Two phylogenetically divergent isocitrate dehydrogenases are encoded in Leishmania parasites. Molecular and functional characterization of Leishmania mexicana isoenzymes with specificity towards NAD+ and NADP+

Giordana, Lucila; Nowicki, Cristina

doi:10.1016/j.molbiopara.2020.111320

Cited by 5 publications

(8 citation statements)

References 55 publications

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“…Previous research demonstrated that NADP-dependent IDH of Plasmodium falciparum (pfICDH) generates nicotinamide adenine dinucleotide phosphate H (NADPH) and is crucial for parasite survival and pathogenicity, which is also an important drug target in P. falciparum infection ( Chan and Sim, 2003 ). The biochemical and structural features of leishmanial IDHs showed that they are potential new therapeutic targets of metabolic processes in Leishmania parasites ( Giordana and Nowicki, 2020 ). Label-free LC−MS/MS analysis of DEPs between Trichinella spiralis muscle larvae (ML) and intestinal infective larvae (IIL) showed that NADP-dependent IDH might be a molting-related gene, which will be helpful for developing vaccines and new drugs against Trichinella spiralis (T. spiralis) ( Ren et al., 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Comparative proteomics analysis of adult Haemonchus contortus isolates from Ovis ammon

Liu

Liu²,

Han

et al. 2023

Front. Cell. Infect. Microbiol.

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Haemonchus contortus is an important parasite that causes disease that seriously endangers ruminant animals cattle, sheep, goat, and camel. Here, we compared the proeomics analysis of three adult Haemonchus contortus isolates from mouflons (Ovis ammon). A total of 1,299 adult worm proteins were identified, and 461 proteins were quantified, of which 82 (108), 83 (97), and 97 (86) significantly upregulated (downregulated) differentially expressed proteins (DEPs) were detected among pairwise comparisons (1-vs.-3, 2-vs.-3, and 2-vs.-1). Liquid chromatography–tandem mass spectrometry (LC−MS/MS) and bioinformatic analysis indicated that these DEPs are mainly concentrated in cellular composition, molecular function, biological function, and catabolism pathways. In addition, Gene Ontology (GO) classification and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were carried out to screen the DEPs. The main biological processes involved were nucleotide, nucleotide phosphate, ribonucleotide, purine-containing compound, purine ribonucleotide, single-organism, oxoacid, organic, carboxylic, oxoacid metabolic processes and single-organism catabolic processes. The majority of KEGG pathways were found to be related to metabolic pathways, biosynthesis of secondary metabolites, biosynthesis of antibiotics, carbon metabolism, and microbial metabolism in diverse environments. Moreover, we also found differences in the expression of some important or novel regulatory proteases, such as serine hydroxymethyl transferase (SHMT), dihydrolipoyl dehydrogenase (DLD), and transket pyr domain-containing protein (TKPD). In summary, label-free proteomic analysis of adult H. contortus worms displayed significant differences in three different individual isolates, which helps to improve our understanding of the growth and metabolic mechanisms of H. contortus in different individuals and relative natural environments and provides novel drug targets for the treatment of parasitic diseases.

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Section: Discussionmentioning

confidence: 99%

Comparative proteomics analysis of adult Haemonchus contortus isolates from Ovis ammon

Liu

Liu²,

Han

et al. 2023

Front. Cell. Infect. Microbiol.

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“…possesses a possible peroxisomal targeting signal 1 ( van Weelden et al 2005 ; Colasante et al 2006 ) and was recently experimentally shown to localize to both mitochondrion and cytosol in T. brucei ( Pyrih et al 2023 ). Complicating the situation even more, both the NADP + -dependent (related to IDH2) and NAD + -dependent (related to IDH3) isoforms with dual mitochondrial and cytosolic localization were described in Leishmania mexicana ( Giordana and Nowicki 2020 ).…”

Section: Introductionmentioning

confidence: 97%

“…Isocitrate dehydrogenases (IDHs) are broadly distributed enzymes that, among trypanosomatids, have been mostly studied in dixenous parasites of vertebrates and plants, but not in the group as a whole ( Fernández-Ramos et al 1999 ; Leroux et al 2011 ; Giordana and Nowicki 2020 ). The IDHs catalyze oxidative decarboxylation of isocitrate into α-ketoglutarate (2-oxoglutarate) with the concomitant release of CO 2 and the reduction of the cofactor NAD + or NADP + .…”

Section: Introductionmentioning

confidence: 99%

Distribution and Functional Analysis of Isocitrate Dehydrogenases across Kinetoplastids

