The Sphingolipid Biosynthetic Pathway Is a Potential Target for Chemotherapy against Chagas Disease

Koeller, Carolina M.; Heise, Norton

doi:10.4061/2011/648159

Cited by 18 publications

(17 citation statements)

References 100 publications

(187 reference statements)

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“…With several enzymatic activities absent in mammals, T . cruzi produce some fatty acids that are typically found in much lower abundance in mammalian host cells [ 32 – 34 ]. An example is linoleic acid (C18:2 cis , cis- Δ 9,12 ) which, in a gas chromatography with flame ionization detection (GC-FID) analysis of the esterified FA content of total lipid pools is found to be highly enriched in isolated T .…”

Section: Resultsmentioning

confidence: 99%

Host triacylglycerols shape the lipidome of intracellular trypanosomes and modulate their growth

et al. 2017

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Intracellular infection and multi-organ colonization by the protozoan parasite, Trypanosoma cruzi, underlie the complex etiology of human Chagas disease. While T. cruzi can establish cytosolic residence in a broad range of mammalian cell types, the molecular mechanisms governing this process remain poorly understood. Despite the anticipated capacity for fatty acid synthesis in this parasite, recent observations suggest that intracellular T. cruzi amastigotes may rely on host fatty acid metabolism to support infection. To investigate this prediction, it was necessary to establish baseline lipidome information for the mammalian-infective stages of T. cruzi and their mammalian host cells. An unbiased, quantitative mass spectrometric analysis of lipid fractions was performed with the identification of 1079 lipids within 30 classes. From these profiles we deduced that T. cruzi amastigotes maintain an overall lipid identity that is distinguishable from mammalian host cells. A deeper analysis of the fatty acid moiety distributions within each lipid subclass facilitated the high confidence assignment of host- and parasite-like lipid signatures. This analysis unexpectedly revealed a strong host lipid signature in the parasite lipidome, most notably within its glycerolipid fraction. The near complete overlap of fatty acid moiety distributions observed for host and parasite triacylglycerols suggested that T. cruzi amastigotes acquired a significant portion of their lipidome from host triacylglycerol pools. Metabolic tracer studies confirmed long-chain fatty acid scavenging by intracellular T. cruzi amastigotes, a capacity that was significantly diminished in host cells deficient for de novo triacylglycerol synthesis via the diacylglycerol acyltransferases (DGAT1/2). Reduced T. cruzi amastigote proliferation in DGAT1/2-deficient fibroblasts further underscored the importance of parasite coupling to host triacylglycerol pools during the intracellular infection cycle. Thus, our comprehensive lipidomic dataset provides a substantially enhanced view of T. cruzi infection biology highlighting the interplay between host and parasite lipid metabolism with potential bearing on future therapeutic intervention strategies.

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Section: Resultsmentioning

confidence: 99%

Host triacylglycerols shape the lipidome of intracellular trypanosomes and modulate their growth

et al. 2017

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“…To find if the increase in fatty acid pools is accompanied by a change in the levels of enzymes related to fatty acid metabolism, we evaluated the specific activities of the enzymes hexokinase (HK), which is responsible for the initial step of glycolysis and an indicator of active glycolysis; acetyl-CoA carboxylase (ACC), which produces malonyl-CoA for fatty acid synthesis and carnitine palmitoyltransferase 1 (CPT1), the complex that plays a central role in fatty acid oxidation (FAO) by controlling the entrance of long-chain fatty acids into the mitochondria [30]. For the control, we selected the enzyme serine palmitoyltransferase 1 (SPT1), a constitutively expressed protein in T. cruzi [31] (Fig 7). The hexokinase activity diminished up to 30% with the progression of the proliferation curve and the correlated depletion of glucose (Fig 7A).…”

Section: Resultsmentioning

confidence: 99%

“…cruzi [31] (Fig 7). The hexokinase activity diminished up to 30% with the progression of the proliferation curve and the correlated depletion of glucose ( Fig 7A).…”

