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首页> 外文期刊>Protein & Cell >An unusual UMP C-5 methylase in nucleoside antibiotic polyoxin biosynthesis
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An unusual UMP C-5 methylase in nucleoside antibiotic polyoxin biosynthesis

机译：核苷类抗生素多恶菌素生物合成中异常的UMP C-5甲基化酶

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Polyoxin is a group of structurally-related peptidyl nucleoside antibiotics bearing C-5 modifications on the nucleoside skeleton. Although the structural diversity and bioactivity preference of polyoxin are, to some extent, affected by such modifications, the biosynthetic logic for their occurence remains obscure. Here we report the identification of PolB in polyoxin pathway as an unusual UMP C-5 methylase with thymidylate synthase activity which is responsible for the C-5 methylation of the nucleoside skeleton. To probe its molecular mechanism, we determined the crystal structures of PolB alone and in complexes with 5-Br UMP and 5-Br dUMP at 2.15 ?, 1.76 ? and 2.28 ? resolutions, respectively. Loop 1 (residues 117–131), Loop 2 (residues 192–201) and the substrate recognition peptide (residues 94–102) of PolB exhibit considerable conformational flexibility and adopt distinct structures upon binding to different substrate analogs. Consistent with the structural findings, a PolB homolog that harbors an identical function from Streptomyces viridochromogenes DSM 40736 was identified. The discovery of UMP C5-methylase opens the way to rational pathway engineering for polyoxin component optimization, and will also enrich the toolbox for natural nucleotide chemistry.
机译：Polyoxin是一组与结构相关的肽基核苷抗生素，在核苷骨架上带有C-5修饰。尽管多氧合蛋白的结构多样性和生物活性偏好在一定程度上受此类修饰的影响，但其发生的生物合成逻辑仍然不清楚。在这里，我们报告在多氧合酶途径中的PolB鉴定为具有胸苷酸合酶活性的不寻常的UMP C-5甲基化酶，该酶负责核苷骨架的C-5甲基化。为了探究其分子机理，我们确定了单独的PolB晶体结构以及与5-Br UMP和5-Br dUMP形成复合物的频率分别为2.15？，1.76？。和2.28吗？决议。 PolB的环1（残基117-131），环2（残基192-201）和底物识别肽（残基94-102）表现出相当的构象柔韧性，并且在与不同的底物类似物结合时采用不同的结构。与结构发现一致，鉴定了具有与病毒链霉菌DSM 40736相同功能的PolB同源物。 UMP C5-甲基化酶的发现为合理的途径设计多氧合酶成分优化开辟了道路，也将丰富天然核苷酸化学的工具箱。

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