蛋氨酸合酶
钴胺素
蛋氨酸
同型半胱氨酸
生物化学
胱硫醚β合酶
ATP合酶
化学
核苷酸
生物
蛋氨酸腺苷转移酶
新陈代谢
酶
基因
氨基酸
维生素B12
作者
Joshua Z. Wang,Jonathan M. Ghergurovich,Lifeng Yang,Joshua D. Rabinowitz
标识
DOI:10.1101/2020.09.05.284521
摘要
Abstract Mammalian cells require activated folates to generate nucleotides for growth and division. The most abundant circulating folate species is 5-methyl tetrahydrofolate (5-methyl-THF), which is used to synthesize methionine from homocysteine via the cobalamin-dependent enzyme methionine synthase (MTR). Cobalamin deficiency traps folates as 5-methyl-THF. Here, we show using isotope tracing that methionine synthase is only a minor source of methionine in cell culture, tissues, or xenografted tumors. Instead, methionine synthase is required for cells to avoid folate trapping and assimilate 5-methyl-THF into other folate species. Under conditions of physiological extracellular folates, genetic MTR knockout in tumor cells leads to folate trapping, purine synthesis stalling, nucleotide depletion, and impaired growth in cell culture and as xenografts. These defects are rescued by free folate but not one-carbon unit supplementation. Thus, MTR plays a crucial role in liberating tetrahydrofolate for use in one-carbon metabolism.
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