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  • Review Article
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Targeting lipid biosynthesis and salvage in apicomplexan parasites for improved chemotherapies

Nature Reviews Microbiology volume 11, pages 823–835 (2013)Cite this article

Subjects

Key Points

  • Apicomplexa infections are widespread, life-threatening and therapeutically challenging. They include malaria, toxoplasmosis and cryptosporidiosis.

  • Plasmodium spp., Toxoplasma gondii and Cryptosporidium spp. are obligate intracellular pathogens that multiply in a parasitophorous vacuole within mammalian cells. As rapidly dividing parasites, they meet their high demand for lipids through networks of synthesis and scavenging.

  • The lipids of these Apicomplexa differ from those of their mammalian hosts, and therefore their lipid biosynthetic pathways, such as the prokaryotic methylerythritol phosphate pathway that produces isoprenoid precursors, are unique. These parasite-specific pathways are key targets for the development of selective drugs. One of these drugs, fosmidomycin, is currently used in clinics to treat malaria.

  • These apicomplexan parasites are auxotrophic for several lipids, such as cholesterol and selected sphingolipids. They scavenge these lipids from their host using unique lipid-transporter systems, which deserve to be explored as potential drug targets.

  • Apicomplexa can store lipids such as cholesteryl esters using unique enzymes. Blocking cholesterol esterification is lethal for T. gondii.

  • Very little information exists on the lipid metabolism of Cryptosporidium spp. These parasites can prenylate proteins, but the source of their isoprenoid precursors is unknown. Furthermore, no studies on sphingolipid content or sources have been undertaken in Cryptosporidium spp.

Abstract

Apicomplexa are some of the most widespread and poorly controlled pathogens in the world. The metabolism of lipids in these parasites, which include Plasmodium spp., Toxoplasma gondii and Cryptosporidium spp., is essential for the production of infectious progeny and pathogen persistence in their mammalian hosts. Metabolic maps of apicomplexan lipid syntheses reveal auxotrophies for many lipid species, which force these parasites to meet their high demand for lipids through networks of both synthesis and scavenging. Here, I review the unique lipid biosynthetic enzymes and lipid transporter systems of Apicomplexa, focusing on isoprenoids, sphingolipids and cholesterol, and highlight promising chemotherapeutic targets in the lipid synthetic and salvage pathways.

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Figure 1: Isoprenoid precursor biosynthesis.
Figure 2: Isoprenoid biosynthetic pathways.
Figure 3: Sources of sphingolipids for Plasmodium spp. and Toxoplasma gondii.
Figure 4: Host cholesterol sources for Apicomplexa.

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Acknowledgements

I thank all former and current members of my laboratory for their scientific contributions highlighted in this Review. I am also grateful to J. Romano for editorial assistance and scientific comments and to A. Odom for discussions on sphingolipids in malaria. Finally, I acknowledge grants from the US National Institutes of Health and the American Heart Association.

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  1. Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, 21205, Maryland, USA

    Isabelle Coppens

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Glossary

Auxotrophies

The inability of an organism to synthesize particular organic compounds that are required for its growth, metabolism and reproduction.

Pyrophosphate

An ester of pyrophosphoric acid, such as isopentenyl pyrophosphate, geranyl pyrophosphate and farnesyl pyrophosphate.

Ubiquinones

Electron carriers and major components of the aerobic respiratory chains located in mitochondria.

Dolichols

Compounds that are composed of a chain of isoprene units of varying lengths and are found either free or phosphorylated in the membranes of the endoplasmic reticulum and Golgi apparatus. They play a part in the co-translational modification of proteins known as N-glycosylation.

Phytoene desaturase

One of the key enzymes in the carotenoid biosynthetic pathway that converts the colourless phytoene to coloured carotenoids. This enzyme is present in nearly all types of plastids in plants and is a target for herbicides, such as norflurazon.

Chitobiose core

A disaccharide made of two N-acetylglucosamines. N-linked oligosaccharides are attached to the amide nitrogen of asparagine in proteins, and the linkage occurs through a chitobiose core.

Parasitophorous vacuole

A specialized, membrane-bound compartment created by apicomplexan parasites at the interface between the host-cell cytosol and the parasite for their multiplication. The parasitophorous vacuole membrane contains numerous parasite proteins involved in its structural organization, nutrient acquisition and signalling.

Schizont

A multinucleate stage in the development of malaria parasites, producing a varied number of daughter merozoites. This process of reproduction is called schizogony.

Low-density lipoprotein particles

(LDL particles). Plasma lipoproteins involved in the transport of cholesterol from the liver to all of the body's tissues. They deliver cholesterol to cells through LDL receptor-mediated endocytosis, and intracellular cholesterol is used for membrane biogenesis and function. LDL particles are highly atherogenic.

High-density lipoprotein particles

(HDL particles). Plasma lipoproteins involved in collecting cholesterol from the body's tissues and transporting the lipid back to the liver for excretion into the bile. Cholesterol incorporated into HDL is expelled from liver cells by HDL receptors, such as scavenger receptor class B type I. HDL particles also transport cholesterol to steroidogenic organs for the synthesis of steroid hormones.

Micelles

Aggregates of surfactant molecules dispersed in a liquid colloid. In the intestine, micelles are made of monoglycerides and fatty acids that associate with bile salts and phospholipids. Dietary cholesterol is incorporated into micelles and taken up into enterocytes via the Niemann–Pick type C1-like 1 transporter.

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Coppens, I. Targeting lipid biosynthesis and salvage in apicomplexan parasites for improved chemotherapies. Nat Rev Microbiol 11, 823–835 (2013). https://doi.org/10.1038/nrmicro3139

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