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Doctoral Thesis
DOI
10.11606/T.42.2013.tde-26092013-100436
Document
Author
Full name
Natália Mazini Ribeiro
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2013
Supervisor
Committee
Ferro, Emer Suavinho (President)
Oliveira, Vitor Marcelo Silveira Bueno Brandão de
Pagano, Rosana de Lima
Portaro, Fernanda Calheta Vieira
Torrão, Andréa da Silva
Title in Portuguese
AGH é um novo fragmento da cadeia alfa da hemoglobina com atividade antinociceptiva.
Keywords in Portuguese
Dor
Espectrometria de massas
Hemoglobinas
Metabolismo de proteína
Nociceptores
Peptídeos
Abstract in Portuguese
A proteólise limitada de certas proteínas leva à liberação de peptídeos opióides endógenos. Vários relatos apontam que peptídeos derivados da hemoglobina como hemorfinas e hemopressinas têm efeito antinociceptivo, pela atividade de modulação de receptores acoplados a proteínas G. No presente estudo, um ensaio de captura do substrato (ECS) foi combinado com a marcação isotópica e LC-MS/MS para identificar e caracterizar um novo fragmento da hemoglobina que se liga à EP24.15. O peptídeo AGH, identificado neste trabalho, inibe respostas de hipernocicepção periféricas através de receptores opióides do tipo m . A persistência do peptídeo AGH no tecido nervoso perfundido sugere relevância fisiológica. Embora o AGH seja derivado de hemoglobina e tenha atividade opióide, falta-lhe a sequência chave das hemorfinas (YPWT), indicando que ele pode pertencer a uma nova classe de peptídeos derivados da hemoglobina. Adicionalmente, o AGH modula as interações entre as proteínas 14-3-3e e EP24.15 in vitro, podendo estar relacionado com a secreção não convencional da EP24.15.
Title in English
AGH is a new hemoglobin alpha-chain fragment with antinociceptive activity.
Keywords in English
Hemoglobin
Mass spectrometry
Nociceptors
Pain
Peptides
Protein metabolism
Abstract in English
Limited proteolysis of certain proteins leads to the release of endogenous opioid peptides. Several reports have shown that hemoglobin-derived peptides such as hemorphins and hemopressins have an antinociceptive effect by modulating GPCR activity. In the present study, a substrate capture assay (SCA) was combined with isotopic labeling and LC-MS/MS to identify and characterize a new bioactive hemoglobin fragment that binds to EP24.15. AGH, a new peptide identified in this work, inhibits peripheral hyperalgesic responses through m opioid receptors (MOR). The persistence of AGH peptide in perfused nervous tissue suggests its physiological relevance. Although AGH is derived from hemoglobin and it is a peptide with opioid activity, it lacks the key sequence of hemorphins (YPWT), indicating that it is part of a new class of peptides derived from hemoglobin. Additionally, the AGH modulates interactions between 14-3-3e and EP24.15 proteins in vitro and may be related to the unconventional EP24.15 secretion.
 
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Publishing Date
2013-12-06
 
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