Role of trypanosomatid's arginase in polyamine biosynthesis and pathogenesis

Balaña‐Fouce, Rafael; Calvo-Álvarez, Estefanía; Álvarez-Velilla, Raquel; Fernández-Prada, Christopher; Pérez-Pertejo, Yolanda; Reguera, Rosa M.

doi:10.1016/j.molbiopara.2011.10.007

Cited by 51 publications

(48 citation statements)

References 120 publications

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“…The model of putrescine and relative spermidine deficiencies in the host cell is supported by the observation that macrophages rapidly convert these smaller polyamines to spermine (69). Previous Leishmania infection models have proposed that an increased host ARGI activity in infected macrophages provides polyamines for salvage and parasite proliferation (70, 71); however, our findings imply a refined model where ornithine, rather than polyamines, is available for salvage by the parasite (Fig. 7).…”

Section: Discussionmentioning

confidence: 50%

Arginase Is Essential for Survival of Leishmania donovani Promastigotes but Not Intracellular Amastigotes

et al. 2017

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Studies of Leishmania donovani have shown that both ornithine decarboxylase and spermidine synthase, two enzymes of the polyamine biosynthetic pathway, are critical for promastigote proliferation and required for maximum infection in mice. However, the importance of arginase (ARG), the first enzyme of the polyamine pathway in Leishmania, has not been analyzed in L. donovani. To test ARG function in intact parasites, we generated Δarg null mutants in L. donovani and evaluated their ability to proliferate in vitro and trigger infections in mice. The Δarg knockout was incapable of growth in the absence of polyamine supplementation, but the auxotrophic phenotype could be bypassed by addition of either millimolar concentrations of ornithine or micromolar concentrations of putrescine or by complementation with either glycosomal or cytosolic versions of ARG. Spermidine supplementation of the medium did not circumvent the polyamine auxotrophy of the Δarg line. Although ARG was found to be essential for ornithine and polyamine synthesis, ornithine decarboxylase appeared to be the rate-limiting enzyme for polyamine production. Mouse infectivity studies revealed that the Δarg lesion reduced parasite burdens in livers by an order of magnitude but had little impact on the numbers of parasites recovered from spleens. Thus, ARG is essential for proliferation of promastigotes but not intracellular amastigotes. Coupled with previous studies, these data support a model in which L. donovani amastigotes readily salvage ornithine and have some access to host spermidine pools, while host putrescine appears to be unavailable for salvage by the parasite.

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Section: Discussionmentioning

confidence: 50%

Arginase Is Essential for Survival of Leishmania donovani Promastigotes but Not Intracellular Amastigotes

et al. 2017

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“…Therefore, glycosome is vital for enzyme activity in Leishmania parasites [21]. Our sequence analysis of Leishmania PTS-1 showed no equivalent PTS-1 sequence among 31 ARG family members [18, 44, 57–59]. In our investigation, all sequenced Leishmania spp.…”

Section: Discussionmentioning

confidence: 75%

“…A unique and notable feature of Leishmania spp. ARG protein is the existence of a glycosomal (peroxisomal) targeting signal SKL and AKL, a tripeptide located in the deduced COOH terminus [18, 44]. Like other arg of Leishmania species [17, 18, 21], the L .…”

Section: Resultsmentioning

confidence: 99%

“…They have now been genetically confirmed as the peroxisomal targeting signal (PTS-1) that serves as the topogenic signal for targeting ARG to the unique Leishmania glycosome [44]. Leishmania glycosome, a peroxisome like organelle, was found only in kinetoplastids, and the presence of this organelle shows one of the major differences among the Leishmania parasites and the host.…”

Section: Discussionmentioning

confidence: 99%

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Arginase activity in pathogenic and non-pathogenic species of Leishmania parasites

et al. 2017

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Proliferation of Leishmania (L.) parasites depends on polyamine availability, which can be generated by the L-arginine catabolism and the enzymatic activity of arginase (ARG) of the parasites and of the mammalian hosts. In the present study, we characterized and compared the arginase (arg) genes from pathogenic L. major and L. tropica and from non-pathogenic L. tarentolae. We quantified the level of the ARG activity in promastigotes and macrophages infected with pathogenic L. major and L. tropica and non-pathogenic L. tarentolae amastigotes. The ARG's amino acid sequences of the pathogenic and non-pathogenic Leishmania demonstrated virtually 98.6% and 88% identities with the reference L. major Friedlin ARG. Higher ARG activity was observed in all pathogenic promastigotes as compared to non-pathogenic L. tarentolae. In vitro infection of human macrophage cell line (THP1) with pathogenic and non-pathogenic Leishmania spp. resulted in increased ARG activities in the infected macrophages. The ARG activities present in vivo were assessed in susceptible BALB/c and resistant C57BL/6 mice infected with L. major, L. tropica and L. tarentolae. We demonstrated that during the development of the infection, ARG is induced in both strains of mice infected with pathogenic Leishmania. However, in L. major infected BALB/c mice, the induction of ARG and parasite load increased simultaneously according to the time course of infection, whereas in C57BL/6 mice, the enzyme is upregulated solely during the period of footpad swelling. In L. tropica infected mice, the footpads' swellings were slow to develop and demonstrated minimal cutaneous pathology and ARG activity. In contrast, ARG activity was undetectable in mice inoculated with the non-pathogenic L. tarentolae. Our data suggest that infection by Leishmania parasites can increase ARG activity of the host and provides essential polyamines for parasite salvage and its replication. Moreover, the ARG of Leishmania is vital for parasite proliferation and required for infection in mice. ARG activity can be used as one of the main marker of the disease severity.

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“…T. brucei responds to citrate exposure at the initiation of its life cycle during transmission to the tsetse fly (98). Furthermore, in Leishmania parasites, enolase and arginase represent examples of enzymes that participate in the infection process or pathogenesis (99,100).…”

Section: Discussionmentioning

confidence: 99%

Role of Δ1-Pyrroline-5-Carboxylate Dehydrogenase Supports Mitochondrial Metabolism and Host-Cell Invasion of Trypanosoma cruzi

Mantilla

Paes

Pral

et al. 2015

Journal of Biological Chemistry

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Role of trypanosomatid's arginase in polyamine biosynthesis and pathogenesis

Cited by 51 publications

References 120 publications

Arginase Is Essential for Survival of Leishmania donovani Promastigotes but Not Intracellular Amastigotes

Arginase Is Essential for Survival of Leishmania donovani Promastigotes but Not Intracellular Amastigotes

Arginase activity in pathogenic and non-pathogenic species of Leishmania parasites

Role of Δ1-Pyrroline-5-Carboxylate Dehydrogenase Supports Mitochondrial Metabolism and Host-Cell Invasion of Trypanosoma cruzi

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