Up-regulation of the expressions of phospholipase A2 inhibitors in the liver of a venomous snake by its own venom phospholipase A2

Kinkawa, Kohshi; Shirai, Ryoichi; Watanabe, Shin; Toriba, Michihisa; Hayashi, Kyozo; Ikeda, Kiyoshi; Inoue, Shintaro

doi:10.1016/j.bbrc.2010.04.024

Cited by 24 publications

(16 citation statements)

References 15 publications

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“…Bearing in mind the results described by Kinkawa et al (2010), regarding the control of PLIs expression, and taken together the results presented in herein, it is tempting to suggest that the higher expression levels of γ-PLI, inter-alpha inhibitor and C1-inhibitor observed in adult snakes might be a natural physiological response of the snakes to the recurrent contact with their own venom throughout the life.…”

Section: Discussionmentioning

confidence: 51%

“…Three structural classes of PLIs have been described in snake plasma: (1) α-PLIs, which inhibit specifically acidic PLA 2 s from group II (found in the venom of Viperidae snakes), (2) β-PLIs, which inhibit specifically basic PLA 2 s from group II, and (3) γ-PLIs, which show inhibitory activity towards group I (from venom of Elapidae, Hydrophiidae and Colubridae snakes) and II PLA 2 s (Estevao-Costa et al, 2008; Inoue et al, 1997; Kinkawa et al, 2010). Considering the broad spectrum of pharmacological activities displayed by snake venom PLA 2 s, as neurotoxicity, myotoxicity, edema-inducing and anticoagulant activities, the presence of PLIs in the plasma of these animals is of paramount importance.…”

Section: Discussionmentioning

confidence: 99%

“…At a first glance, these are unexpected results, since a previous plasma proteomic analysis indicated that γ-PLI are found in a higher relative abundance in the plasma of juvenile B. jararaca (De Morais-Zani et al, 2013) and the venom of juvenile specimens also displayed higher catalytic PLA 2 activity (Antunes et al, 2010). However, a study conducted by Kinkawa et al (2010) showed that the gene expression of α-, β- and γ-PLIs was induced by the intramuscular injection of venom in the venomous snake Gloydius brevicaudus . Therefore, the higher expression levels of γ-PLI in adult B. jararaca liver described herein might be the result of the physiological response of the snakes to the repeatedly contact with their own venom during their development.…”

Section: Discussionmentioning

confidence: 99%

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Differential transcript profile of inhibitors with potential anti-venom role in the liver of juvenile and adultBothrops jararacasnake

Gomes

Buarque

et al. 2017

PeerJ

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BackgroundSnakes belonging to the Bothrops genus are vastly distributed in Central and South America and are responsible for most cases of reported snake bites in Latin America. The clinical manifestations of the envenomation caused by this genus are due to three major activities—proteolytic, hemorrhagic and coagulant—mediated by metalloproteinases, serine proteinases, phospholipases A2 and other toxic compounds present in snake venom. Interestingly, it was observed that snakes are resistant to the toxic effects of its own and other snake’s venoms. This natural immunity may occur due the absence of toxin target or the presence of molecules in the snake plasma able to neutralize such toxins.MethodsIn order to identify anti-venom molecules, we construct a cDNA library from the liver of B. jararaca snakes. Moreover, we analyzed the expression profile of four molecules—the already known anti-hemorrhagic factor Bj46a, one gamma-phospholipase A2 inhibitor, one inter-alpha inhibitor and one C1 plasma protease inhibitor—in the liver of juvenile and adult snakes by qPCR.ResultsThe results revealed a 30-fold increase of gamma-phospholipase A2 inhibitor and a minor increase of the inter-alpha inhibitor (5-fold) and of the C1 inhibitor (3-fold) in adults. However, the Bj46a factor seems to be equally transcribed in adults and juveniles.DiscussionThe results suggest the up-regulation of different inhibitors observed in the adult snakes might be a physiological adaptation to the recurrent contact with their own and even other snake’s venoms throughout its lifespan. This is the first comparative analysis of ontogenetic variation of expression profiles of plasmatic proteins with potential anti-venom activities of the venomous snake B. jararaca. Furthermore, the present data contributes to the understanding of the natural resistance described in these snakes.

