Ureases de canavalia ensiformis : estudos estruturais e da atividade pró-convulsivante
Ano de defesa: | 2020 |
---|---|
Autor(a) principal: | |
Orientador(a): | |
Banca de defesa: | |
Tipo de documento: | Tese |
Tipo de acesso: | Acesso aberto |
Idioma: | por |
Instituição de defesa: |
Pontifícia Universidade Católica do Rio Grande do Sul
|
Programa de Pós-Graduação: |
Programa de Pós-Graduação em Medicina e Ciências da Saúde
|
Departamento: |
Escola de Medicina
|
País: |
Brasil
|
Palavras-chave em Português: | |
Palavras-chave em Inglês: | |
Área do conhecimento CNPq: | |
Link de acesso: | http://tede2.pucrs.br/tede2/handle/tede/9444 |
Resumo: | Ureases, metalloenzymes that catalyze the hydrolysis of urea into carbamate and ammonia, are well conserved proteins although differing in their quaternary structures in different organisms. Most plant ureases are hexamers of a single chain subunit, such as the most abundant isoform of the jack bean (Canavalia ensiformis) urease (JBU). Canatoxin (CNTX), originally isolated as a neurotoxic protein from jack bean seeds, was later characterized as an isoform of JBU, with a smaller molecular mass and lower ureolytic activity. Purified CNTX is unstable upon storage, forming inactive oligomers. Treatment of CNTX with 0.02 % v/v formaldehyde stabilizes its toxicity and avoids oligomerization. Canatoxin (CNTX) and Jack Bean Urease (JBU), isoforms of Canavalia ensiformis urease, displays a potent neurotoxicity whose mechanisms of action is not yet completely understood. The neurotoxins provokes convulsions preceding death in mice and rats (Ld50 ~2 mg/kg). Besides promoting hypoxia, hypothermia and inflammation in vivo, the proteins stimulates exocytosis in several cell models, induces neurotransmitter release from synaptosomes and affects calcium transport in platelets and in vesicles of sarcoplasmatic reticulum. For all these effects, CNTX acts by triggering eicosanoid signaling. In this work, we aimed to further characterize CNTX and elucidate the mechanism of its stabilization by formaldehyde treatment and to better understand its neurotoxic convulsant activity through a series of electrophysiological and brain imaging techniques. In this work, we successfully characterized CNTX as a trimeric state of JBU. The mechanism by which the formaldehyde treatment of CNTX avoids its oligomerization and stabilizes its biologically active conformation was elucidated and attributed to modifications introduced in the side chain of amino acid residues located at the interface between the two trimers that form the hexameric JBU. There could be multiple mechanisms underlying the seizures induced by C. ensiformis ureases. The mode of action seems to be an indirect one as no effect was detected on several isolated ion channels. It is more likely that CNTX and JBU could be acting at a neuronal network level, thereby disturbing electroencephalographic rhythms and causing metabolic alterations in key areas related to epileptogenesis and to neurogenic pulmonary edema. In the context of neuroinflammation, modulation of lipoxygenase pathways in the CNS appears as an interesting target to focus aiming to unveil the action of these neurotoxins. The lack of LTP induction is more likely caused by a neuroprotection mechanism and/or release of lipoxygenase products than direct interaction of CNTX or JBU with receptors and ion channels. The L-glutamate release induced by JBU could be a result of its membrane disturbing properties or of a lipoxygenase mediated mechanism, as observed for CNTX-induced exocytosis in many cell types. FDGmicroPET data indicated an increase in whole brain metabolism, and in areas related to epileptogenesis such as hippocampus and thalamus. A neurogenic pulmonary edema could be implicated in the convulsant activity of canatoxin, as suggested by the higher [18]FDG uptake in areas responsible for breathing control. Altogether the data emphasize the complexity of the neurotoxic mechanism of action of C. ensiformis ureases. Considering that non-enzymatic properties are shared by ureases of different kingdoms, we hope that deepening the knowledge on the mechanism of neurotoxic action of C. ensiformis ureases would help to establish the relevance of these toxins in many infectious diseases caused by urease-producing microorganisms, particularly those affecting the human central nervous system. |
