当前位置: X-MOL 学术Genes Dis. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Metabolomic studies in the inborn error of metabolism alkaptonuria reveal new biotransformations in tyrosine metabolism
Genes & Diseases ( IF 6.8 ) Pub Date : 2021-02-22 , DOI: 10.1016/j.gendis.2021.02.007
Brendan P Norman 1 , Andrew S Davison 2 , Juliette H Hughes 1 , Hazel Sutherland 1, 3 , Peter Jm Wilson 1 , Neil G Berry 4 , Andrew T Hughes 2 , Anna M Milan 2 , Jonathan C Jarvis 3 , Norman B Roberts 1 , Lakshminarayan R Ranganath 2 , George Bou-Gharios 1 , James A Gallagher 1
Affiliation  

Alkaptonuria (AKU) is an inherited disorder of tyrosine metabolism caused by lack of active enzyme homogentisate 1,2-dioxygenase (HGD). The primary consequence of HGD deficiency is increased circulating homogentisic acid (HGA), the main agent in the pathology of AKU disease. Here we report the first metabolomic analysis of AKU homozygous Hgd knockout (Hgd−/−) mice to model the wider metabolic effects of Hgd deletion and the implication for AKU in humans. Untargeted metabolic profiling was performed on urine from Hgd−/− AKU (n = 15) and Hgd+/− non-AKU control (n = 14) mice by liquid chromatography high-resolution time-of-flight mass spectrometry (Experiment 1). The metabolites showing alteration in Hgd−/− were further investigated in AKU mice (n = 18) and patients from the UK National AKU Centre (n = 25) at baseline and after treatment with the HGA-lowering agent nitisinone (Experiment 2). A metabolic flux experiment was carried out after administration of 13C-labelled HGA to Hgd−/−(n = 4) and Hgd+/−(n = 4) mice (Experiment 3) to confirm direct association with HGA. Hgd−/− mice showed the expected increase in HGA, together with unexpected alterations in tyrosine, purine and TCA-cycle pathways. Metabolites with the greatest abundance increases in Hgd−/− were HGA and previously unreported sulfate and glucuronide HGA conjugates, these were decreased in mice and patients on nitisinone and shown to be products from HGA by the 13C-labelled HGA tracer. Our findings reveal that increased HGA in AKU undergoes further metabolism by mainly phase II biotransformations. The data advance our understanding of overall tyrosine metabolism, demonstrating how specific metabolic conditions can elucidate hitherto undiscovered pathways in biochemistry and metabolism.



中文翻译:

先天性代谢性白蛋白尿症的代谢组学研究揭示了酪氨酸代谢中的新生物转化

Alkaptonuria (AKU) 是一种遗传性酪氨酸代谢障碍,由缺乏活性酶高黑酸 1,2-双加氧酶 (HGD) 引起。HGD 缺乏的主要后果是循环高黑酸 (HGA) 增加,这是 AKU 疾病病理学的主要因素。在这里,我们报告了 AKU 纯合Hgd敲除 ( Hgd -/- ) 小鼠的首次代谢组学分析,以模拟Hgd缺失的更广泛的代谢影响以及 AKU 对人类的影响。对来自Hgd -/- AKU ( n  = 15) 和Hgd +/-非 AKU 对照 ( n = 14) 小鼠通过液相色谱高分辨率飞行时间质谱法 (实验 1)。 在基线和用 HGA 降低剂尼替西农治疗后,在 AKU 小鼠 ( n  = 18) 和来自英国国家 AKU 中心的患者 ( n = 25)中进一步研究了显示Hgd -/-改变的代谢物(实验 2)。在向Hgd -/- ( n  = 4)和Hgd +/- ( n = 4)小鼠(实验3)施用13 C-标记的HGA后进行代谢通量实验 以确认与HGA的直接关联。Hgd -/-小鼠表现出预期的 HGA 增加,以及酪氨酸、嘌呤和 TCA 循环途径的意外改变。Hgd -/-中丰度增加最多的代谢物是 HGA 和以前未报道的硫酸盐和葡糖苷酸 HGA 缀合物,这些在服用尼替西农的小鼠和患者中减少,并通过13 C 标记的 HGA 示踪剂显示为来自 HGA 的产物。我们的研究结果表明,AKU 中增加的 HGA 主要通过 II 期生物转化进行进一步代谢。这些数据促进了我们对整体酪氨酸代谢的理解,展示了特定的代谢条件如何阐明迄今为止尚未发现的生物化学和代谢途径。

更新日期:2021-02-22
down
wechat
bug