Chmelová,

Záhonová,

Albanaz

et al. 2024

Genome Biology and Evolution

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Isocitrate dehydrogenase (IDH) is an enzyme converting isocitrate to α-ketoglutarate in the canonical tricarboxylic acid (TCA) cycle. There are three different types of IDH documented in eukaryotes. Our study points out the complex evolutionary history of IDHs across kinetoplastids, where the common ancestor of Trypanosomatidae and Bodonidae was equipped with two isoforms of the IDH enzyme: the NADP+-dependent IDH1 with possibly dual localization in the cytosol and mitochondrion and NADP+-dependent mitochondrial IDH2. In the extant trypanosomatids, IDH1 is present only in a few species suggesting that it was lost upon separation of Trypanosoma spp. and replaced by the mainly NADP+-dependent cytosolic IDH3 of bacterial origin in all the derived lineages. In this study, we experimentally demonstrate that the omnipresent IDH2 has a dual localization in both mitochondrion and cytosol in at least four species that possess only this isoform. The apparent lack of the NAD+-dependent IDH activity in trypanosomatid mitochondrion provides further support to the existence of the non-canonical TCA cycle across trypanosomatids and the bidirectional activity of IDH3 when operating with NADP+ cofactor instead of NAD+. This observation can be extended to all 17 species analyzed in this study, except for Leishmania mexicana which showed only low IDH activity in the cytosol. The variability in isocitrate oxidation capacity among species may reflect the distinct metabolic strategies and needs for reduced cofactors in particular environments.

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“…No evidence was found for the typical TCA cycle-related NAD + -dependent IDH3 in the Trypanosoma species. In L. mexicana two IDH isoenzymes are also found: one, with an MTS and high NADP + specificity is most related to IDH2 of trypanosomes, whereas the other exclusively uses NAD + , and is very different ( Giordana and Nowicki, 2020 ). This isoform contains no strong targeting motif, and appears most related to the TCA-cycle IDH3 enzyme of bacteria and other eukaryotes.…”

Section: Introductionmentioning

confidence: 99%

Delineating transitions during the evolution of specialised peroxisomes: Glycosome formation in kinetoplastid and diplonemid protists

Andrade-Alviárez

Bonive-Boscan

Cáceres

et al. 2022

Front. Cell Dev. Biol.

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One peculiarity of protists belonging to classes Kinetoplastea and Diplonemea within the phylum Euglenozoa is compartmentalisation of most glycolytic enzymes within peroxisomes that are hence called glycosomes. This pathway is not sequestered in peroxisomes of the third Euglenozoan class, Euglenida. Previous analysis of well-studied kinetoplastids, the ‘TriTryps’ parasites Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp., identified within glycosomes other metabolic processes usually not present in peroxisomes. In addition, trypanosomatid peroxins, i.e. proteins involved in biogenesis of these organelles, are divergent from human and yeast orthologues. In recent years, genomes, transcriptomes and proteomes for a variety of euglenozoans have become available. Here, we track the possible evolution of glycosomes by querying these databases, as well as the genome of Naegleria gruberi, a non-euglenozoan, which belongs to the same protist supergroup Discoba. We searched for orthologues of TriTryps proteins involved in glycosomal metabolism and biogenesis. Predicted cellular location(s) of each metabolic enzyme identified was inferred from presence or absence of peroxisomal-targeting signals. Combined with a survey of relevant literature, we refine extensively our previously postulated hypothesis about glycosome evolution. The data agree glycolysis was compartmentalised in a common ancestor of the kinetoplastids and diplonemids, yet additionally indicates most other processes found in glycosomes of extant trypanosomatids, but not in peroxisomes of other eukaryotes were either sequestered in this ancestor or shortly after separation of the two lineages. In contrast, peroxin divergence is evident in all euglenozoans. Following their gain of pathway complexity, subsequent evolution of peroxisome/glycosome function is complex. We hypothesize compartmentalisation in glycosomes of glycolytic enzymes, their cofactors and subsequently other metabolic enzymes provided selective advantage to kinetoplastids and diplonemids during their evolution in changing marine environments. We contend two specific properties derived from the ancestral peroxisomes were key: existence of nonselective pores for small solutes and the possibility of high turnover by pexophagy. Critically, such pores and pexophagy are characterised in extant trypanosomatids. Increasing amenability of free-living kinetoplastids and recently isolated diplonemids to experimental study means our hypothesis and interpretation of bioinformatic data are suited to experimental interrogation.

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Two phylogenetically divergent isocitrate dehydrogenases are encoded in Leishmania parasites. Molecular and functional characterization of Leishmania mexicana isoenzymes with specificity towards NAD+ and NADP+

Cited by 5 publications

References 55 publications

Comparative proteomics analysis of adult Haemonchus contortus isolates from Ovis ammon

Comparative proteomics analysis of adult Haemonchus contortus isolates from Ovis ammon

Distribution and Functional Analysis of Isocitrate Dehydrogenases across Kinetoplastids

Delineating transitions during the evolution of specialised peroxisomes: Glycosome formation in kinetoplastid and diplonemid protists

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