Leishmania amazonensis: PKC-like protein kinase modulates the (Na++K+)ATPase activity

Almeida-Amaral, Elmo Eduardo; Caruso‐Neves, Celso; Lara, Lucienne S.; Pinheiro, Carla Mônica; Meyer‐Fernandes, José Roberto

doi:10.1016/j.exppara.2007.02.010

Cited by 16 publications

(18 citation statements)

References 31 publications

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“…The only recognizable sequence features are leucine-rich repeats (LRR) that are often involved in protein-protein interactions and may be important for the subcellular localisation. In fact, T. brucei PKAR is [47]; 5 [44]; 6 [41]. Table 5.1 Expression regulation of PKAC isoforms and PKAR; syntenic genes (see Figure 5.2) of T. cruzi and Leishmania are listed under the T. brucei gene name.…”

Section: -Phosphoinositide-dependent Kinase-1 (Pdk-1)mentioning

confidence: 99%

“…Although in trypanosomatids no gene orthologous to PKC has been identified [4], PKC-like activities have been described by several groups [6][7][8][9][10][11][12][13][14][15][16][17][18]. Hypothesized roles of PKC-like activity in T. cruzi are regulation of membrane transporters [11] or involvement in metacyclogenesis [9,18].…”

Section: Pkc-like Kinase Activitymentioning

confidence: 99%

“…Hypothesized roles of PKC-like activity in T. cruzi are regulation of membrane transporters [11] or involvement in metacyclogenesis [9,18]. In Leishmania amazonensis, a connection between PKC signaling and Na þ -K þ -ATPase was hypothesized [6], whereas in Leishmania mexicana a role of PKC-like activity was proposed in macrophage infection [8]. However, the PKC inhibitors used in many of these studies are known to be very unspecific; for example, staurosporine shows a very low selectivity to PKC as it interferes with the ATP-binding sites of many kinases.…”

Section: Pkc-like Kinase Activitymentioning

confidence: 99%

“…The trypanosomatid genome harbors a gene homologous to PDK-1 (Tb927.9.4910), which suggests a conservation of this mechanism. Whereas genes homologous to PKA, PKB, NDR and RSK (90 kDa ribosomal S6 kinase) kinases were identified in a previous bioinformatic survey of the kinetoplastid genomes [4], the large PKC subfamily is virtually absent in spite of numerous earlier reports of PKC-like activity [6][7][8][9][10][11][12][13][14][15][16][17][18]. The other AGC kinases identified in trypanosomatids by Parsons et al [4] do not seem to have orthologs in other organisms, and few of them have been analyzed to date.…”

Section: Introductionmentioning

confidence: 99%

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Kinetoplastid AGC Kinases

Bachmaier

Boshart

2013

Protein Phosphorylation in Parasites

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Genes encoding protein kinases homologous to the AGC (PKA-PKG-PKC-like) group are relatively under-represented in trypanosomatid genomes, and most of them cannot be assigned to one of the subfamilies conserved in higher organisms, as illustrated by the zinc finger kinase ZFK, a kinase with unique and kinetoplastid-specific domain architecture outside the catalytic core. Second messenger-regulated kinases are apparently absent, like the PKC and PKG subfamilies, or have controversial ligand-binding properties, like PKA. Hence, the AGC group is very unconventional in kinetoplastids. Only the nuclear DBF2-related (NDR) kinases PK50 and PK53 are currently being prioritized for drug development. In this chapter the currently available knowledge on AGC kinases is reviewed, and the suggestion made that further investigations of this group of kinases will most likely deliver parasite-specific kinase drug targets.

