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Review
. 2013 Oct;52(4):488-512.
doi: 10.1016/j.plipres.2013.06.003. Epub 2013 Jul 1.

Lipid synthesis in protozoan parasites: a comparison between kinetoplastids and apicomplexans

Srinivasan Ramakrishnan  1 , Mauro Serricchio, Boris Striepen, Peter Bütikofer
Affiliations
Review

Lipid synthesis in protozoan parasites: a comparison between kinetoplastids and apicomplexans

Srinivasan Ramakrishnan et al. Prog Lipid Res. 2013 Oct.

Abstract

Lipid metabolism is of crucial importance for pathogens. Lipids serve as cellular building blocks, signalling molecules, energy stores, posttranslational modifiers, and pathogenesis factors. Parasites rely on a complex system of uptake and synthesis mechanisms to satisfy their lipid needs. The parameters of this system change dramatically as the parasite transits through the various stages of its life cycle. Here we discuss the tremendous recent advances that have been made in the understanding of the synthesis and uptake pathways for fatty acids and phospholipids in apicomplexan and kinetoplastid parasites, including Plasmodium, Toxoplasma, Cryptosporidium, Trypanosoma and Leishmania. Lipid synthesis differs in significant ways between parasites from both phyla and the human host. Parasites have acquired novel pathways through endosymbiosis, as in the case of the apicoplast, have dramatically reshaped substrate and product profiles, and have evolved specialized lipids to interact with or manipulate the host. These differences potentially provide opportunities for drug development. We outline the lipid pathways for key species in detail as they progress through the developmental cycle and highlight those that are of particular importance to the biology of the pathogens and/or are the most promising targets for parasite-specific treatment.

Keywords: ACC; ACP; Apicomplexa; CDP-choline/ethanolamine:diacylglycerol phosphotransferase; CDP-ethanolamine:diacylglycerol phosphotransferase; CEPT; CL; Drugs; EPC; EPT; ER; FAE; FASI; FASII; Fatty acid synthesis; GPI; IPC; Kinetoplastida; MSP1; MUFAs; PC; PE; PG; PGP; PI; PKS; PS; PUFAs; Phospholipid synthesis; Protozoa; RNA interference; RNAi; SCD; SM; TS; acetyl-CoA carboxylase; acyl carrier protein; cardiolipin; endoplasmic reticulum; ethanolamine phosphorylceramide; fatty acid elongation; fatty acid synthase type I; fatty acid synthase type II; glycosylphosphatidylinositol; inositol phosphorylceramide; merozoite surface protein-1; monounsaturated fatty acids; phosphatidylcholine; phosphatidylethanolamine; phosphatidylglycerol; phosphatidylglycerophosphate; phosphatidylinositol; phosphatidylserine; polyketide synthase; polyunsaturated fatty acids; sphingomyelin; stearoyl-CoA desaturase; thiastearates.

