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.
ThoMson Mass Spectrometry Laboratory, Universidade Estadual de Campinas (UNICAMP), 13083-861 Campinas, SP, Brazil.
Biochim Biophys Acta Mol Basis Dis. 2017 Jan;1863(1):121-128. doi: 10.1016/j.bbadis.2016.09.006. Epub 2016 Sep 8.
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-N) or nitrogen alpha (α-N). Analysis of ε-N and α-N 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.
赖氨酸在哺乳动物中通过 saccharopine 和 pipecolate 途径进行分解代谢 - 前者主要在肝脏和肾脏中进行，而后者被认为在大脑赖氨酸氧化中发挥作用。这两种途径都会导致氨基己二酸半醛（AASA）的形成，然后由 antiquitin（ALDH7A1）将其氧化为氨基己二酸（AAA）。ALDH7A1 基因的突变会导致 AASA 及其环状形式哌啶-6-羧酸（P6C）的积累，从而导致吡哆醇依赖性癫痫（PDE）。P6C 与吡哆醛 5'-磷酸（PLP）反应导致其失活。在这里，我们使用液相色谱-质谱法研究了用氮 ε（ε-N）或氮 α（α-N）标记的赖氨酸注射的小鼠中的赖氨酸分解代谢。对血浆、肝脏和大脑中 ε-N 和 α-N 赖氨酸分解代谢产物的分析表明 saccharopine 是 AAA 生物合成的主要途径。尽管有证据表明存在大脑上游 pipecolate 途径的活性，但产生的 pipecolate 似乎不会进一步氧化成 AASA/P6C/AAA。迄今为止，赖氨酸降解的大部分，因此也是赖氨酸分解代谢产物的主要来源是肝脏和肾脏。结果表明，saccharopine 途径主要负责体内 AASA/P6C 的产生。saccharopine 途径在全身赖氨酸分解代谢中的中心地位为 PDE 开辟了新的治疗靶点的可能性。我们建议，抑制 AASA/P6C 合成上游的 saccharopine 途径可能有助于防止其积累，从而使 PDE 患者受益。例如，抑制氨基己二酸半醛合酶可能构成治疗 PDE 和其他赖氨酸分解代谢遗传疾病的新策略。