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Carlini, Celia Regina Ribeiro da Silvahttp://lattes.cnpq.br/5587901760491970Belo, Cháriston André Dalhttp://lattes.cnpq.br/3500651347964867http://lattes.cnpq.br/9653443466915942Almeida, Carlos Gabriel Moreira de2020-11-30T13:24:57Z2020-03-27http://tede2.pucrs.br/tede2/handle/tede/9444Ureases, metalloenzymes that catalyze the hydrolysis of urea into carbamate and ammonia, are well conserved proteins although differing in their quaternary structures in different organisms. Most plant ureases are hexamers of a single chain subunit, such as the most abundant isoform of the jack bean (Canavalia ensiformis) urease (JBU). Canatoxin (CNTX), originally isolated as a neurotoxic protein from jack bean seeds, was later characterized as an isoform of JBU, with a smaller molecular mass and lower ureolytic activity. Purified CNTX is unstable upon storage, forming inactive oligomers. Treatment of CNTX with 0.02 % v/v formaldehyde stabilizes its toxicity and avoids oligomerization. Canatoxin (CNTX) and Jack Bean Urease (JBU), isoforms of Canavalia ensiformis urease, displays a potent neurotoxicity whose mechanisms of action is not yet completely understood. The neurotoxins provokes convulsions preceding death in mice and rats (Ld50 ~2 mg/kg). Besides promoting hypoxia, hypothermia and inflammation in vivo, the proteins stimulates exocytosis in several cell models, induces neurotransmitter release from synaptosomes and affects calcium transport in platelets and in vesicles of sarcoplasmatic reticulum. For all these effects, CNTX acts by triggering eicosanoid signaling. In this work, we aimed to further characterize CNTX and elucidate the mechanism of its stabilization by formaldehyde treatment and to better understand its neurotoxic convulsant activity through a series of electrophysiological and brain imaging techniques. In this work, we successfully characterized CNTX as a trimeric state of JBU. The mechanism by which the formaldehyde treatment of CNTX avoids its oligomerization and stabilizes its biologically active conformation was elucidated and attributed to modifications introduced in the side chain of amino acid residues located at the interface between the two trimers that form the hexameric JBU. There could be multiple mechanisms underlying the seizures induced by C. ensiformis ureases. The mode of action seems to be an indirect one as no effect was detected on several isolated ion channels. It is more likely that CNTX and JBU could be acting at a neuronal network level, thereby disturbing electroencephalographic rhythms and causing metabolic alterations in key areas related to epileptogenesis and to neurogenic pulmonary edema. In the context of neuroinflammation, modulation of lipoxygenase pathways in the CNS appears as an interesting target to focus aiming to unveil the action of these neurotoxins. The lack of LTP induction is more likely caused by a neuroprotection mechanism and/or release of lipoxygenase products than direct interaction of CNTX or JBU with receptors and ion channels. The L-glutamate release induced by JBU could be a result of its membrane disturbing properties or of a lipoxygenase mediated mechanism, as observed for CNTX-induced exocytosis in many cell types. FDGmicroPET data indicated an increase in whole brain metabolism, and in areas related to epileptogenesis such as hippocampus and thalamus. A neurogenic pulmonary edema could be implicated in the convulsant activity of canatoxin, as suggested by the higher [18]FDG uptake in areas responsible for breathing control. Altogether the data emphasize the complexity of the neurotoxic mechanism of action of C. ensiformis ureases. Considering that non-enzymatic properties are shared by ureases of different kingdoms, we hope that deepening the knowledge on the mechanism of neurotoxic action of C. ensiformis ureases would help to establish the relevance of these toxins in many infectious diseases caused by urease-producing microorganisms, particularly those affecting the human central nervous system.As ureases, metaloenzimas que catalisam a hidrólise da ureia em carbamato e amônia, são proteínas bem conservadas embora