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Mouse lysine catabolism to aminoadipate occurs primarily through the saccharopine pathway; implications for pyridoxine dependent epilepsy (PDE).
Pena, Izabella Agostinho; Marques, Lygia Azevedo; Laranjeira, Ângelo B A; Yunes, José A; Eberlin, Marcos N; MacKenzie, Alex; Arruda, Paulo.
Afiliação
  • Pena IA; Centro de Biologia Molecular e Engenharia Genética, Universidade Estadual de Campinas (UNICAMP), 13083-875 Campinas, SP, Brazil; Children's Hospital of Eastern Ontario (CHEO) Research Institute, Ottawa, ON, Canada.
  • Marques LA; ThoMson Mass Spectrometry Laboratory, Universidade Estadual de Campinas (UNICAMP), 13083-861 Campinas, SP, Brazil.
  • Laranjeira ÂB; Departamento de Genética Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas (UNICAMP), 13083-887 Campinas, SP, Brazil.
  • Yunes JA; Centro Infantil Boldrini, Universidade Estadual de Campinas (UNICAMP),13083-210 Campinas, SP, Brazil; Departamento de Genética Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas (UNICAMP), 13083-887 Campinas, SP, Brazil.
  • Eberlin MN; ThoMson Mass Spectrometry Laboratory, Universidade Estadual de Campinas (UNICAMP), 13083-861 Campinas, SP, Brazil.
  • MacKenzie A; Children's Hospital of Eastern Ontario (CHEO) Research Institute, Ottawa, ON, Canada.
  • Arruda P; Centro de Biologia Molecular e Engenharia Genética, Universidade Estadual de Campinas (UNICAMP), 13083-875 Campinas, SP, Brazil; Departamento de Genética e Evolução, Instituto de Biologia, Universidade Estadual de Campinas (UNICAMP), 13083-970 Campinas, SP, Brazil; Structural Genomics Consortium, Un
Biochim Biophys Acta Mol Basis Dis ; 1863(1): 121-128, 2017 01.
Article em En | MEDLINE | ID: mdl-27615426
Lysine is catabolized in mammals through the saccharopine and pipecolate pathways - the former is mainly hepatic and renal, and the latter is believed to play a role in the cerebral lysine oxidation. Both pathways lead to the formation of aminoadipic semialdehyde (AASA) that is then oxidized to aminoadipate (AAA) by antiquitin (ALDH7A1). Mutations in the ALDH7A1 gene result in the accumulation of AASA and its cyclic form, piperideine-6-carboxylate (P6C), which causes pyridoxine-dependent epilepsy (PDE). P6C reacts with pyridoxal 5'-phosphate (PLP) causing its inactivation. Here, we used liquid chromatography-mass spectrometry to investigate lysine catabolism in mice injected with lysine labelled at either its nitrogen epsilon (ε-15N) or nitrogen alpha (α-15N). Analysis of ε-15N and α-15N lysine catabolites in plasma, liver and brain suggested the saccharopine as the main pathway for AAA biosynthesis. Although there was evidence for upstream cerebral pipecolate pathway activity, the resulting pipecolate does not appear to be further oxidized into AASA/P6C/AAA. By far the bulk of lysine degradation and therefore, the primary source of lysine catabolites are hepatic and renal. The results indicate that the saccharopine pathway is primarily responsible for body's production of AASA/P6C. The centrality of the saccharopine pathway in whole body lysine catabolism opens new possibilities of therapeutic targets for PDE. We suggest that inhibition of this pathway upstream of AASA/P6C synthesis may be used to prevent its accumulation benefiting PDE patients. Inhibition of the enzyme aminoadipic semialdehyde synthase, for example, could constitute a new strategy to treat PDE and other inherited diseases of lysine catabolism.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Epilepsia / Redes e Vias Metabólicas / Ácido 2-Aminoadípico / Lisina Limite: Animals Idioma: En Revista: Biochim Biophys Acta Mol Basis Dis Ano de publicação: 2017 Tipo de documento: Article País de afiliação: Canadá

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Epilepsia / Redes e Vias Metabólicas / Ácido 2-Aminoadípico / Lisina Limite: Animals Idioma: En Revista: Biochim Biophys Acta Mol Basis Dis Ano de publicação: 2017 Tipo de documento: Article País de afiliação: Canadá