Cytoplasmic serine hydroxymethyltransferase mediates competition between folate-dependent deoxyribonucleotide and S-adenosylmethionine biosyntheses
Cytoplasmic serine hydroxymethyltransferase mediates competition between folate-dependent deoxyribonucleotide and S-adenosylmethionine biosyntheses
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DOI：
10.1074/jbc.m205000200
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发表时间：
2002-10-11
影响因子：
4.8
通讯作者：
Stover, PJ
中科院分区：
文献类型：
--
作者：
Herbig, K;Chiang, EP;Stover, PJ
依赖叶酸的一碳代谢是合成嘌呤和胸腺苷所必需的，也是同型半胱氨酸重新甲基化为蛋氨酸所必需的。蛋氨酸随后被腺化为S腺苷蛋氨酸，这是一种辅助因子，使脱氧核糖核酸、蛋白质和许多代谢物甲基化。以前的实验和理论模拟研究表明，叶酸辅助因子对细胞质叶酸依赖的反应是有限的，DNA前体的合成与SAM的合成竞争。每一项研究都得出结论，SAM合成比DTMP合成具有更高的代谢优先级。在MCF-7细胞中检测胞浆丝氨酸羟甲基转移酶(CSHMT)对这一竞争的影响。CSHMT表达的增加通过两种机制抑制SAM浓度：(1)cSHMT催化的丝氨酸合成以甘氨酸依赖的方式与亚甲基四氢叶酸还原酶竞争亚甲基四氢叶酸；(2)cSHMT是一种高亲和力的5-甲基四氢叶酸结合蛋白，它隔离了这种辅因子并以甘氨酸不依赖的方式抑制蛋氨酸的合成。稳定同位素示踪研究表明，cSHMT在DTMP和SAM合成之间的一碳单元通量中起着重要的调节作用。我们认为，cSHMT在细胞质中有三个重要功能：(1)优先为胸苷生物合成提供一碳单位；(2)通过合成丝氨酸耗尽四氢叶酸亚甲酯合成SAM；(3)隔离5-甲基四氢叶酸并抑制SAM合成。这些结果表明，cSHMT是一个代谢开关，当被激活时，DTMP合成比SAM合成具有更高的代谢优先级。
Folate-dependent one-carbon metabolism is required for the synthesis of purines and thymidylate and for the remethylation of homocysteine to methionine. Methionine is subsequently adenylated to S-adenosylmethionine (SAM), a cofactor that methylates DNA, RNA, proteins, and many metabolites. Previous experimental and theoretical modeling studies have indicated that folate cofactors are limiting for cytoplasmic folate-dependent reactions and that the synthesis of DNA precursors competes with SAM synthesis. Each of these studies concluded that SAM synthesis has a higher metabolic priority than dTMP synthesis. The influence of cytoplasmic serine hydroxymethyltransferase (cSHMT) on this competition was examined in MCF-7 cells. Increases in cSHMT expression inhibit SAM concentrations by two proposed mechanisms: (1) cSHMT-catalyzed serine synthesis competes with the enzyme methylenetetrahydrofolate reductase for methylenetetrahydrofolate in a glycine-dependent manner, and (2) cSHMT, a high affinity 5-methyltetrahydrofolate-binding protein, sequesters this cofactor and inhibits methionine synthesis in a glycine-independent manner. Stable isotope tracer studies indicate that cSHMT plays an important role in mediating the flux of one-carbon units between dTMP and SAM syntheses. We conclude that cSHMT has three important functions in the cytoplasm: (1) it preferentially supplies one-carbon units for thymidylate biosynthesis, (2) it depletes methylenctetrahydrofolate pools for SAM synthesis by synthesizing serine, and (3) it sequesters 5-methyltetrahydrofolate and inhibits SAM synthesis. These results indicate that cSHMT is a metabolic switch that, when activated, gives dTMP synthesis higher metabolic priority than SAM synthesis.