Leishmania donovani PP2C: Kinetics, structural attributes and in vitro immune response

Jakkula, Pranay; Qureshi, Rahila; Iqbal, Atif; Sagurthi, Someswar Rao; Qureshi, Insaf Ahmed

doi:10.1016/j.molbiopara.2018.06.005

Cited by 12 publications

(9 citation statements)

References 55 publications

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“…For example, purified LdPP2C is enzymatically active, and according to an inhibition study, sanguinarine likely acts as a non-competitive inhibitor (at pH 3.5-8.5). The molecular weight of the purified protein was 45 kDa (Jakkula et al, 2018). LcPP2C was reported to have a molecular weight of 42 kDa in both the infective promastigotes and the tissue amastigotes of L. chagasi and L. amazonensis.…”

Section: Discussionmentioning

confidence: 96%

“…PP2C protein phosphatases have been characterized in Leishmania, including the PP2C of L. chagasi (LcPP2C), L. major (LmPP2C) and L. donovani (LdPP2C), (Burns et al, 1993;Escalona-Montaño et al, 2017;Jakkula et al, 2018). These enzymes share very similar biochemical characteristics.…”

Section: Discussionmentioning

confidence: 99%

“…However, the function of PP2C enzymes in the Leishmania species is still unknown. LdPP2C affects the host innate immune response by upregulating pro-inflammatory cytokines (TNF-a and IL-6) as well as nitric oxide (Jakkula et al, 2018), while LcPP2C elicits a strong proliferative response of T cells in patients with leishmaniasis (Burns et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

“…PP2C enzymes have been cloned and characterized in Leishmania chagasi (LcPP2C), Leishmania major (LmPP2C) and Leishmania donovani (LdPP2C). To our knowledge, however, there is no information in the literature about the function of this enzyme, either in the parasite or cells of the host (Burns et al, 1993;Escalona-Montaño et al, 2017;Jakkula et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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Protein Serine/Threonine Phosphatase Type 2C of Leishmania mexicana

Escalona‐Montaño

Zuñiga-Fabián²,

Cabrera

et al. 2021

Front. Cell. Infect. Microbiol.

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Protein phosphorylation and dephosphorylation are increasingly recognized as important processes for regulating multiple physiological mechanisms. Phosphorylation is carried out by protein kinases and dephosphorylation by protein phosphatases. Phosphoprotein phosphatases (PPPs), one of three families of protein serine/threonine phosphatases, have great structural diversity and are involved in regulating many cell functions. PP2C, a type of PPP, is found in Leishmania, a dimorphic protozoan parasite and the causal agent of leishmaniasis. The aim of this study was to clone, purify, biochemically characterize and quantify the expression of PP2C in Leishmania mexicana (LmxPP2C). Recombinant LmxPP2C dephosphorylated a specific threonine (with optimal activity at pH 8) in the presence of the manganese divalent cation (Mn+2). LmxPP2C activity was inhibited by sanguinarine (a specific inhibitor) but was unaffected by protein tyrosine phosphatase inhibitors. Western blot analysis indicated that anti-LmxPP2C antibodies recognized a molecule of 45.2 kDa. Transmission electron microscopy with immunodetection localized LmxPP2C in the flagellar pocket and flagellum of promastigotes but showed poor staining in amastigotes. Interestingly, LmxPP2C belongs to the ortholog group OG6_142542, which contains only protozoa of the family Trypanosomatidae. This suggests a specific function of the enzyme in the flagellar pocket of these microorganisms.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Protein Serine/Threonine Phosphatase Type 2C of Leishmania mexicana

Escalona‐Montaño

Zuñiga-Fabián²,

Cabrera

et al. 2021

Front. Cell. Infect. Microbiol.

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“…Different STPs expressed by Leishmania parasites have been identified and characterized by biochemical and molecular means, including protein phosphatase 5 (PP5) (Norris-Mullins et al, 2018), protein phosphatase 1 (PP1) (Qureshi et al, 2019), protein phosphatase 2C (PP2C) (Jakkula et al, 2018), and protein phosphatase 2B (PP2B) (Banerjee et al, 1999) of Leishmania donovani; PP2B (Naderer et al, 2011), protein phosphatase with EF-Hand (PPEF) (Mills et al, 2007), and arsenate reductase 2 (ACR2) (Zhou et al, 2004;Zhou et al, 2006) of Leishmania major; PP2C (Escalona-Montaño et al, 2016) of Leishmania mexicana; and PP2C (Burns et al, 1993) of Leishmania chagasi.…”

Section: Introductionmentioning

confidence: 99%

Involvement of Leishmania Phosphatases in Parasite Biology and Pathogeny

Freitas-Mesquita

Dos-Santos

Meyer‐Fernandes

2021

Front. Cell. Infect. Microbiol.

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In the Leishmania lifecycle, the motile promastigote form is transmitted from the sand fly vector to a mammalian host during a blood meal. Inside vertebrate host macrophages, the parasites can differentiate into the amastigote form and multiply, causing leishmaniasis, one of the most significant neglected tropical diseases. Leishmania parasites face different conditions throughout their development inside sand flies. Once in the mammalian host, the parasites have to overcome the microbicide repertoire of the cells of the immune system to successfully establish the infection. In this context, the expression of protein phosphatases is of particular interest. Several members of the serine/threonine-specific protein phosphatase (STP), protein tyrosine phosphatase (PTP), and histidine acid phosphatase (HAcP) families have been described in different Leishmania species. Although their physiological roles have not been fully elucidated, many studies suggest they have an involvement with parasite biology and pathogeny. Phosphatases play a role in adaptation to nutrient starvation during parasite passage through the sand fly midgut. They are also important to parasite virulence, mainly due to the modulation of host cytokine production and impairment of the microbiocidal potential of macrophages. Furthermore, recent whole-genome expression analyses have shown that different phosphatases are upregulated in metacyclic promastigotes, the infective form of the mammalian host. Leishmania phosphatases are also upregulated in drug-resistant strains, probably due to the increase in drug efflux related to the activation of ABC transporters. Throughout this review, we will describe the physiological roles that have been attributed to Leishmania endogenous phosphatases, including their involvement in the adaptation, survival, and proliferation of the parasites inside their hosts.

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