Mouse lysine catabolism to aminoadipate occurs primarily through the saccharopine pathway; implications for pyridoxine dependent epilepsy (PDE).
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.
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.
Izabella Agostinho
IA
Pena
ThoMson Mass Spectrometry Laboratory, Universidade Estadual de Campinas (UNICAMP), 13083-861 Campinas, SP, Brazil.
Lygia Azevedo
LA
Marques
Departamento de Genética Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas (UNICAMP), 13083-887 Campinas, SP, Brazil.
Ângelo B A
ÂB
Laranjeira
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.
José A
JA
Yunes
ThoMson Mass Spectrometry Laboratory, Universidade Estadual de Campinas (UNICAMP), 13083-861 Campinas, SP, Brazil.
Marcos N
MN
Eberlin
Children's Hospital of Eastern Ontario (CHEO) Research Institute, Ottawa, ON, Canada.
Alex
A
MacKenzie
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, University of Campinas, R. Dr. André Tosello, 550 - CEP: 13083-886, Campinas, OX3 7DQ, Brazil. Electronic address: parruda@unicamp.br.
Paulo
P
Arruda
D015074:2-Aminoadipic Acid / Q000031:analogs & derivatives / Q000378:metabolism*; D000818:Animals; D004827:Epilepsy / Q000378:metabolism*; D005260:Female; D008239:Lysine / Q000031:analogs & derivatives* / Q000378:metabolism*; D053858:Metabolic Networks and Pathways; D051379:Mice; D008810:Mice, Inbred C57BL; D010848:Picolinic Acids / Q000378:metabolism; D011732:Pyridoxal Phosphate / Q000378:metabolism
D010848:Picolinic Acids; D015074:2-Aminoadipic Acid; C008919:delta-1-piperidine-6-carboxylic acid; C000061:allysine; D011732:Pyridoxal Phosphate; D008239:Lysine; C100169:saccharopine
Aminoadipate semialdehyde synthase; Lysine catabolism; Pipecolate; Pyridoxine dependent epilepsy; Saccharopine