diferindo em suas estruturas quaternárias em diferentes organismos. A maioria das ureases vegetais são hexâmeros de uma subunidade de cadeia única, como a isoforma mais abundante da urease do feijão de porco (Canavalia ensiformis) (JBU). A canatoxina (CNTX), originalmente isolada como proteína neurotóxica de sementes de feijão de porco, foi posteriormente caracterizada como uma isoforma de JBU, com menor massa molecular e menor atividade ureolítica. A CNTX purificada é instável durante o armazenamento, formando oligômeros inativos. O tratamento da CNTX com formaldeído a 0,02% v/v estabiliza sua toxicidade e evita a oligomerização. Canatoxina (CNTX) e Jack Bean Urease (JBU), isoformas da urease de Canavalia ensiformis, apresentam uma potente neurotoxicidade cujos mecanismos de ação ainda não estão completamente esclarecidos. As neurotoxinas provocam convulsões que precedem a morte em camundongos e ratos (Ld50 ~ 2 mg/kg). Além de promover hipóxia, hipotermia e inflamação in vivo, as proteínas estimulam a exocitose em diversos modelos celulares, induzem a liberação de neurotransmissores dos sinaptossomas e afetam o transporte de cálcio nas plaquetas e nas vesículas do retículo sarcoplasmático. Para todos esses efeitos, a CNTX atua desencadeando a sinalização de eicosanóides. Neste trabalho, objetivamos caracterizar ainda mais a CNTX e elucidar o mecanismo de sua estabilização pelo tratamento com formaldeído e compreender melhor sua atividade convulsiva neurotóxica por meio de uma série de técnicas eletrofisiológicas e de neuroimagem. Neste trabalho, caracterizamos com sucesso a CNTX como um estado trimérico de JBU. O mecanismo pelo qual o tratamento com formaldeído do CNTX evita sua oligomerização e estabiliza sua conformação biologicamente ativa foi elucidado e atribuído às modificações introduzidas na cadeia lateral de resíduos de aminoácidos localizados na interface entre os dois trímeros que formam a JBU hexamérica. Pode haver vários mecanismos subjacentes às convulsões induzidas por ureases de C. ensiformis. O modo de ação parece ser indireto, pois nenhum efeito foi detectado em vários canais iônicos isolados. É mais provável que a CNTX e a JBU possam estar atuando em um nível de rede neuronal, perturbando assim os ritmos eletroencefalográficos e causando alterações metabólicas em áreas-chave relacionadas à epileptogênese e ao edema pulmonar neurogênico. No contexto da neuroinflamação, a modulação das vias da lipoxigenase no SNC surge como um alvo interessante a ser focado com o objetivo de desvendar a ação dessas neurotoxinas. A falta de indução de LTP é mais provavelmente causada por um mecanismo de neuroproteção e / ou liberação de produtos de lipoxigenase do que a interação direta de CNTX ou JBU com receptores e canais iônicos. A liberação de L-glutamato induzida por JBU pode ser resultado de suas propriedades de perturbação da membrana ou de um mecanismo mediado pela lipoxigenase, conforme observado para a exocitose induzida por CNTX em muitos tipos de células. Os dados do [18]FDGmicroPET indicaram um aumento no metabolismo cerebral de glicose em áreas relacionadas à epileptogênese, como hipocampo e tálamo. Um edema pulmonar neurogênico pode contribuir para a atividade convulsiva da canatoxina, como sugerido pela captação mais elevada de [18]FDG em áreas responsáveis pelo controle da respiração. Em conjunto, os dados enfatizam a complexidade do mecanismo de ação neurotóxico das ureases de C. ensiformis. Considerando que as propriedades não enzimáticas são compartilhadas por ureases de diferentes reinos, esperamos que o aprofundamento do conhecimento sobre o mecanismo de ação neurotóxica das ureases de C. ensiformis ajude a estabelecer a relevância dessas toxinas em muitas doenças infecciosas causadas por microrganismos produtores de urease, particularmente aqueles que afetam o sistema nervoso central humano.Submitted by PPG Medicina e Ciências da Saúde (medicina-pg@pucrs.br) on 2020-07-24T13:33:47Z No. of bitstreams: 1 Tese doutorado Gabriel Versão Final Português.pdf: 3080031 bytes, checksum: 1897655a022663600aa4ddcab9945ab7 (MD5)Rejected by Caroline Xavier (caroline.xavier@pucrs.br), reason: Devolvido devido ao material PDF não possui folha de rosto (página com as principais informações), passando direto da capa para a