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|Title:||Mouse Lysine Catabolism To Aminoadipate Occurs Primarily Through The Saccharopine Pathway; Implications For Pyridoxine Dependent Epilepsy (pde)|
Mouse lysine catabolism to aminoadipate occurs primarily through the saccharopine pathway
implications for pyridoxine dependent epilepsy (PDE)
|Author:||Pena, Izabella Agostinho|
Marques, Lygia Azevedo
Laranjeira, Ângelo B.A.
Yunes, José A.
Eberlin, Marcos N.
|Abstract:||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 (epsilon-N-15) or nitrogen alpha (alpha-N-15). Analysis of epsilon-N-15 and alpha-N-15 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. (C) 2016 Elsevier B.V. All rights reserved.|
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 semi
Pyridoxine Dependent Epilepsy
Aminoadipate Semialdehyde Synthase
Lisina - Catabolismo
Epilepsia dependente de piridoxina
|Citation:||Biochimica Et Biophysica Acta (bba) - Molecular Basis Of Disease. Elsevier Science Bv, v. 1863, p. 121 - 128, 2017.|
|Appears in Collections:||IQ - Artigos e Outros Documentos|
IB - Artigos e Outros Documentos
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