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Section: -Phosphoinositide-dependent Kinase-1 (Pdk-1)mentioning

confidence: 99%

Section: Pkc-like Kinase Activitymentioning

confidence: 99%

Section: Pkc-like Kinase Activitymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Kinetoplastid AGC Kinases

Bachmaier

Boshart

2013

Protein Phosphorylation in Parasites

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“…The PKC family consists of serine/threonine kinases that are involved in a variety of signals. Studies show evidence of the existence of specific PKC-like activity in Leishmania [25,27,29,30]. Knowing that heme is a pro-oxidant molecule and the importance of H 2 O 2 in signal transduction, our goal in this work is to investigate if heme can promote an increase in the H 2 O 2 production by L .…”

Section: Introductionmentioning

confidence: 99%

Modulation of Na+/K+ ATPase Activity by Hydrogen Peroxide Generated through Heme in L. amazonensis

2015

Self Cite

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Leishmania amazonensis is a protozoan parasite that occurs in many areas of Brazil and causes skin lesions. Using this parasite, our group showed the activation of Na+/K+ ATPase through a signaling cascade that involves the presence of heme and protein kinase C (PKC) activity. Heme is an important biomolecule that has pro-oxidant activity and signaling capacity. Reactive oxygen species (ROS) can act as second messengers, which are required in various signaling cascades. Our goal in this work is to investigate the role of hydrogen peroxide (H2O2) generated in the presence of heme in the Na+/K+ ATPase activity of L. amazonensis. Our results show that increasing concentrations of heme stimulates the production of H2O2 in a dose-dependent manner until a concentration of 2.5 μM heme. To confirm that the effect of heme on the Na+/K+ ATPase is through the generation of H2O2, we measured enzyme activity using increasing concentrations of H2O2 and, as expected, the activity increased in a dose-dependent manner until a concentration of 0.1 μM H2O2. To investigate the role of PKC in this signaling pathway, we observed the production of H2O2 in the presence of its activator phorbol 12-myristate 13-acetate (PMA) and its inhibitor calphostin C. Both showed no effect on the generation of H2O2. Furthermore, we found that PKC activity is increased in the presence of H2O2, and that in the presence of calphostin C, H2O2 is unable to activate the Na+/K+ ATPase. 100 μM of Mito-TEMPO was capable of abolishing the stimulatory effect of heme on Na+/K+ ATPase activity, indicating that mitochondria might be the source of the hydrogen peroxide production induced by heme. The modulation of L. amazonensis Na+/K+ ATPase by H2O2 opens new possibilities for understanding the signaling pathways of this parasite.

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Design and synthesis of imidazolidinone derivatives as potent anti‐leishmanial agents by bioisosterism

Ramu

Jain

Kumar

et al. 2019

Archiv der Pharmazie

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Bioisosterism is a useful strategy in rational drug design to improve pharmacodynamic and pharmacokinetic properties of lead compounds. Imidazolidinones have been reported as potent kinase inhibitors and antileishmanial agents. In this study, bioisosteres of imidazolidinones (compounds 1-3) were evaluated for their antileishmanial properties. The modified imidazolidinones exhibited potent antileishmanial activity against extracellular as well as intracellular Leishmania donovani parasites in nanomolar concentrations. The selectivity index of these compounds on host cells was found to be more than 1000, emphasizing their specificity toward the parasite. Using SwissTargetPrediction software, we assessed the potential targets of these compounds and found MAPK as the most probable target. To in vitro validate, we developed a novel in vitro kinase assay that mimics the in vivo nature of the functional kinome. Compounds 1-3 displayed specific inhibition of parasite kinase activity accompanied by an increase in intracellular sodium levels in the parasites. This might be the effect of kinase inhibition that regulates sodium homeostasis through Na-ATPases.Finally, the compound-treated parasites underwent apoptosis-like death. This study represents bioisoterism as a novel approach for drug design to establish the structureactivity relationship, which in turn helps to improve the therapeutic activity of lead compounds. K E Y W O R D Sbioisosterism, high-throughput kinase assay, imidazolidinones, leishmaniasis, target deconvolution

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Leishmania amazonensis: PKC-like protein kinase modulates the (Na++K+)ATPase activity

Cited by 16 publications

References 31 publications

Kinetoplastid AGC Kinases

Kinetoplastid AGC Kinases

Modulation of Na+/K+ ATPase Activity by Hydrogen Peroxide Generated through Heme in L. amazonensis

Design and synthesis of imidazolidinone derivatives as potent anti‐leishmanial agents by bioisosterism

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