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Figures

Figure 1
Figure 1. Three mechanisms of fatty acid synthesis
A, All fatty acid synthesis mechanisms follow a similar sequence of enzymatic reactions. A starter molecule is transferred to the phosphopantetheinyl group on ACP or CoA. The starter is then elongated by two carbon atoms and involving a four-reaction mechanism: decarboxylative condensation with a malonyl group by a synthase, reduction by a ketoreductase, dehydration by a dehydratase and reduction by an enoyl reductase. The product is released, or condensation with another malonyl group initiates the next round of elongation. B, Fatty acid synthase type I. All enzymes are domains of a single polypeptide (note that the apicomplexan FASI has a more complex multimodular architecture). C, Fatty acid synthase type II. All enzymes are encoded as individual proteins. D, Fatty acid elongation pathway. The system consists of enzymes encoded as individual proteins, acting on a CoA-bound starter molecule–typically a longer fatty acid (16 carbon or longer). ACP, acyl carrier protein; CoA, Coenzyme-A; FASI, fatty acid synthase type I pathway; FASII, fatty acid synthase type II pathway; FAE, fatty acid elongation pathway.
Figure 2
Figure 2. Apicomplexans can acquire fatty acids through a complex network of synthesis and uptake
A, T. gondii is shown as a representative apicomplexan parasite (pink) and intracellular pathogen capable of fatty acid and lipid salvage from the host cell (blue). This process can intersect host cell import as well as synthesis routes. B, In addition, the parasite harbors three fatty acid synthesis pathways that are localized to different cellular compartments. C, Apicoplast (green)-localized FASII pathway produces significant amounts of myristic and palmitic acid, in addition to lipoic acid relying on cytoplasmic glycolysis for precursors. E, Apicomplexan parasites also maintain an ER-associated elongase system that synthesizes very long chain monounsaturated fatty acids, subsequently using the activity of ELO-B and ELO-C. D, Apicomplexan FASI remains largely uncharacterized. Its stage-specific expression pattern and localization are not established. It is also unclear whether this megasynthase synthesizes fatty acids de novo, like the FASI of humans, or acts as an elongase for saturated fatty acids, as demonstrated for FASI of C. parvum. Major products are highlighted in red. Des, desaturase; PEP, phosphoenolpyruvate; Mal, malonate; Ac, acetate; vlcFA, very long chain fatty acids; Ac-CoA, acetyl-CoA; Mal-CoA, malonyl-CoA; ER, endoplasmic reticulum; KAS, ketoacyl-ACP synthase; KAR, ketoacyl-ACP reductase; HAD, hydroxyacyl-ACP dehydratase; EAR, enoyl-ACP reductase; ELO, elongase; KCR, ketoacyl-CoA reductase; DEH, acyl-CoA dehydratase; ECR, enoyl-CoA reductase. Other abbreviations are as in the legend of Fig. 1. Reproduced with minor modifications from [74].
Figure 3
Figure 3. Kinetoplastid fatty acid synthesis occurs in the mitochondrion and the ER
Kinetoplastids obtain fatty acids using synthesis and import mechanisms. A, Kinetoplastid parasites replicate extracellularly in the bloodstream of the mammalian host, red blood cells are also shown (red). B, Additionally, the parasite harbors two mechanisms of fatty acid synthesis that are localized in two different organelles (redrawn in part after [323]). C, A FASII pathway localizes to the mitochondrion (light violet), where it is required for the synthesis of lipoic acid and palmitic acid. D, Kinetoplastid parasites also harbor an ER-localized fatty acid elongase system. Unlike all other organisms, kinetoplastid FAE is used for de novo synthesis of fatty acids. The kinetoplastid FAE uses butyrate and malonate as substrates to generate myristate/stearate and adrenate as products. Major products are highlighted in red. Mal, malonate; Ac, acetate. Other abbreviations are as in the legend of Fig. 2.
Figure 4
Figure 4. Phospholipid synthesis pathways in kinetoplastids and apicomplexans
Schematic overview on the major pathways for phospholipid synthesis in kinetoplastid and apicomplexan parasites. Metabolites taken up from the environment appear in a black box, major phospholipid classes are indicated by a green circle. 3KSR, 3-ketosphinganine reductase; CDS, cytidine diphosphate diacylglycerol synthase; CEPT, choline/ethanolamine phosphotransferase; CK, choline kinase; CLS, cardiolipin synthase; CT, choline-phosphate cytidylyltransferase; DAG, diacylglycerol; DHCD, dihydroceramide desaturase; DHCS, dihydroceramide synthase; EK, ethanolamine kinase; PMT, phosphoethanolamine N-methyltransferase; EPT, ethanolamine phosphotransferase; ET, ethanolamine-phosphate cytidylyltransferase; PEMT, PE N-methyltransferase; PGPP, PGP phosphatase; PGPS, PGP synthase; PIS, PI synthase; PSD, PS decarboxylase; PSS/PSS2, PS synthase/PS synthase-2; SAM, S-adenosyl methionine; SD, serine decarboxylase; SLS, sphingolipid synthase; SPL, sphingosine-1-phosphate lyase; SPT, serine palmitoyltransferase. * the substrate for prokaryotic-type CLS in protozoan parasites has not been confirmed experimentally.
Figure 5
Figure 5. Common and unique phospholipid synthesis pathways in kinetoplastids and apicomplexans
Schematic representation of lipid biosynthetic pathways that are common (black squares) or unique (colored squares) to selected apicomplexan and kinetoplastid parasites to indicate their potential as drug targets. The colored squares indicate experimental evidence of enzyme activity or the presence of a predicted gene in the genome of a given parasite species. The absence of a square indicates that no enzyme activity or candidate gene has been reported. Abbreviations are as in the legend of Fig. 4.
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