ficha catalográfica. on 2020-10-29T19:57:43Z (GMT)Submitted by PPG Medicina e Ciências da Saúde (medicina-pg@pucrs.br) on 2020-10-30T17:35:47Z No. of bitstreams: 1 Tese final - Carlos Gabriel.pdf: 3064493 bytes, checksum: c8b311f316bb724c46fda4fc7cca7527 (MD5)Rejected by Sheila Dias (sheila.dias@pucrs.br), reason: Retornei novamente, via sistema TEDE2, a tese do aluno Carlos Gabriel Moreira de Almeida, devido continuar faltando a folha de rosto no trabalho que consta as principais informações, como por exemplo orientador, e falta também resumo e abstract geral. on 2020-11-23T14:31:58Z (GMT)Submitted by PPG Medicina e Ciências da Saúde (medicina-pg@pucrs.br) on 2020-11-25T11:09:08Z No. of bitstreams: 1 Tese CORRIGIDA.pdf: 3097861 bytes, checksum: 3c3b6431b3f4b8247b28f13fd5498e16 (MD5)Approved for entry into archive by Sheila Dias (sheila.dias@pucrs.br) on 2020-11-30T13:01:28Z (GMT) No. of bitstreams: 1 Tese CORRIGIDA.pdf: 3097861 bytes, checksum: 3c3b6431b3f4b8247b28f13fd5498e16 (MD5)Made available in DSpace on 2020-11-30T13:24:57Z (GMT). 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dc.title.por.fl_str_mv |
Ureases de canavalia ensiformis : estudos estruturais e da atividade pró-convulsivante |
title |
Ureases de canavalia ensiformis : estudos estruturais e da atividade pró-convulsivante |
spellingShingle |
Ureases de canavalia ensiformis : estudos estruturais e da atividade pró-convulsivante Almeida, Carlos Gabriel Moreira de Ureases Canatoxina JBU Canavalia Ensiformis Espectrometria de Massas Eletrofisiologia Neuroimagem Ureases Canatoxin JBU Canavalia Ensiformis Electrophysiology Neuroimage CIENCIAS DA SAUDE::MEDICINA |
title_short |
Ureases de canavalia ensiformis : estudos estruturais e da atividade pró-convulsivante |
title_full |
Ureases de canavalia ensiformis : estudos estruturais e da atividade pró-convulsivante |
title_fullStr |
Ureases de canavalia ensiformis : estudos estruturais e da atividade pró-convulsivante |
title_full_unstemmed |
Ureases de canavalia ensiformis : estudos estruturais e da atividade pró-convulsivante |
title_sort |
Ureases de canavalia ensiformis : estudos estruturais e da atividade pró-convulsivante |
author |
Almeida, Carlos Gabriel Moreira de |
author_facet |
Almeida, Carlos Gabriel Moreira de |
author_role |
author |
dc.contributor.advisor1.fl_str_mv |
Carlini, Celia Regina Ribeiro da Silva |
dc.contributor.advisor1Lattes.fl_str_mv |
http://lattes.cnpq.br/5587901760491970 |
dc.contributor.advisor-co1.fl_str_mv |
Belo, Cháriston André Dal |
dc.contributor.advisor-co1Lattes.fl_str_mv |
http://lattes.cnpq.br/3500651347964867 |
dc.contributor.authorLattes.fl_str_mv |
http://lattes.cnpq.br/9653443466915942 |
dc.contributor.author.fl_str_mv |
Almeida, Carlos Gabriel Moreira de |
contributor_str_mv |
Carlini, Celia Regina Ribeiro da Silva Belo, Cháriston André Dal |
dc.subject.por.fl_str_mv |
Ureases Canatoxina JBU Canavalia Ensiformis Espectrometria de Massas Eletrofisiologia Neuroimagem |
topic |
Ureases Canatoxina JBU Canavalia Ensiformis Espectrometria de Massas Eletrofisiologia Neuroimagem Ureases Canatoxin JBU Canavalia Ensiformis Electrophysiology Neuroimage CIENCIAS DA SAUDE::MEDICINA |
dc.subject.eng.fl_str_mv |
Ureases Canatoxin JBU Canavalia Ensiformis Electrophysiology Neuroimage |
dc.subject.cnpq.fl_str_mv |
CIENCIAS DA SAUDE::MEDICINA |
description |
Ureases, metalloenzymes that catalyze the hydrolysis of urea into carbamate and ammonia, are well conserved proteins although differing in their quaternary structures in different organisms. Most plant ureases are hexamers of a single chain subunit, such as the most abundant isoform of the jack bean (Canavalia ensiformis) urease (JBU). Canatoxin (CNTX), originally isolated as a neurotoxic protein from jack bean seeds, was later characterized as an isoform of JBU, with a smaller molecular mass and lower ureolytic activity. Purified CNTX is unstable upon storage, forming inactive oligomers. Treatment of CNTX with 0.02 % v/v formaldehyde stabilizes its toxicity and avoids oligomerization. Canatoxin (CNTX) and Jack Bean Urease (JBU), isoforms of Canavalia ensiformis urease, displays a potent neurotoxicity whose mechanisms of action is not yet completely understood. The neurotoxins provokes convulsions preceding death in mice and rats (Ld50 ~2 mg/kg). Besides promoting hypoxia, hypothermia and inflammation in vivo, the proteins stimulates exocytosis in several cell models, induces neurotransmitter release from synaptosomes and affects calcium transport in platelets and in vesicles of sarcoplasmatic reticulum. For all these effects, CNTX acts by triggering eicosanoid signaling. In this work, we aimed to further characterize CNTX and elucidate the mechanism of its stabilization by formaldehyde treatment and to better understand its neurotoxic convulsant activity through a series of electrophysiological and brain imaging techniques. In this work, we successfully characterized CNTX as a trimeric state of JBU. The mechanism by which the formaldehyde treatment of CNTX avoids its oligomerization and stabilizes its biologically active conformation was elucidated and attributed to modifications introduced in the side chain of amino acid residues located at the interface between the two trimers that form the hexameric JBU. There could be multiple mechanisms underlying the seizures induced by C. ensiformis ureases. The mode of action seems to be an indirect one as no effect was detected on several isolated ion channels. It is more likely that CNTX and JBU could be acting at a neuronal network level, thereby disturbing electroencephalographic rhythms and causing metabolic alterations in key areas related to epileptogenesis and to neurogenic pulmonary edema. In the context of neuroinflammation, modulation of lipoxygenase pathways in the CNS appears as an interesting target to focus aiming to unveil the action of these neurotoxins. The lack of LTP induction is more likely caused by a neuroprotection mechanism and/or release of lipoxygenase products than direct interaction of CNTX or JBU with receptors and ion channels. The L-glutamate release induced by JBU could be a result of its membrane disturbing properties or of a lipoxygenase mediated mechanism, as observed for CNTX-induced exocytosis in many cell types. FDGmicroPET data indicated an increase in whole brain metabolism, and in areas related to epileptogenesis such as hippocampus and thalamus. A neurogenic pulmonary edema could be implicated in the convulsant activity of canatoxin, as suggested by the higher [18]FDG uptake in areas responsible for breathing control. Altogether the data emphasize the complexity of the neurotoxic mechanism of action of C. ensiformis ureases. Considering that non-enzymatic properties are shared by ureases of different kingdoms, we hope that deepening the knowledge on the mechanism of neurotoxic action of C. ensiformis ureases would help to establish the relevance of these toxins in many infectious diseases caused by urease-producing microorganisms, particularly those affecting the human central nervous system. |
publishDate |
2020 |
dc.date.accessioned.fl_str_mv |
2020-11-30T13:24:57Z |
dc.date.issued.fl_str_mv |
2020-03-27 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/doctoralThesis |
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doctoralThesis |
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publishedVersion |
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http://tede2.pucrs.br/tede2/handle/tede/9444 |
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http://tede2.pucrs.br/tede2/handle/tede/9444 |
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por |
language |
por |
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-721401722658532398 |
dc.relation.confidence.fl_str_mv |
500 500 500 600 |
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info:eu-repo/semantics/openAccess |
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openAccess |
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application/pdf |
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Pontifícia Universidade Católica do Rio Grande do Sul |
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Programa de Pós-Graduação em Medicina e Ciências da Saúde |
dc.publisher.initials.fl_str_mv |
PUCRS |
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Brasil |
dc.publisher.department.fl_str_mv |
Escola de Medicina |
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Pontifícia Universidade Católica do Rio Grande do Sul |
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