Thomas Philip, Fenech Michael
CSIRO Human Nutrition, Adelaide BC, Adelaide, South Australia 5000.
Vitam Horm. 2008;79:375-92. doi: 10.1016/S0083-6729(08)00413-5.
Folate plays a key role in maintaining genomic stability and providing methyl groups for the formation of dTMP from dUMP which is required for DNA synthesis and repair and for the maintenance of methylation patterns involving cytosine or specific sites such as CpG islands. Under conditions of low folate, dUMP accumulates producing DNA strand breaks and micronucleus formation as a result of excessive uracil incorporation into DNA in place of thymine. Methylenetetrahydrofolate reductase (MTHFR) is an important folate metabolizing enzyme that catalyzes the irreversible conversion of 5,10-methylenetretrahydrofolate, which is the methyl donor for the conversion of dUMP to dTMP, into 5-methyltetrahydrofolate, which is the methyl donor for remethylation of homocysteine to methionine. Certain common polymorphisms within the MTHFR gene (C677T, A1298C) result in reduced enzymatic activity and have been associated with reduced risk for a variety of cancers such as acute lymphocytic leukemia, lung and colorectal cancer. These common polymorphisms are also associated with hyperhomocysteinemia that has been reported to be an increased risk factor for neural tube defects and cardiovascular disease. In this chapter, we consider the role that MTHFR plays in relation to folate metabolism and the possible contribution made in relation to certain important clinical outcomes.
叶酸在维持基因组稳定性以及为从脱氧尿苷单磷酸（dUMP）形成脱氧胸苷单磷酸（dTMP）提供甲基基团方面发挥着关键作用，这对于DNA合成、修复以及维持涉及胞嘧啶或特定位点（如CpG岛）的甲基化模式是必需的。在低叶酸条件下，dUMP积累，由于尿嘧啶过量掺入DNA取代胸腺嘧啶，导致DNA链断裂和微核形成。亚甲基四氢叶酸还原酶（MTHFR）是一种重要的叶酸代谢酶，它催化5,10 - 亚甲基四氢叶酸（dUMP转化为dTMP的甲基供体）不可逆地转化为5 - 甲基四氢叶酸（同型半胱氨酸再甲基化生成甲硫氨酸的甲基供体）。MTHFR基因内的某些常见多态性（C677T、A1298C）会导致酶活性降低，并与多种癌症（如急性淋巴细胞白血病、肺癌和结直肠癌）的风险降低有关。这些常见多态性还与高同型半胱氨酸血症有关，据报道，高同型半胱氨酸血症是神经管缺陷和心血管疾病的一个风险增加因素。在本章中，我们将探讨MTHFR在叶酸代谢中的作用以及与某些重要临床结果的可能关系。
