MacFarlane Amanda J, Liu Xiaowen, Perry Cheryll A, Flodby Per, Allen Robert H, Stabler Sally P, Stover Patrick J
Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853, USA.
J Biol Chem. 2008 Sep 19;283(38):25846-53. doi: 10.1074/jbc.M802671200. Epub 2008 Jul 21.
The hydroxymethyl group of serine is a primary source of tetrahydrofolate (THF)-activated one-carbon units that are required for the synthesis of purines and thymidylate and for S-adenosylmethionine (AdoMet)-dependent methylation reactions. Serine hydroxymethyltransferase (SHMT) catalyzes the reversible and THF-dependent conversion of serine to glycine and 5,10-methylene-THF. SHMT is present in eukaryotic cells as mitochondrial SHMT and cytoplasmic (cSHMT) isozymes that are encoded by distinct genes. In this study, the essentiality of cSHMT-derived THF-activated one-carbons was investigated by gene disruption in the mouse germ line. Mice lacking cSHMT are viable and fertile, demonstrating that cSHMT is not an essential source of THF-activated one-carbon units. cSHMT-deficient mice exhibit altered hepatic AdoMet levels and uracil content in DNA, validating previous in vitro studies that indicated this enzyme regulates the partitioning of methylenetetrahydrofolate between the thymidylate and homocysteine remethylation pathways. This study suggests that mitochondrial SHMT-derived one-carbon units are essential for folate-mediated one-carbon metabolism in the cytoplasm.
丝氨酸的羟甲基是四氢叶酸（THF）激活的一碳单位的主要来源，这些一碳单位是嘌呤和胸苷酸合成以及S-腺苷甲硫氨酸（AdoMet）依赖性甲基化反应所必需的。丝氨酸羟甲基转移酶（SHMT）催化丝氨酸可逆且依赖THF的转化为甘氨酸和5,10-亚甲基-THF。SHMT在真核细胞中以线粒体SHMT和细胞质（cSHMT）同工酶的形式存在，它们由不同的基因编码。在本研究中，通过小鼠种系中的基因敲除研究了cSHMT衍生的THF激活的一碳单位的必要性。缺乏cSHMT的小鼠是存活且可育的，这表明cSHMT不是THF激活的一碳单位的必需来源。cSHMT缺陷小鼠表现出肝脏AdoMet水平和DNA中尿嘧啶含量的改变，证实了先前的体外研究，该研究表明该酶调节亚甲基四氢叶酸在胸苷酸和同型半胱氨酸再甲基化途径之间的分配。这项研究表明，线粒体SHMT衍生的一碳单位对于细胞质中叶酸介导的一碳代谢至关重要。
