Crithidia fasciculata: a catalase-containing trypanosomatid sensitive to nitroheterocyclic drugs

Gutteridge, W. E.; Ross, Janice; Hargadon, Martin R.J.; Hudson, J.E.

doi:10.1016/0035-9203(82)90146-8

Cited by 12 publications

(4 citation statements)

References 13 publications

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“…Heme can possibly be stored in catalase and used under the heme‐limited conditions. It has been shown that after 2 days of heme starvation, only 6% of the catalase activity in C. fasciculata was retained, whereas the oxygen consumption and cytochrome‐mediated respiration remained unaffected . In T. brucei , we recapitulated (to some extent) the phenotype observed in T. cruzi after the expression of a bacterial catalase in vitro .…”

Section: Discussionmentioning

confidence: 76%

Catalase compromises the development of the insect and mammalian stages of Trypanosoma brucei

et al. 2019

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Catalase is a widespread heme‐containing enzyme, which converts hydrogen peroxide (H2O2) to water and molecular oxygen, thereby protecting cells from the toxic effects of H2O2. Trypanosoma brucei is an aerobic protist, which conspicuously lacks this potent enzyme, present in virtually all organisms exposed to oxidative stress. To uncover the reasons for its absence in T. brucei, we overexpressed different catalases in procyclic and bloodstream stages of the parasite. The heterologous enzymes originated from the related insect‐confined trypanosomatid Crithidia fasciculata and the human. While the trypanosomatid enzyme (cCAT) operates at low temperatures, its human homolog (hCAT) is adapted to the warm‐blooded environment. Despite the presence of peroxisomal targeting signal in hCAT, both human and C. fasciculata catalases localized to the cytosol of T. brucei. Even though cCAT was efficiently expressed in both life cycle stages, the enzyme was active in the procyclic stage, increasing cell's resistance to the H2O2 stress, yet its activity was suppressed in the cultured bloodstream stage. Surprisingly, following the expression of hCAT, the ability to establish the T. brucei infection in the tsetse fly midgut was compromised. In the mouse model, hCAT attenuated parasitemia and, consequently, increased the host's survival. Hence, we suggest that the activity of catalase in T. brucei is beneficial in vitro, yet it becomes detrimental for parasite's proliferation in both invertebrate and vertebrate hosts, leading to an inability to carry this, otherwise omnipresent, enzyme.

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Section: Discussionmentioning

confidence: 76%

Catalase compromises the development of the insect and mammalian stages of Trypanosoma brucei

et al. 2019

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“…One study with C. fasciculate, showed that organisms with low levels of the enzyme trypanosomatid catalase maintain their sensitivity to nifurtimox (2). These results contradict the hypothesis that the action of nifurtimox (2) involves the accumulation of hydrogen peroxide due to the absence of catalase (Gutteridge et al, 1982). Moreover, recently, five peroxidases were identified in T. cruzi: two tryparedoxin peroxidases (Wilkinson et al, 2000;Piacenza et al, 2008;Trujillo et al, 2004), two glutathione-dependent peroxidases (Wilkinson et al 2002a;Wilkinson et al, 2002b), and one ascorbate-dependent heme peroxidase (Wilkinson et al, 2002c) showing, in contrast to previous studies that the parasite has a complex and effective system to deal with oxidative stress.…”

Section: Nifurtimox and Benznidazolementioning

confidence: 73%

Novel Therapeutic Strategies for Chagas` Disease

Vermelho¹,

Fraga²,

Carvalho³

et al. 2011

Drug Development - A Case Study Based Insight Into Modern Strategies

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“…Activity of ACOXs and other H 2 O 2 -producing enzymes such as d -amino acid oxidase and 2-hydroxy acid oxidase could not be detected in T. brucei , nor have these enzymes been detected in any of the more recent glycosomal proteome analyses. However, the latter two oxidases and catalase have been reported for other trypanosomatids like C. fasciculata , but not in association with the organelles ( Opperdoes et al, 1977 ; Gutteridge et al, 1982 ; Opperdoes, 1987 ). We detected in TriTrypDB an A. deanei oxidase with a FAD-binding domain and PTS1, annotated as having a predicted 2-hydroxy acid oxidase function ( Supplementary Table S2 ).…”

Section: Introductionmentioning

confidence: 88%

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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Crithidia fasciculata: a catalase-containing trypanosomatid sensitive to nitroheterocyclic drugs

Cited by 12 publications

References 13 publications

Catalase compromises the development of the insect and mammalian stages of Trypanosoma brucei

Catalase compromises the development of the insect and mammalian stages of Trypanosoma brucei

Novel Therapeutic Strategies for Chagas` Disease

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

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