Aminopeptidase N1 (EtAPN1), an M1 Metalloprotease of the Apicomplexan Parasite Eimeria tenella, Participates in Parasite Development

Gras, Simon; Byzia, Anna; Gilbert, Florence; McGowan, Sheena; Drąg, Marcin; Silvestre, Anne; Niepceron, Alisson; Lecaille, Fabien; Lalmanach, Gilles; Brossier, Fabien

doi:10.1128/ec.00062-14

Cited by 19 publications

(20 citation statements)

References 52 publications

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“…Fluorogenic substrates, derived from unnatural α-amino acids that comprise bulky hydrophobic P1 side-chain residues bearing a fragment of a basic character, were ranked among the most favored ligands. A similar hydrophobic and base-oriented P1 specificity profile was observed for mammalian (human and porcine) [5] and protozoan ( Plasmodium falciparum [6] and Eimeria tenella [7]) alanine aminopeptidases, the abundantly spread metallohydrolases of multiple functions and medical implications [8-10]. The privileged features of the amino acid substrates can be readily translated into the structure of potential inhibitors.…”

Section: Introductionmentioning

confidence: 71%

A structural insight into the P1 S1 binding mode of diaminoethylphosphonic and phosphinic acids, selective inhibitors of alanine aminopeptidases

Węglarz-Tomczak

Berlicki

Pawełczak

et al. 2016

European Journal of Medicinal Chemistry

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N'-substituted 1,2-diaminoethylphosphonic acids and 1,2-diaminoethylphosphinic dipeptides were explored to unveil the structural context of the unexpected selectivity of these inhibitors of M1 alanine aminopeptidases (APNs) versus M17 leucine aminopeptidase (LAP). The diaminophosphonic acids were obtained via aziridines in an improved synthetic procedure that was further expanded for the phosphinic pseudodipeptide system. The inhibitory activity, measured for three M1 and one M17 metalloaminopeptidases of different sources (bacterial, human and porcine), revealed several potent compounds (e.g., Ki = 65 nM of 1u for HsAPN). Two structures of an M1 representative (APN from Neisseria meningitidis) in complex with N-benzyl-1,2-diaminoethylphosphonic acid and N-cyclohexyl-1,2-diaminoethylphosphonic acid were determined by the X-ray crystallography. The analysis of these structures and the models of the phosphonic acid complexes of the human ortholog provided an insight into the role of the additional amino group and the hydrophobic substituents of the ligands within the S1 active site region.

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Section: Introductionmentioning

confidence: 71%

A structural insight into the P1 S1 binding mode of diaminoethylphosphonic and phosphinic acids, selective inhibitors of alanine aminopeptidases

Węglarz-Tomczak

Berlicki

Pawełczak

et al. 2016

European Journal of Medicinal Chemistry

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“…The CRISPR-Cas9-mediated genome editing approach should soon keep its promises and allow the generation of knockout virulence-attenuated strains that may be valuable for vaccination. (Bussiere et al, 2018;Gras et al, 2014) were maintained by serial passages in chicken. Freshly excysted sporozoites were purified as described (Bussiere et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…E. tenella Wisconsin strain (Wis) expressing yellow fluorescent protein (YFP) or E. tenella INRA strain expressing mCherry fluorescent protein (Bussiere et al, ; Gras et al, ) were maintained by serial passages in chicken. Freshly excysted sporozoites were purified as described (Bussiere et al, ).…”

Section: Methodsmentioning

confidence: 99%

Eimeria tenellaROPkinaseEtROP1induces G0/G1 cell cycle arrest and inhibits host cell apoptosis

Diallo

Sausset

Gnahoui-David

et al. 2019

Cellular Microbiology

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Coccidia are obligate intracellular protozoan parasites responsible for human and veterinary diseases. Eimeria tenella, the aetiologic agent of caecal coccidiosis, is a major pathogen of chickens. In Toxoplasma gondii, some kinases from the rhoptry compartment (ROP) are key virulence factors. ROP kinases hijack and modulate many cellular functions and pathways, allowing T. gondii survival and development. E. tenella's kinome comprises 28 putative members of the ROP kinase family; most of them are predicted, as pseudokinases and their functions have never been characterised. One of the predicted kinase, EtROP1, was identified in the rhoptry proteome of E. tenella sporozoites. Here, we demonstrated that EtROP1 is active, and the N‐terminal extension is necessary for its catalytic kinase activity. Ectopic expression of EtROP1 followed by co‐immunoprecipitation identified cellular p53 as EtROP1 partner. Further characterisation confirmed the interaction and the phosphorylation of p53 by EtROP1. E. tenella infection or overexpression of EtROP1 resulted both in inhibition of host cell apoptosis and G0/G1 cell cycle arrest. This work functionally described the first ROP kinase from E. tenella and its noncanonical structure. Our study provides the first mechanistic insight into host cell apoptosis inhibition by E. tenella. EtROP1 appears as a new candidate for coccidiosis control.

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“…Interestingly, the sporoplasm release was prevented by 1,10-phenanthroline (metalloprotease) and it suggested that metalloprotease is related the sporoplasm release in K. septempunctata [26]. Metalloproteases of parasite have been related to pathogenesis and are involved in processes such as immunity evasion, development, and metabolism [8,17]. In addition, the activity of metalloproteases are affected by pH of environment [13].…”

Section: Discussionmentioning

confidence: 99%

Characterization of proteases isolated from Kudoa septempunctata

Shin¹,

Zenke²,

Yokoyama³

2015

Korean Journal of Veterinary Research

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: Proteases play important roles in parasite development and host parasite interactions. The protease of Kudoa spp. has been recognized as a key factor of severe proteolysis of fish muscle post-mortem; however, there is little information available regarding the protease of Kudoa (K.) septempunctata, which was recently identified as a cause of food poisoning in humans. The present study was conducted to isolate and characterize proteases to elucidate the type of protease contained in the parasite and determine the optimal pH for protease activity. We confirmed the cysteine protease and metalloprotease produced by K. septempunctata. While the cysteine protease showed optimal activity at pH 5 that decreased rapidly with increasing pH, the optimal activity of metalloprotease was pH 7, and it remained stable from pH 6 to pH 8. These results indicate that the pH of cysteine protease is not proper for fish muscle postmortem, and that metalloprotease can act in human intestines. Overall, the present study provides important information that improves our understanding of the role of protease physiology and the subsequent food poisoning caused by K. septempunctata.

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Aminopeptidase N1 (EtAPN1), an M1 Metalloprotease of the Apicomplexan Parasite Eimeria tenella, Participates in Parasite Development

Cited by 19 publications

References 52 publications

A structural insight into the P1 S1 binding mode of diaminoethylphosphonic and phosphinic acids, selective inhibitors of alanine aminopeptidases

A structural insight into the P1 S1 binding mode of diaminoethylphosphonic and phosphinic acids, selective inhibitors of alanine aminopeptidases

Eimeria tenellaROPkinaseEtROP1induces G0/G1 cell cycle arrest and inhibits host cell apoptosis

Characterization of proteases isolated from Kudoa septempunctata

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