera and Roos, 1997;McConkey et al, 1997). The apicoplast genome is only 35 kb in size and, as with the apicomplexan mitochondrion, many proteins functioning within the apicoplast are encoded in the nuclear genome and targeted post-translationally to the apicoplast (Wilson et al, 1996;Foth et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

GFP‐targeting allows visualization of the apicoplast throughout the life cycle of live malaria parasites

Stanway

Witt

Zobiak

et al. 2009

Biology of the Cell

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Background information. The Plasmodium parasite, during its life cycle, undergoes three phases of asexual reproduction, these being repeated rounds of erythrocytic schizogony, sporogony within oocysts on the mosquito midgut wall and exo-erythrocytic schizogony within the hepatocyte. During each phase of asexual reproduction, the parasite must ensure that every new daughter cell contains an apicoplast, as this organelle cannot be formed de novo and is essential for parasite survival. To date, studies visualizing the apicoplast in live Plasmodium parasites have been restricted to the blood stages of Plasmodium falciparum.Results. In the present study, we have generated Plasmodium berghei parasites in which GFP (green fluorescent protein) is targeted to the apicoplast using the specific targeting sequence of ACP (acyl carrier protein), which has allowed us to visualize this organelle in live Plasmodium parasites. During each phase of asexual reproduction, the apicoplast becomes highly branched, but remains as a single organelle until the completion of nuclear division, whereupon it divides and is rapidly segregated into newly forming daughter cells. We have shown that the antimicrobial agents azithromycin, clindamycin and doxycycline block development of the apicoplast during exo-erythrocytic schizogony in vitro, leading to impaired parasite maturation.Conclusions. Using a range of powerful live microscopy techniques, we show for the first time the development of a Plasmodium organelle through the entire life cycle of the parasite. Evidence is provided that interference with the development of the Plasmodium apicoplast results in the failure to produce red-blood-cell-infective merozoites.

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Dissecting Apicoplast Targeting in the Malaria Parasite Plasmodium falciparum

Cited by 424 publications

References 27 publications

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

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

An improved prediction of chloroplast proteins reveals diversities and commonalities in the chloroplast proteomes of Arabidopsis and rice

GFP‐targeting allows visualization of the apicoplast throughout the life cycle of live malaria parasites

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