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An Unusual Mechanism Of Thymidylate Biosynthesis In Organisms Containing The Thyx Gene

机译：含有Thyx基因的生物体内胸苷生物合成的异常机制

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摘要

Biosynthesis of the DNA base thymine depends on activity of the enzyme thymidylate synthase to catalyse the methylation of the uracil moiety of 2'-deoxyuridine-5'-monophosphate. All known thymidylate synthases rely on an active site residue of the enzyme to activate 2'-deoxyuridine-5'-monophosphate. This functionality has been demonstrated for classical thymidylate synthases, including human thymidylate synthase, and is instrumental in mechanism-based inhibition of these enzymes. Here we report an example of thymidylate biosynthesis that occurs without an enzymatic nucleophile. This unusual biosynthetic pathway occurs in organisms containing the thyX gene, which codes for a flavin-dependent thymidylate synthase (FDTS), and is present in several human pathogens. Our findings indicate that the putative active site nucleophile is not required for FDTS catalysis, and no alternative nucleophilic residues capable of serving this function can be identified. Instead, our findings suggest that a hydride equivalent (that is, a proton and two electrons) is transferred from the reduced flavin cofactor directly to the uracil ring, followed by an isomeriza-tion of the intermediate to form the product, 2'-deoxythymidine-5'-monophosphate. These observations indicate a very different chemical cascade than that of classical thymidylate synthases or any other known biological methylation. The findings and chemical mechanism proposed here, together with available structural data, suggest that selective inhibition of FDTSs, with little effect on human thymine biosynthesis, should be feasible. Because several human pathogens depend on FDTS for DNA biosynthesis, its unique mechanism makes it an attractive target for antibiotic drugs.
机译：DNA碱基胸腺嘧啶的生物合成取决于胸苷酸合酶酶催化2'-脱氧尿苷-5'-单磷酸尿嘧啶部分甲基化的活性。所有已知的胸苷酸合酶都依赖于酶的活性位点残基来活化2'-脱氧尿苷-5'-单磷酸酯。已经针对包括人胸苷酸合酶的经典胸苷酸合酶证明了该功能，并且在基于机制的抑制这些酶中起作用。在这里，我们报告了在没有酶促亲核试剂的情况下发生胸苷酸生物合成的例子。这种异常的生物合成途径发生在含有thyX基因的生物中，该基因编码黄素依赖性胸苷酸合酶（FDTS），并存在于几种人类病原体中。我们的发现表明，FDTS催化不需要假定的活性位点亲核试剂，并且无法鉴定出能够发挥此功能的其他亲核残基。相反，我们的发现表明，氢化物当量（质子和两个电子）从还原的黄素辅因子直接转移至尿嘧啶环，然后异构化中间体以形成产物2'-脱氧胸苷-5'-单磷酸酯。这些观察结果表明化学级联与经典的胸苷酸合酶或任何其他已知的生物甲基化相差很大。本文提出的发现和化学机制，以及可用的结构数据表明，选择性抑制FDTS对人类胸腺嘧啶的生物合成影响很小。由于几种人类病原体依赖FDTS进行DNA生物合成，因此其独特的机制使其成为抗生素药物的有吸引力的靶标。

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