胸腺嘧啶（四種普遍存在的DNA堿基之一）是由胸苷酸合成酶合成的,，這種酶催化“2′-脫氧尿苷-5′-單磷酸鹽”的尿嘧啶部分的甲基化,。傳統(tǒng)胸苷酸合成酶，包括人體的這種酶,，利用一個(gè)活性點(diǎn)氨基酸側(cè)鏈來(lái)在該反應(yīng)的這一階段激發(fā)基質(zhì)。
幾年前,，研究人員在若干種生物（其中包括幾種人類病原體）中識(shí)別出了另一種形式的胸苷酸生物合成,，這種形式涉及一種依賴于黃素的胸苷酸合成酶，后者是thyX基因的產(chǎn)物,。
現(xiàn)在,，Koenhn等人對(duì)合成胸腺嘧啶的這一替代途徑進(jìn)行了定性，并且發(fā)現(xiàn)它并不需要一種酶類親核試劑,；相反,，實(shí)際情況似乎是，一個(gè)氫負(fù)離子從被還原的黃素輔因子被直接轉(zhuǎn)移到尿嘧啶環(huán)上,。因?yàn)閹追N人類病原體依靠這一生物合成通道來(lái)進(jìn)行DNA生物合成,，所以我們有可能開發(fā)出以這種酶為目標(biāo)的具有高度選擇性的新型抗生素。（生物谷Bioon.com）
生物谷推薦原始出處：
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.
