Wang Mengdie, Zheng Qiwen, You Lei, Wang Huihui, Jia Peilin, Liu Xinyu, Zeng Changqing, Xu Guowang
State Key Laboratory of Medical Proteomics, CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, 116023, China.
Liaoning Province Key Laboratory of Metabolomics, Dalian, 116023, China.
Anal Bioanal Chem. 2025 May;417(13):2807-2821. doi: 10.1007/s00216-024-05688-w. Epub 2024 Dec 18.
Folate, serving as a crucial micronutrient, plays an important role in promoting human growth and supporting transformations to a variety of metabolic pathways including one-carbon, pyrimidine, purine, and homocysteine metabolism. The 5,10-methylenetetrahydrofolate reductase (MTHFR) enzyme is pivotal in the folate metabolic pathway. Polymorphism in the MTHFR gene, especially C677T, was associated with decreased enzyme activity and disturbance of folate metabolism, which is linked to various diseases including birth defects in newborns and neural tube abnormalities. However, the detailed metabolic disturbance induced by MTHFR C677T polymorphism is still elusive. In this study, a novel liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the precise quantification of 93 metabolites from six important metabolic pathways related to folate metabolism. The method characteristics demonstrated high accuracy and precision, with r values ranging from 0.981 to 1.000 for all metabolites. Then the impact of the MTHFR C677T polymorphism on folate metabolism was further investigated, revealing a significant reduction in the level of 5-methyltetrahydrofolate and abnormal levels of metabolites associated with DNA synthesis pathways in individuals carrying the mutation. These data highlight the pivotal role of folic acid supplementation for individuals with the MTHFR C677T polymorphism to mitigate health risks and show the value of precision measurement of folate-related metabolites.
叶酸作为一种关键的微量营养素，在促进人体生长以及支持向多种代谢途径的转变中发挥着重要作用，这些代谢途径包括一碳代谢、嘧啶代谢、嘌呤代谢和同型半胱氨酸代谢。5,10-亚甲基四氢叶酸还原酶（MTHFR）在叶酸代谢途径中起关键作用。MTHFR基因的多态性，尤其是C677T，与酶活性降低和叶酸代谢紊乱有关，这与包括新生儿出生缺陷和神经管异常在内的多种疾病相关。然而，MTHFR C677T多态性引起的详细代谢紊乱仍不清楚。在本研究中，开发了一种新型液相色谱-串联质谱（LC-MS/MS）方法，用于精确测定与叶酸代谢相关的六个重要代谢途径中的93种代谢物。该方法具有高准确性和精密度，所有代谢物的r值范围为0.981至1.000。然后进一步研究了MTHFR C677T多态性对叶酸代谢的影响，结果显示携带该突变的个体中5-甲基四氢叶酸水平显著降低，与DNA合成途径相关的代谢物水平异常。这些数据突出了叶酸补充剂对携带MTHFR C677T多态性个体减轻健康风险的关键作用，并显示了精确测量叶酸相关代谢物的价值。
