Nosiheptide biosynthesis featuring a unique indole side ring formation on the characteristic thiopeptide framework.
Nosiheptide biosynthesis featuring a unique indole side ring formation on the characteristic thiopeptide framework.
复制标题
DOI：
10.1021/cb900133x
复制
发表时间：
2009-10-16
影响因子：
4
通讯作者：
Liu, Wen
中科院分区：
文献类型：
--
作者：
Yu, Yi;Duan, Lian;Zhang, Qi;Liao, Rijing;Ding, Ying;Pan, Haixue;Wendt-Pienkowski, Evelyn;Tang, Gongli;Shen, Ben;Liu, Wen
那西肽（NOS）是e系列硫肽类抗生素，具有独特的吲哚侧环结构和区域特异性的羟基，对多种细菌病原体具有较强的抗菌活性。在这里，从Streptomyces actuosus ATCC 25421的nos基因簇的克隆，测序和表征作为这一系列硫肽的模型，揭示了他们的生物合成的新见解。基于生物信息学的序列分析和对基因功能的体内研究表明，NOS生物合成与最近表征的B或c系列硫肽具有共同的策略，用于形成特征性的大环核心，其特征在于具有保守的翻译后修饰的核糖体合成的前体肽。然而，它显然是通过不同的途径进行定制的硫肽框架，使最终产品表现出独特的结构特征的e系列硫肽，如吲哚侧环系统。化学互补支持的概念，S-腺苷甲硫氨酸（NAMET）依赖性蛋白NosL可能发挥核心作用，在转换色氨酸的关键3-甲基吲哚部分的不寻常的碳侧链重排，最有可能通过自由基引发的机制。来自nosN突变株的NOS的吲哚侧开环类似物的表征与其编码蛋白的拟议甲基转移酶活性一致，从而揭示了吲哚侧环生物合成的各个步骤的时间。这些结果也表明了通过操纵NOS生物合成机制来设计新型硫肽用于药物发现的可行性。
Nosiheptide (NOS), belonging to the e series of thiopeptide antibiotics that exhibit potent activity against various bacterial pathogens, bears a unique indole side ring system and regiospecific hydroxyl groups on the characteristic macrocyclic core. Here, cloning, sequencing and characterization of the nos gene cluster from Streptomyces actuosus ATCC 25421 as a model for this series of thiopeptides has unveiled new insights into their biosynthesis. Bioinformatics-based sequence analysis and in vivo investigation into the gene functions show that NOS biosynthesis shares a common strategy with recently characterized b or c series thiopeptides for forming the characteristic macrocyclic core, which features a ribosomally synthesized precursor peptide with conserved posttranslational modifications. However, it apparently proceeds via a different route for tailoring the thiopeptide framework, allowing the final product to exhibit the distinct structural characteristics of e series thiopeptides, such as the indole side ring system. Chemical complementation supports the notion that the S-adenosylmethionine (AdoMet)-dependent protein NosL may play a central role in converting Trp to the key 3-methylindole moiety by an unusual carbon side chain rearrangement, most likely via a radical-initiated mechanism. Characterization of the indole side ring-opened analog of NOS from the nosN mutant strain is consistent with the proposed methyltransferase activity of its encoded protein, shedding light into the timing of the individual steps for indole side ring biosynthesis. These results also suggest the feasibility of engineering novel thiopeptides for drug discovery by manipulating the NOS biosynthetic machinery.
登录
查看更多内容
影响因子：
3.3
作者：
Li, WY;Leet, JE;Lam, KS
通讯作者：
Lam, KS
影响因子：
15
作者：
Morris, Rowan P.;Leeds, Jennifer A.;Krastel, Philipp
通讯作者：
Krastel, Philipp
影响因子：
14.8
作者：
Donia, Mohamed S.;Ravel, Jacques;Schmidt, Eric W.
通讯作者：
Schmidt, Eric W.
DOI：
10.1073/pnas.0900008106
发表时间：
2009-02-24
影响因子：
11.1
作者：
Brown, Laura C. Wieland;Acker, Michael G.;Fischbach, Michael A.
通讯作者：
Fischbach, Michael A.
影响因子：
3.6
作者：
JONES, CD
通讯作者：
JONES, CD