Section: Glucose Metabolism Represses the Fatty Acid Oxidation In Epimentioning

confidence: 99%

Fatty acid oxidation participates of the survival to starvation, cell cycle progression and differentiation in the insect stages ofTrypanosoma cruzi

Souza

Damasceno

Marsiccobetre

et al. 2021

Preprint

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During its complex life cycle, Trypanosoma cruzi colonizes different niches in its insect and mammalian hosts. This characteristic determined the types of parasites that adapted to face challenging environmental cues. The primary environmental challenge, particularly in the insect stages, is poor nutrient availability. These T. cruzi stages could be exposed to fatty acids originating from the degradation of the perimicrovillar membrane. In this study, we revisit the metabolic fate of fatty acid breakdown in T. cruzi. Herein, we show that during parasite proliferation, the glucose concentration in the medium can regulate the fatty acid metabolism. At the stationary phase, the parasites fully oxidize fatty acids. [U-14C]-palmitate can be taken up from the medium, leading to CO2 production via beta-oxidation. Lastly, we also show that fatty acids are degraded through beta-oxidation. Additionally, through beta-oxidation, electrons are fed directly to oxidative phosphorylation, and acetyl-CoA is supplied to the tricarboxylic acid cycle, which can be used to feed other anabolic pathways such as the de novo biosynthesis of fatty acids.Author SummaryTrypanosoma cruzi is a protist parasite with a life cycle involving two types of hosts, a vertebrate one (which includes humans, causing Chagas disease) and an invertebrate one (kissing bugs, which vectorize the infection among mammals). In both hosts, the parasite faces environmental challenges such as sudden changes in the metabolic composition of the medium in which they develop, severe starvation, osmotic stress and redox imbalance, among others. Because kissing bugs feed infrequently in nature, an intriguing aspect of T. cruzi biology (it exclusively inhabits the digestive tube of these insects) is how they subsist during long periods of starvation. In this work, we show that this parasite performs a metabolic switch from glucose consumption to lipid oxidation, and it is able to consume lipids and the lipid-derived fatty acids from both internal origins as well as externally supplied compounds. When fatty acid oxidation is chemically inhibited by etomoxir, a very well-known drug that inhibits the translocation of fatty acids into the mitochondria, the proliferative insect stage of the parasites has dramatically diminished survival under severe metabolic stress and its differentiation into its infective forms is impaired. Our findings place fatty acids in the centre of the scene regarding their extraordinary resistance to nutrient-depleted environments.

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“…CerSs exhibit differential preferences for the chain length of the acyl-CoA substrate (Park et al 2014 ) and its hydroxylation pattern (Layre & Moody, 2013 ), with 6 isoforms present in humans suggesting a different role for each CER species produced (Levy & Futerman, 2010 ; Figueiredo et al 2012 ). To-date, one or, maximum, two genes encoding CerS function have been identified in protozoan parasite species (Koeller & Heise, 2011 ). However, most interesting is the variation in the complex SL formed in the Golgi, reflecting significant differences in the active site of the SL synthases catalysing the transfer reaction.…”

Section: Sl Metabolismmentioning

confidence: 99%

Everybody needs sphingolipids, right! Mining for new drug targets in protozoan sphingolipid biosynthesis

Mina

Denny

2017

Parasitology

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The Sphingolipid Biosynthetic Pathway Is a Potential Target for Chemotherapy against Chagas Disease

Cited by 18 publications

References 100 publications

Host triacylglycerols shape the lipidome of intracellular trypanosomes and modulate their growth

Host triacylglycerols shape the lipidome of intracellular trypanosomes and modulate their growth

Fatty acid oxidation participates of the survival to starvation, cell cycle progression and differentiation in the insect stages ofTrypanosoma cruzi

Everybody needs sphingolipids, right! Mining for new drug targets in protozoan sphingolipid biosynthesis

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