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  • Review Article
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Tropical infectious diseases

Metabolic maps and functions of the Plasmodium falciparum apicoplast

Key Points

  • Identification of apicoplast-targeted proteins

    Proteins that function in the apicoplast must be targeted back to the organelle, which is accomplished by means of a bipartite leader sequence. Bioinformatic tools and their use to find the complement of apicoplast proteins are described.

  • Apicoplast function

    The apicoplast is indispensable for parasite replication and continued infection of host cells. Investigating proteins that are produced by, or function in, the apicoplast could generate answers to the questions surrounding the function of the apicoplast.

  • Apicoplast metabolic networks

    The networks of pathways in the apicoplast have been reconstructed using bioinformatics and comparisons with plant and bacterial metabolic pathways. Many of the pathways that have been detected are involved in lipid or lipid-related functions, which might reveal apicoplast-specific functions that make this plastid essential.

  • Carbon and energy requirements

    The apicoplast is non-photosynthetic, so how does it obtain energy, reducing powew and components, particularly carbon, for anabolic syntheses? Possible pathways based on reconstructed metabolic networks are reviewed.

  • Isopentenyl diphosphate synthesis

    A complete virtual pathway of plastid isoprenoid synthesis has been assembled which provides a starting point for future biochemical verification. This pathway is important for synthesis of prosthetic groups.

  • Fatty-acid synthesis

    The dogma that parasites lack de novo fatty-acid synthesis has been challenged by the discovery and characterization of several Plasmodium falciparum fatty-acid-synthesis enzymes. A complete biosynthetic pathway for lipids in the apicoplast is described.

  • Haem biosynthesis

    How does the malaria parasite, an organism with a plastid but no ability to synthesize chlorophyll, obtain haem? The authors reconstruct pathways to haem biosynthesis and speculate that the apicoplast and the mitochondrion, which co-localize in the parasite cell, exhange substrates to produce haem.

Abstract

Discovery of a relict chloroplast (the apicoplast) in malarial parasites presented new opportunities for drug development. The apicoplast – although no longer photosynthetic – is essential to parasites. Combining bioinformatics approaches with experimental validation in the laboratory, we have identified more than 500 proteins predicted to function in the apicoplast. By comparison with plant chloroplasts, we have reconstructed several anabolic pathways for the parasite plastid that are fundamentally different to the analogous pathways in the human host and are potentially good targets for drug development. Products of these pathways seem to be exported from the apicoplast and might be involved in host-cell invasion.

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Figure 1: Flowchart for the identification of apicoplast-targeted proteins.
Figure 2: Classification of genes encoding predicted apicoplast-targeted proteins.
Figure 3: Overview of apicoplast metabolism and pathways.
Figure 4: Apicoplast fatty-acid and isopentenyl diphosphate biosynthesis.
Figure 5: A model for Plasmodium falciparum haem biosynthesis.
Figure 6: Intimate association between apicoplasts (green; GFP) and mitochondria (red; Mitotracker dye) in two infected erythrocytes.

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Acknowledgements

G.G.v.D. and R.F.W. were supported by Australian Postgraduate Awards during this work. S.A.R. and C.J.T. were supported by Melbourne Research Scholarships, and B.J.F. was supported by a Melbourne International Research Scholarship. G.I.M. is supported by a HHMI International Scholar Grant and an ARC Professorial Fellowship. M.F. was supported by a fellowship from the Deutsche Forschungsgemeinschaft. M.J.C. was supported by a postdoctoral fellowship from the National Institutes of Health (NIH). D.S.R. was supported by grants from the NIH and scholar awards from the Burroughs Wellcome Fund and the Ellison Medical Foundation. Support from the Australian Research Council and a Program grant from the National Health and Medical Research Council are gratefully acknowledged.

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DATABASES

Entrez

Plasmodium

Toxoplasma

Infectious Disease Information

Malaria

SwissProt

PPT

FURTHER INFORMATION

ApiESTDB

Medicines for Malaria Venture

PlasMit

Plasmodium genome sequencing project

SignalP

Toxoplasma genome resource

Geoff McFadden's laboratory

David Roos' laboratory

Glossary

BIPARTITE LEADER

A protein targeting segment characteristic of secondary endosymbiotic plastids, consisting of a hydrophobic signal peptide followed by a basic transit peptide.

ENDOMEMBRANE

The intracellular membrane system of a eukaryotic cell, comprising the endoplasmic reticulum, the Golgi apparatus, lysosomes and the plasma membrane. These membrane systems are interconnected by a flow of membrane from one to another using small membrane vesicles.

ARTIFICIAL NEURAL NETWORK

(ANN). An information processing system that is loosely modelled on the organization of the humain brain, and which possesses highly interconnected processing elements. ANNs are often useful for forming a model on the basis of a complex population of examples where no algorithm or descriptive rule exists.

PARASITOPHOROUS VACUOLE

During invasion of the host cell, the parasite initiates the formation of a membrane — the parasitophorous vacuole — which surrounds the parasite, and is substantially different from other endomembranes and the phagolysosome membrane.

REDUCING POWER

The capacity of an electron carrier to donate electrons to another compound.

PRENYLATION

The addition to a protein of a chain that has been formed by the polymerization of two or more units of isopentenyl pyrophosphate. This attachment can be covalent or non-covalent and is normally found at the carboxy terminus of the protein chain. Signals for the prenylation of a given protein are normally found in the final 3–4 amino acids of that protein.

SHEMIN PATHWAY

The pathway by which δ-aminolevulanate (ALA) is synthesized from glycine and succinyl CoA in animals, yeast and purple photosynthetic bacteria. In plants and most bacteria ALA is made from glutamate by the C5 pathway.

PORPHOBILINOGEN

An intermediate in the biosynthesis of haem.

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Ralph, S., van Dooren, G., Waller, R. et al. Metabolic maps and functions of the Plasmodium falciparum apicoplast. Nat Rev Microbiol 2, 203–216 (2004). https://doi.org/10.1038/nrmicro843

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