Vargason Troy, Howsmon Daniel P, Melnyk Stepan, James S Jill, Hahn Juergen
Department of Biomedical Engineering, Rensselaer Polytechnic Institute, 110 8th Street, Troy, NY 12180, USA.
Department of Chemical and Biological Engineering, Rensselaer Polytechnic Institute, 110 8th Street, Troy, NY 12180, USA.
J Theor Biol. 2017 Mar 7;416:28-37. doi: 10.1016/j.jtbi.2016.12.021. Epub 2016 Dec 29.
Previous research has shown a connection between metabolic abnormalities in the methionine cycle and transsulfuration pathway and autism spectrum disorder. Using clinical data from a case-control study investigating measurements of transmethylation and transsulfuration metabolites, a steady-state model of these metabolites in liver cells was developed and participant-specific parameters were identified. Comparison of mean parameter values and parameter distributions between neurotypical study participants and those on the autism spectrum revealed significant differences for four model parameters. Sensitivity analysis identified the parameter describing the rate of glutamylcysteine synthesis, the rate-limiting step in glutathione production, to be particularly important in determining steady-state metabolite concentrations. These results may provide insight into key reactions to target for potential intervention strategies relating to autism spectrum disorder.
先前的研究表明，甲硫氨酸循环和转硫途径中的代谢异常与自闭症谱系障碍之间存在联系。利用一项病例对照研究的临床数据，该研究调查了转甲基化和转硫代谢物的测量值，建立了肝细胞中这些代谢物的稳态模型，并确定了参与者特异性参数。对神经典型研究参与者和自闭症谱系参与者之间的平均参数值和参数分布进行比较，发现四个模型参数存在显著差异。敏感性分析确定，描述谷氨酰半胱氨酸合成速率（谷胱甘肽产生的限速步骤）的参数在确定稳态代谢物浓度方面尤为重要。这些结果可能为与自闭症谱系障碍相关的潜在干预策略的关键靶点反应提供见解。
