胸腺嘧啶（四种普遍存在的DNA碱基之一）是由胸苷酸合成酶合成的，这种酶催化“2′-脱氧尿苷-5′-单磷酸盐”的尿嘧啶部分的甲基化。传统胸苷酸合成酶，包括人体的这种酶，利用一个活性点氨基酸侧链来在该反应的这一阶段激发基质。
几年前，研究人员在若干种生物（其中包括几种人类病原体）中识别出了另一种形式的胸苷酸生物合成，这种形式涉及一种依赖于黄素的胸苷酸合成酶，后者是thyX基因的产物。
现在，Koenhn等人对合成胸腺嘧啶的这一替代途径进行了定性，并且发现它并不需要一种酶类亲核试剂；相反，实际情况似乎是，一个氢负离子从被还原的黄素辅因子被直接转移到尿嘧啶环上。因为几种人类病原体依靠这一生物合成通道来进行DNA生物合成，所以我们有可能开发出以这种酶为目标的具有高度选择性的新型抗生素。（生物谷Bioon.com）
生物谷推荐原始出处：
Nature 458, 919-923 (16 April 2009) | doi:10.1038/nature07973
An unusual mechanism of thymidylate biosynthesis in organisms containing the thyX gene
Eric M. Koehn1, Todd Fleischmann1, John A. Conrad2, Bruce A. Palfey2, Scott A. Lesley3, Irimpan I. Mathews4 & Amnon Kohen1
1 Department of Chemistry, University of Iowa, Iowa City, Iowa 52242, USA
2 Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA
3 The Joint Center for Structural Genomics at the Genomics Institute of Novartis Research Foundation, San Diego, California 92121, USA
4 Stanford Synchrotron Radiation Laboratory, Stanford University, Menlo Park, California 94025, USA
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'-monophosphate1, 2. 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 pathogens3, 4, 5. 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 isomerization 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.
