The characterization and evolutionary relationships of a trypanosomal thiolase

Mazet, Muriel; Harijan, R.K.; Kiema, Tiila Riika; Haapalainen, Antti M.; Morand, Pauline; Morales, Jorge; Bringaud, Frédéric; Wierenga, Rik K.; Michels, Paul A.M.

doi:10.1016/j.ijpara.2011.07.009

Cited by 17 publications

(21 citation statements)

References 55 publications

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“…The ASCT-SCS cycle part of the PDH:DHLD bypass pathway has been identified in trypanosomatids [48]. Further investigations are required to confirm the presence of this PDH:DHLD bypass pathway in Leishmania and to identify the putative thiolase but it is noteworthy that three different thiolases are encoded in the genome of Leishmania with at least one in the mitochondrion [49]. Alternatively, an acetyl-COA synthase (ACS in Figure 3) recently described in Leishmania [32] might be used to reconvert acetate to acetyl-CoA.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Proteomics of Antimony and Miltefosine Resistant Leishmania infantum

et al. 2015

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Antimony (SbIII) and miltefosine (MIL) are important drugs for the treatment of Leishmania parasite infections. The mitochondrion is likely to play a central role in SbIII and MIL induced cell death in this parasite. Enriched mitochondrial samples from Leishmania promastigotes selected step by step for in vitro resistance to SbIII and MIL were subjected to differential proteomic analysis. A shared decrease in both mutants in the levels of pyruvate dehydrogenase, dihydrolipoamide dehydrogenase, and isocitrate dehydrogenase was observed, as well as a differential abundance in two calcium-binding proteins and the unique dynamin-1-like protein of the parasite. Both mutants presented a shared increase in the succinyl-CoA:3-ketoacid-coenzyme A transferase and the abundance of numerous hypothetical proteins was also altered in both mutants. In general, the proteomic changes observed in the MIL mutant were less pronounced than in the SbIII mutant, probably due to the early appearance of a mutation in the miltefosine transporter abrogating the need for a strong mitochondrial adaptation. This study is the first analysis of the Leishmania mitochondrial proteome and offers powerful insights into the adaptations to this organelle during SbIII and MIL drug resistance.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial Proteomics of Antimony and Miltefosine Resistant Leishmania infantum

et al. 2015

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“…Here we show that threonine is the preferred carbon source for lipid biosynthesis, as previously proposed (Klein and Linstead, ), contributing to both the fatty acid and sterol biosynthetic pathways ∼ 2.5 times more than glucose contributes to the same pathways. This implies that it is degraded to acetyl‐CoA and acetate to feed the initial steps of sterol and fatty acid biosynthesis, which are respectively located in the mitochondrion (Carrero‐Lerida et al ., ; Mazet et al ., ) and the cytosol (Vigueira and Paul, ) (see Fig. ).…”

Section: Discussionmentioning

confidence: 99%

“…Thus, acetyl-CoA production and initiation of sterol biosynthesis take place in the same subcellular compartment; the first three steps of sterol biosynthesis from acetyl-CoA being catalysed by mitochondrial enzymes, i.e. thiolase, 3-hydroxy-3-methylglutary-CoA (HMG-CoA) synthetase and HMG-CoA reductase (Carrero-Lerida et al, 2009;Mazet et al, 2011). However, acetyl-CoA must be transferred from the mitochondrion to the cytosol to feed the first step of the fatty acid biosynthetic pathways catalysed by the cytosolic acetyl-CoA carboxylase (Vigueira and Paul, 2011).…”

Section: Discussionmentioning

confidence: 99%

The threonine degradation pathway of the Trypanosoma brucei procyclic form: the main carbon source for lipid biosynthesis is under metabolic control

Millerioux

Ebikeme

Biran

et al. 2013

Molecular Microbiology

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The Trypanosoma brucei procyclic form resides within the digestive tract of its insect vector, where it exploits amino acids as carbon sources. Threonine is the amino acid most rapidly consumed by this parasite, however its role is poorly understood. Here, we show that the procyclic trypanosomes grown in rich medium only use glucose and threonine for lipid biosynthesis, with threonine's contribution being ∼ 2.5 times higher than that of glucose. A combination of reverse genetics and NMR analysis of excreted end-products from threonine and glucose metabolism, shows that acetate, which feeds lipid biosynthesis, is also produced primarily from threonine. Interestingly, the first enzymatic step of the threonine degradation pathway, threonine dehydrogenase (TDH, EC 1.1.1.103), is under metabolic control and plays a key role in the rate of catabolism. Indeed, a trypanosome mutant deleted for the phosphoenolpyruvate decarboxylase gene (PEPCK, EC 4.1.1.49) shows a 1.7-fold and twofold decrease of TDH protein level and activity, respectively, associated with a 1.8-fold reduction in threonine-derived acetate production. We conclude that TDH expression is under control and can be downregulated in response to metabolic perturbations, such as in the PEPCK mutant in which the glycolytic metabolic flux was redirected towards acetate production.

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“…However, an ortholog of this protein was not found in B. saltans. The fourth step is catalyzed by mitochondrial 3-ketoacyl-CoA thiolase (Mazet et al 2011) present in all Kinetoplastea, except T. congolense. Aside from the African trypanosomes and Phytomonas spp., the kinetoplastids also have a cytosolic thiolase.…”

Section: Lipid Metabolismmentioning

confidence: 99%

Comparative Metabolism of Free‐living Bodo saltans and Parasitic Trypanosomatids

Opperdoes

Butenko

Flegontov

et al. 2016

J Eukaryotic Microbiology

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Comparison of the genomes of free-living Bodo saltans and those of parasitic trypanosomatids reveals that the transition from a free-living to a parasitic life style has resulted in the loss of approximately 50% of protein-coding genes. Despite this dramatic reduction in genome size, B. saltans and trypanosomatids still share a significant number of common metabolic traits: glycosomes; a unique set of the pyrimidine biosynthetic pathway genes; an ATP-PFK which is homologous to the bacterial PPi -PFKs rather than to the canonical eukaryotic ATP-PFKs; an alternative oxidase; three phosphoglycerate kinases and two GAPDH isoenzymes; a pyruvate kinase regulated by fructose-2,6-bisphosphate; trypanothione as a substitute for glutathione; synthesis of fatty acids via a unique set of elongase enzymes; and a mitochondrial acetate:succinate coenzyme A transferase. B. saltans has lost the capacity to synthesize ubiquinone. Among genes that are present in B. saltans and lost in all trypanosomatids are those involved in the degradation of mureine, tryptophan and lysine. Novel acquisitions of trypanosomatids are components of pentose sugar metabolism, pteridine reductase and bromodomain-factor proteins. In addition, only the subfamily Leishmaniinae has acquired a gene for catalase and the capacity to convert diaminopimelic acid to lysine.

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The characterization and evolutionary relationships of a trypanosomal thiolase

Cited by 17 publications

References 55 publications

Mitochondrial Proteomics of Antimony and Miltefosine Resistant Leishmania infantum

Mitochondrial Proteomics of Antimony and Miltefosine Resistant Leishmania infantum

The threonine degradation pathway of the Trypanosoma brucei procyclic form: the main carbon source for lipid biosynthesis is under metabolic control

Comparative Metabolism of Free‐living Bodo saltans and Parasitic Trypanosomatids

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