Coordinative Modulation of Chlorothricin Biosynthesis by Binding of the Glycosylated Intermediates and End Product to a Responsive Regulator ChlF1
Coordinative Modulation of Chlorothricin Biosynthesis by Binding of the Glycosylated Intermediates and End Product to a Responsive Regulator ChlF1
复制标题
通过糖基化中间体和终产物与响应调节剂 ChlF1 结合协调调节氯丝菌素生物合成
DOI：
10.1074/jbc.m115.695874
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发表时间：
2016-03-04
影响因子：
4.8
通讯作者：
Tan, Huarong
中科院分区：
文献类型：
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作者：
Li, Yue;Li, Jingjing;Tan, Huarong
氯丝菌素是从链霉菌中分离得到的一种具有显著生物活性的抗生素，属于螺环内酯类抗生素家族。ChlF 1通过与其靶基因（chlJ、chlF 1、chlG和chlK）结合而在氯丝菌素生物合成中发挥双功能作用。ChlF_1与这些基因的解离常数约为102-140 nm。在这些结合位点中发现了一个共有序列5-GTAANNATTTAC-3。ChlF 1抑制chlF 1、chlG和chlK的转录，但激活chlJ，其编码参与氯丝菌素生物合成的关键酶酰基辅酶A羧基转移酶。我们证明，最终产品的chlorothricin和同样的生物合成中间体（去甲基水杨环酰chlorothricin和deschloro-chlorothricin）可以作为信号分子，以调节ChlF 1的结合，其靶基因。有趣的是，清楚地观察到抗菌活性和信号分子与调节剂ChlFl的结合能力之间的相关性。信号分子的这些特征与螺替膦酸酯大环内酯苷元的糖基化有关。这些发现为TetR家族调节因子对信号分子特殊结构的响应提供了新的见解，我们首次揭示了ChlF 1介导的调节小网络在氯丝菌素生物合成中的作用。
Chlorothricin, isolated from Streptomyces antibioticus, is a parent member of spirotetronate family of antibiotics that have long been appreciated for their remarkable biological activities. ChlF1 plays bifunctional roles in chlorothricin biosynthesis by binding to its target genes (chlJ, chlF1, chlG, and chlK). The dissociation constants of ChlF1 to these genes are approximate to 102-140 nm. A consensus sequence, 5-GTAANNATTTAC-3, was found in these binding sites. ChlF1 represses the transcription of chlF1, chlG, and chlK but activates chlJ, which encodes a key enzyme acyl-CoA carboxyl transferase involved in the chlorothricin biosynthesis. We demonstrate that the end product chlorothricin and likewise its biosynthetic intermediates (demethylsalicycloyl chlorothricin and deschloro-chlorothricin) can act as signaling molecules to modulate the binding of ChlF1 to its target genes. Intriguingly, a correlation between the antibacterial activity and binding ability of signaling molecules to the regulator ChlF1 is clearly observed. These features of the signaling molecules are associated with the glycosylation of spirotetronate macrolide aglycone. The findings provide new insights into the TetR family regulators responding to special structure of signaling molecules, and we reveal the regulatory mini-network mediated by ChlF1 in chlorothricin biosynthesis for the first time.