Fatty acid oxidation participates in resistance to nutrient-depleted environments in the insect stages of Trypanosoma cruzi

Trypanosoma cruzi , the parasite causing Chagas disease, is a digenetic flagellated protist that infects mammals (including humans) and reduviid insect vectors. Therefore, T . cruzi must colonize different niches in order to complete its life cycle in both hosts. This fact determines the need of adaptations to face challenging environmental cues. The primary environmental challenge, particularly in the insect stages, is poor nutrient availability. In this regard, it is well known that T . cruzi has a flexible metabolism able to rapidly switch from carbohydrates (mainly glucose) to amino acids (mostly proline) consumption. Also established has been the capability of T . cruzi to use glucose and amino acids to support the differentiation process occurring in the insect, from replicative non-infective epimastigotes to non-replicative infective metacyclic trypomastigotes. However, little is known about the possibilities of using externally available and internally stored fatty acids as resources to survive in nutrient-poor environments, and to sustain metacyclogenesis. 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- 14 C]-palmitate can be taken up from the medium, leading to CO 2 production. Additionally, we show that electrons are fed directly to oxidative phosphorylation, and acetyl-CoA is supplied to the tricarboxylic acid (TCA) cycle, which can be used to feed anabolic pathways such as the de novo biosynthesis of fatty acids. Finally, we show as well that the inhibition of fatty acids mobilization into the mitochondrion diminishes the survival to severe starvation, and impairs metacyclogenesis.Voies métaboliques glycosomales non glycolytiques: nouvelles fonctions pour le développement et la virulence des trypanosomesInteractions métaboliques entre les adipocytes et les trypanosomes, un nouveau paradigme pour les trypanosomosesAlliance française contre les maladies parasitaire

The Trypanosoma cruzi TcrNT2 nucleoside transporter is a conduit for the uptake of 5-F-2’-deoxyuridine and tubercidin analogues

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Correction: How much (ATP) does it cost to build a trypanosome? A theoretical study on the quantity of ATP needed to maintain and duplicate a bloodstream-form Trypanosoma brucei cell

In the Abstract, the seventh sentence is incorrect. The correct sentence reads: Total biomass production (which involves biomass maintenance and duplication) accounts for ~63% of the total energy budget, while other ATP-dependent processes account for the remaining ~37% of the ATP consumption, with translation being the most expensive process. In the penultimate sentence in the final paragraph of the Introduction, the value “62%” should be “63%.” In the Results section, the fourth paragraph should be preceded by the subtitle “The cost of genome duplication.” The first sentence of the sub-section “Energy cost of sugar nucleotides used in the synthesis of the VSG coat” is incorrect. The correct sentence reads: In the BSF of T. brucei, the major surface protein is the VSG, which is highly glycosylated and linked to the membrane by GPI anchors. The seventh sentence of the sub-section “ATP requirement for transmembrane transport” is incorrect. The correct sentence reads: It is worth mentioning that Stouthamer did not consider the costs of taking up glucose, which could be relevant for many prokaryotes but not for BSF T. brucei where glucose transport happens by facilitated diffusion [115,116]. The penultimate sentence in the sub-section “How much ATP hydrolysis is required to maintain the mitochondrial inner membrane potential (ΔCm)?” is incorrect. The correct sentence reads: We hypothesize that this mitochondrial substrate-level phosphorylation system is the main source of intramitochondrial ATP, and it can provide sufficient ATP to maintain the ΔCm [22,157], despite its relatively low capacity for producing ATP [10]. In Table 11, the BSF Trypanosoma brucei “Total” value should be 6.00 x 1011. The seventeenth sentence of the third Discussion paragraph is incorrect. The correct sentence reads: As we considered 2 ATP molecules being spent per base polymerized, an average transcript length of 2,800 nt, and an average RNA synthesis of 1.2 RNAs/h (estimated in [51]) the estimated ATP expenditure for nuclear transcription is ~2.9 x 107 ATP molecules (0.5% of the total ATP expenditure for the completion of a cell cycle) (Fig 1, S5 Table). The fourth sentence of the fourth Discussion paragraph is incorrect. The correct sentence reads: Therefore, taken together, translation and protein turnover demand 59.6% of the ATP budget (Table 13). The penultimate sentence of the fourth Discussion paragraph is incorrect. The correct sentence reads: These calculations do not include the cost of the synthesis of sugar nucleotides used for the glycosylation of surface proteins (mostly VSGs) and anchoring. The ninth sentence of the seventh Discussion paragraph is incorrect. The correct sentence reads: To estimate the total percentage of the budget used for flagellar beating, we considered the highest value obtained, which resulted in the consumption of 9.5% of ATP produced (Table 13).</p

How much (ATP) does it cost to build a trypanosome? A theoretical study on the quantity of ATP needed to maintain and duplicate a bloodstream-form Trypanosoma brucei cell.

ATP hydrolysis is required for the synthesis, transport and polymerization of monomers for macromolecules as well as for the assembly of the latter into cellular structures. Other cellular processes not directly related to synthesis of biomass, such as maintenance of membrane potential and cellular shape, also require ATP. The unicellular flagellated parasite Trypanosoma brucei has a complex digenetic life cycle. The primary energy source for this parasite in its bloodstream form (BSF) is glucose, which is abundant in the host's bloodstream. Here, we made a detailed estimation of the energy budget during the BSF cell cycle. As glycolysis is the source of most produced ATP, we calculated that a single parasite produces 6.0 x 1011 molecules of ATP/cell cycle. Total biomass production (which involves biomass maintenance and duplication) accounts for ~63% of the total energy budget, while the total biomass duplication accounts for the remaining ~37% of the ATP consumption, with in both cases translation being the most expensive process. These values allowed us to estimate a theoretical YATP of 10.1 (g biomass)/mole ATP and a theoretical [Formula: see text] of 28.6 (g biomass)/mole ATP. Flagellar motility, variant surface glycoprotein recycling, transport and maintenance of transmembrane potential account for less than 30% of the consumed ATP. Finally, there is still ~5.5% available in the budget that is being used for other cellular processes of as yet unknown cost. These data put a new perspective on the assumptions about the relative energetic weight of the processes a BSF trypanosome undergoes during its cell cycle

Synthesis and biological evaluation of ( − )-13,14-dihydroxy-8,11,13-podocarpatrien-7-one and derivatives from (+)-manool

<div><p>13,14-Dihydroxy-8,11,13-podocarpatrien-7-one (<b>1</b>) and a series of ring C aromatic diterpene derivatives were synthesised from (+)-manool (<b>4</b>) and evaluated for their cytotoxic, leishmanicidal and trypanocidal activities. Our results indicated that compound <b>1</b> and other podocarpane-type intermediates are cytotoxic. Cleavage of C6–C7 bond of compound <b>7</b> improved cytotoxic activity, indicating that, in particular, the 6,7-<i>seco</i>-podocarpane-type compound <b>20</b> might serve as a lead compound for further development.</p></div