TcPARP: A DNA damage-dependent poly(ADP-ribose) polymerase from Trypanosoma cruzi

Villamil, Silvia Hebe Fernandez; Baltanás, Rodrigo; Alonso, Guillermo D.; Larrea, Salomé Catalina Vilchez; Torres, Héctor N.; Flawiá, Mirtha M.

doi:10.1016/j.ijpara.2007.08.003

Cited by 28 publications

(38 citation statements)

References 53 publications

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“…This is in agreement with PARPs in other trypanosomatids 16, 17 . The characterized DNA-dependent PARPs function in DNA repair pathways, and have been found to be essential in mice, where PARP-1/2 knockout is embryonically lethal 18 .…”

Section: Discussionsupporting

confidence: 91%

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Structural and Biochemical Characterization of Poly-ADP-ribose Polymerase from Trypanosoma brucei

Haikarainen

Schlesinger

Obaji

et al. 2017

Sci Rep

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Trypanosoma brucei is a unicellular parasite responsible for African trypanosomiasis or sleeping sickness. It contains a single PARP enzyme opposed to many higher eukaryotes, which have numerous PARPs. PARPs are responsible for a post-translational modification, ADP-ribosylation, regulating a multitude of cellular events. T. brucei PARP, like human PARPs-1-3, is activated by DNA binding and it potentially functions in DNA repair processes. Here we characterized activation requirements, structure and subcellular localization of T. brucei PARP. T. brucei PARP was found to be selectively activated by 5′ phosphorylated and 3′ phosphorylated DNA breaks. Importantly, the N-terminal region is responsible for high-affinity DNA-binding and required for DNA-dependent enzymatic activation. This module is also required for nuclear localization of the protein in response to oxidative stress. Solution structures of activating and non-activating PARP-DNA complexes were determined with small-angle X-ray scattering revealing distinct differences in their DNA-binding modes.

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Section: Discussionsupporting

confidence: 91%

“…Unicellular protozoan parasite, T. brucei has only one PARP 16 , which is activated by DNA 6 . This is in agreement with PARPs in other trypanosomatids 16, 17 .…”

Section: Discussionmentioning

confidence: 99%

Structural and Biochemical Characterization of Poly-ADP-ribose Polymerase from Trypanosoma brucei

Haikarainen

Schlesinger

Obaji

et al. 2017

Sci Rep

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“…In the majority of cases, the conformations calculated for compounds are in agreement with the interactions 9 reported in different studies 8,12,13 . Nevertheless, the compounds 2d and 2e did not reproduce the typical interactions of an inhibitor of catPARP-1; related compounds 2f and 2e did not report the typical interactions with their substratum.…”

Section: Analysis Of Potential Candidate Targets For 2a-f Quinoxalinessupporting

confidence: 83%

Trypanocidal properties, structure–activity relationship and computational studies of quinoxaline 1,4-di-N-oxide derivatives

Estevez

Quiliano

Burguete

et al. 2011

Experimental Parasitology

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Two series of pyrazol and propenone quinoxaline derivatives were tested for parasiticidal activity (against amastigotes of Leishmania peruviana and trypomastigotes of Trypanosoma cruzi) and for toxicity against proliferative and non-proliferative cells. The pyrazol series was almost inactive against1,4-dioxide inhibited 50% of Leishmania growth at 8.9 µM with no impact against proliferative kidney cells and low toxicity against Thp-1 and murine macrophages. The compounds of the propenone series were moderately active against T. cruzi. Among them, 2 compounds were particularly interesting: (2E)-1-(7-Fluoro-3-methyl-quinoxalin-2-yl)-3-(3,4,5-trimethoxy-phenyl)-propenone, that showed a selective activity against proliferative cells (cancer and parasites), being inactive against normal murine peritoneal macrophages and (2E)-3-(3,4,5-Trimethoxy-phenyl)-1-(3,6,7-trimethyl-quinoxalin-2-yl)-propenone that was only active against Leishmania and inactive against the other tested cells.Furthermore in silico studies were performed for ADME properties and docking studies, both series of compounds respected the Lipinski's rules and show linear correlation between tripanosomaticidal activities and LogP. Docking studies revealed that compounds of the second series could interact with the poly (ADP-ribose) polymerase protein of Trypanosoma cruzi.3

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“…In this regard, it is noteworthy that PARP activity was reported in all T. cruzi developmental stages (Fernández Villamil et al., 2008). …”

Section: Discussionmentioning

confidence: 93%

Effects of a novel β–lapachone derivative on Trypanosoma cruzi : Parasite death involving apoptosis, autophagy and necrosis

Anjos

Alves

Goncalves

et al. 2016

International Journal for Parasitology: Drugs and Drug Resistan

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Natural products comprise valuable sources for new antiparasitic drugs. Here we tested the effects of a novel β–lapachone derivative on Trypanosoma cruzi parasite survival and proliferation and used microscopy and cytometry techniques to approach the mechanism(s) underlying parasite death. The selectivity index determination indicate that the compound trypanocidal activity was over ten-fold more cytotoxic to epimastigotes than to macrophages or splenocytes. Scanning electron microscopy analysis revealed that the R72 β–lapachone derivative affected the T. cruzi morphology and surface topography. General plasma membrane waving and blebbing particularly on the cytostome region were observed in the R72-treated parasites. Transmission electron microscopy observations confirmed the surface damage at the cytostome opening vicinity. We also observed ultrastructural evidence of the autophagic mechanism termed macroautophagy. Some of the autophagosomes involved large portions of the parasite cytoplasm and their fusion/confluence may lead to necrotic parasite death. The remarkably enhanced frequency of autophagy triggering was confirmed by quantitating monodansylcadaverine labeling. Some cells displayed evidence of chromatin pycnosis and nuclear fragmentation were detected. This latter phenomenon was also indicated by DAPI staining of R72-treated cells. The apoptotis induction was suggested to take place in circa one-third of the parasites assessed by annexin V labeling measured by flow cytometry. TUNEL staining corroborated the apoptosis induction. Propidium iodide labeling indicate that at least 10% of the R72-treated parasites suffered necrosis within 24 h. The present data indicate that the β–lapachone derivative R72 selectively triggers T. cruzi cell death, involving both apoptosis and autophagy-induced necrosis.

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TcPARP: A DNA damage-dependent poly(ADP-ribose) polymerase from Trypanosoma cruzi

Cited by 28 publications

References 53 publications

Structural and Biochemical Characterization of Poly-ADP-ribose Polymerase from Trypanosoma brucei

Structural and Biochemical Characterization of Poly-ADP-ribose Polymerase from Trypanosoma brucei

Trypanocidal properties, structure–activity relationship and computational studies of quinoxaline 1,4-di-N-oxide derivatives

Effects of a novel β–lapachone derivative on Trypanosoma cruzi : Parasite death involving apoptosis, autophagy and necrosis

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