Department of Chemistry, University of Iowa, Iowa City, IA 52242, USA.
Arch Biochem Biophys. 2010 Jan 1;493(1):96-102. doi: 10.1016/j.abb.2009.07.016. Epub 2009 Jul 28.
For several decades only one chemical pathway was known for the de novo biosynthesis of the essential DNA nucleotide, thymidylate. This reaction catalyzed by thyA or TYMS encoded thymidylate synthases is the last committed step in the biosynthesis of thymidylate and proceeds via the reductive methylation of uridylate. However, many microorganisms have recently been shown to produce a novel, flavin-dependent thymidylate synthase encoded by the thyX gene. Preliminary structural and mechanistic studies have shown substantial differences between these deoxyuridylate-methylating enzymes. Recently, both the chemical and kinetic mechanisms of FDTS have provided further insight into the distinctions between thyA and thyX encoded thymidylate synthases. Since FDTSs are found in several severe human pathogens their unusual mechanism offers a promising future for the development of antibiotic and antiviral drugs with little effect on human thymidylate biosynthesis.
几十年来，从头生物合成必需的 DNA 核苷酸胸苷酸的唯一化学途径一直为人所知。该反应由 thyA 或 TYMS 编码的胸苷酸合酶催化，是胸苷酸生物合成的最后一个关键步骤，通过尿苷酸的还原甲基化进行。然而，最近许多微生物已被证明能产生一种新型的黄素依赖性胸苷酸合酶，由 thyX 基因编码。初步的结构和机制研究表明，这些脱氧尿苷酸甲基化酶之间存在显著差异。最近，FDTS 的化学和动力学机制为区分 thyA 和 thyX 编码的胸苷酸合酶提供了进一步的认识。由于 FDTS 存在于几种严重的人类病原体中，它们不寻常的机制为开发抗生素和抗病毒药物提供了有希望的未来，对人类胸苷酸的生物合成几乎没有影响。
