A mathematical model of tryptophan metabolism via the kynurenine pathway provides insights into the effects of vitamin B-6 deficiency, tryptophan loading, and induction of tryptophan 2,3-dioxygenase on tryptophan metabolites.
A mathematical model of tryptophan metabolism via the kynurenine pathway provides insights into the effects of vitamin B-6 deficiency, tryptophan loading, and induction of tryptophan 2,3-dioxygenase on tryptophan metabolites.
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DOI：
10.3945/jn.113.174599
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发表时间：
2013-09
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影响因子：
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通讯作者：
Luisa Rios‐Avila;H. Nijhout;M. Reed;H. Sitren;J. Gregory
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作者：
Luisa Rios‐Avila;H. Nijhout;M. Reed;H. Sitren;J. Gregory
维生素B-6缺乏与色氨酸代谢受损相关，因为吡哆醛5 '-磷酸（PLP）对犬尿氨酸酶和犬尿氨酸氨基转移酶具有辅酶作用。为了研究潜在的机制，我们开发了通过犬尿氨酸途径的色氨酸代谢的数学模型。该模型包括酶动力学和色氨酸从肠腔转运到肝脏，肌肉和大脑的哺乳动物数据。包括调节机制和相关酶的抑制。我们模拟了细胞PLP浓度、色氨酸负荷和色氨酸2，3-双加氧酶（TDO）诱导的分级降低对代谢产物谱和尿排泄的影响。模型预测与实验数据相匹配，并澄清了不同程度的维生素B-6缺乏时代谢物的反应。我们发现中度缺乏会导致3-羟基犬尿氨酸增加，犬尿烯酸和邻氨基苯甲酸减少。更严重的缺乏也导致犬尿氨酸和黄尿酸的增加，并对其他代谢产物产生更明显的影响。维生素B-6缺乏和不缺乏的色氨酸负荷模拟显示与已发表数据一致的代谢物浓度改变。TDO的诱导引起所有代谢物的增加，并且TDO诱导与模拟的维生素B-6缺乏一起，如在口服避孕药使用者中所报道的，产生犬尿氨酸、3-羟基犬尿氨酸和黄尿酸的增加以及犬尿烯酸和邻氨基苯甲酸的减少。这些结果表明，该模型成功地模拟色氨酸代谢通过犬尿氨酸途径，并可用于补充实验研究。
Vitamin B-6 deficiency is associated with impaired tryptophan metabolism because of the coenzyme role of pyridoxal 5'-phosphate (PLP) for kynureninase and kynurenine aminotransferase. To investigate the underlying mechanism, we developed a mathematical model of tryptophan metabolism via the kynurenine pathway. The model includes mammalian data on enzyme kinetics and tryptophan transport from the intestinal lumen to liver, muscle, and brain. Regulatory mechanisms and inhibition of relevant enzymes were included. We simulated the effects of graded reduction in cellular PLP concentration, tryptophan loads and induction of tryptophan 2,3-dioxygenase (TDO) on metabolite profiles and urinary excretion. The model predictions matched experimental data and provided clarification of the response of metabolites in various extents of vitamin B-6 deficiency. We found that moderate deficiency yielded increased 3-hydroxykynurenine and a decrease in kynurenic acid and anthranilic acid. More severe deficiency also yielded an increase in kynurenine and xanthurenic acid and more pronounced effects on the other metabolites. Tryptophan load simulations with and without vitamin B-6 deficiency showed altered metabolite concentrations consistent with published data. Induction of TDO caused an increase in all metabolites, and TDO induction together with a simulated vitamin B-6 deficiency, as has been reported in oral contraceptive users, yielded increases in kynurenine, 3-hydroxykynurenine, and xanthurenic acid and decreases in kynurenic acid and anthranilic acid. These results show that the model successfully simulated tryptophan metabolism via the kynurenine pathway and can be used to complement experimental investigations.