Banerjee R V, Matthews R G
Biophysics Research Division, University of Michigan, Ann Arbor 48109.
FASEB J. 1990 Mar;4(5):1450-9. doi: 10.1096/fasebj.4.5.2407589.
Cobalamin-dependent methionine synthase catalyzes the transfer of a methyl group from N5-methyltetrahydrofolate to homocysteine, producing tetrahydrofolate and methionine. Insufficient availability of cobalamin, or inhibition of methionine synthase by exposure to nitrous oxide, leads to diminished activity of this enzyme. In humans, severe inhibition of methionine synthase results in the development of megaloblastic anemia, and eventually in subacute combined degeneration of the spinal cord. It also results in diminished intracellular folate levels and a redistribution of folate derivatives. In this review, we summarize recent progress in understanding the catalysis and regulation of this important enzyme from both bacterial and mammalian sources. Because inhibition of mammalian methionine synthase can restrict the incorporation of methyltetrahydrofolate from the blood into cellular folate pools that can be used for nucleotide biosynthesis, it is a potential chemotherapeutic target. The review emphasizes the mechanistic information that will be needed in order to design rational inhibitors of the enzyme.
钴胺素依赖型甲硫氨酸合酶催化将N5-甲基四氢叶酸上的甲基基团转移至同型半胱氨酸，生成四氢叶酸和甲硫氨酸。钴胺素供应不足，或因接触一氧化二氮而抑制甲硫氨酸合酶，都会导致该酶活性降低。在人类中，甲硫氨酸合酶受到严重抑制会导致巨幼细胞贫血的发生，并最终发展为亚急性联合变性脊髓病。它还会导致细胞内叶酸水平降低以及叶酸衍生物的重新分布。在这篇综述中，我们总结了从细菌和哺乳动物来源对这种重要酶的催化作用和调节机制理解的最新进展。由于抑制哺乳动物的甲硫氨酸合酶会限制血液中的甲基四氢叶酸掺入可用于核苷酸生物合成的细胞叶酸池中，因此它是一个潜在的化疗靶点。这篇综述强调了设计该酶合理抑制剂所需的机制信息。