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Section: Discussionmentioning

confidence: 51%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Differential transcript profile of inhibitors with potential anti-venom role in the liver of juvenile and adultBothrops jararacasnake

Gomes

Buarque

et al. 2017

PeerJ

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“…In comparison, the purification of the γPLI from Bothrops jararaca (γBjPLI) presented 1% of recovery, using the same methodology applied in this case [30], while under different approaches the γPLI from Crotalus durissus collilineatus (γCdcPLI) presented 2.69% [38]. The higher recovery of PLIs from venomous snakes may be related to the constant contact with the venom, which may stimulate the presence of inhibitors in the plasma [39].…”

Section: Resultsmentioning

confidence: 97%

BoaγPLI: Structural and functional characterization of the gamma phospholipase A2 plasma inhibitor from the non-venomous Brazilian snake Boa constrictor

et al. 2020

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Plasma in several organisms has components that promote resistance to envenomation by inhibiting specific proteins from snake venoms, such as phospholipases A 2 (PLA 2 s). The major hypothesis for inhibitor's presence would be the protection against self-envenomation in venomous snakes, but the occurrence of inhibitors in non-venomous snakes and other animals has opened new perspectives for this molecule. Thus, this study showed for the first time the structural and functional characterization of the PLA 2 inhibitor from the Boa constrictor serum (BoaγPLI), a non-venomous snake that dwells extensively the Brazilian territory. Therefore, the inhibitor was isolated from B. constrictor serum, with 0.63% of recovery. SDS-PAGE showed a band at~25 kDa under reducing conditions and~20 kDa under non-reducing conditions. Chromatographic analyses showed the presence of oligomers formed by BoaγPLI. Primary structure of BoaγPLI suggested an estimated molecular mass of 22 kDa. When BoaγPLI was incubated with Asp-49 and Lys-49 PLA 2 there was no severe change in its dichroism spectrum, suggesting a non-covalent interaction. The enzymatic assay showed a dose-dependent inhibition, up to 48.2%, when BoaγPLI was incubated with Asp-49 PLA 2 , since Lys-49 PLA 2 has a lack of enzymatic activity. The edematogenic and myotoxic effects of PLA 2 s were also inhibited by BoaγPLI. In summary, the present work provides new insights into inhibitors from non-venomous snakes, which possess PLIs in their plasma, although the contact with venom is unlikely. OPEN ACCESS Citation: Rodrigues CFB, Serino-Silva C, Morais-Zani Kd, Kavazoi VK, Carvalho MPN, Grego KF, et al. (2020) BoaγPLI: Structural and functional characterization of the gamma phospholipase A2 plasma inhibitor from the non-venomous Brazilian snake Boa constrictor. PLoS ONE 15(2): e0229657. https://doi.org/10.

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“…Within a few hours after intramuscularly injected with a single dose of the autologous crude venom, there was an upregulation (quantified by real-time qRT-PCR, quantitative reverse transcription polymerase chain reaction) of the expression of all PLI genes in the snake liver tissue (Kinkawa et al 2010). The results were confirmed by the concurrent immunological detection of increased amounts of the inhibitors in the blood plasma of the snake.…”

Section: Natural Resistance To Snake Envenomationmentioning

confidence: 82%

Natural Inhibitors of Snake Venom Metallopeptidases

Neves-Ferreira¹,

Valente²,

Domont³

et al. 2015

Toxins and Drug Discovery

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Protein inhibitors of peptidases are widely distributed among animals, plants, and microorganisms. They are important regulatory molecules that function to avoid proteolysis in various biological systems. From the plasma of animals that are naturally resistant to snake envenomation, a special class of peptidase inhibitors has been identified. These inhibitors have antihemorrhagic properties and form inactive noncovalent complexes with snake venom metallopeptidases. In nonresistant animals, these toxic metallopeptidases induce microvascular damage and are responsible for systemic and local hemorrhage, key events in the pathogenesis of viperid envenomation. The inhibitors isolated from mammalian plasma are grouped into the MEROPS I43 family of immunoglobulin-related proteins; those from reptiles show a typical cystatin-like fold and belong to the MEROPS I25C subfamily. The inhibitors show a reversible tight-binding reaction mechanism of inhibition, although due to a lack of three-dimensional information for the enzyme-inhibitor complexes, the structural features that govern the interaction are largely unknown. This review is intended to highlight the latest advances in the field, analyzing future perspectives in the area of natural immunity against snake venom. The discussion will focus on how endogenous protein inhibitors can be used as structural templates, providing valuable insights into the molecular determinants of selective metallopeptidase inhibition. The wide range of natural toxin inhibitors may constitute a rich source of information leading to new possibilities in intervention not only against snake venom metallopeptidases but also against other metzincins, such as mammalian MMPs and ADAMs.

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Up-regulation of the expressions of phospholipase A2 inhibitors in the liver of a venomous snake by its own venom phospholipase A2

Cited by 24 publications

References 15 publications

Differential transcript profile of inhibitors with potential anti-venom role in the liver of juvenile and adultBothrops jararacasnake

Differential transcript profile of inhibitors with potential anti-venom role in the liver of juvenile and adultBothrops jararacasnake

BoaγPLI: Structural and functional characterization of the gamma phospholipase A2 plasma inhibitor from the non-venomous Brazilian snake Boa constrictor

Natural Inhibitors of Snake Venom Metallopeptidases

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