Brasilicardin A (BraA) is a promising immunosuppressive compound produced naturally by the pathogenic bacterium Nocardia terpenica IFM 0406. Heterologous host expression of brasilicardin gene cluster showed to be efficient to bypass the safety issues, low production levels and lack of genetic tools related with the use of native producer. Further improvement of production yields requires better understanding of gene expression regulation within the BraA biosynthetic gene cluster (Bra‐BGC); however, the only so far known regulator of this gene cluster is Bra12. In this study, we discovered the protein LysRNt, a novel member of the LysR‐type transcriptional regulator family, as a regulator of the Bra‐BGC. Using in vitro approaches, we identified the gene promoters which are controlled by LysRNt within the Bra‐BGC. Corresponding genes encode enzymes involved in BraA biosynthesis as well as the key Bra‐BGC regulator Bra12. Importantly, we provide in vivo evidence that LysRNt negatively affects production of brasilicardin congeners in the heterologous host Amycolatopsis japonicum. Finally, we demonstrate that some of the pathway related metabolites, and their chemical analogs, can interact with LysRNt which in turn affects its DNA‐binding activity.

中文翻译：

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一种新型 LysR 型调节剂对免疫抑制剂巴西利卡定的生物合成产生负面影响


Brasilicardin A (BraA) 是一种很有前途的免疫抑制化合物，由致病菌 Nocardia terpenica IFM 0406 天然产生。 Brasilicardin 基因簇的异源宿主表达可有效绕过安全问题、生产水平低和缺乏与使用相关的遗传工具本土制作人。进一步提高产量需要更好地了解 BraA 生物合成基因簇 (Bra-BGC) 内的基因表达调控；然而，迄今为止唯一已知的该基因簇的调节因子是 Bra12。在这项研究中，我们发现了蛋白质 LysRNt，它是 LysR 型转录调节因子家族的新成员，作为 Bra-BGC 的调节因子。使用体外方法，我们鉴定了 Bra-BGC 内由 LysRNt 控制的基因启动子。相应的基因编码参与 BraA 生物合成的酶以及关键的 Bra-BGC 调节因子 Bra12。重要的是，我们提供的体内证据表明 LysRNt 对异源宿主日本无枝酸菌中巴西卡定同源物的产生产生负面影响。最后，我们证明一些途径相关的代谢物及其化学类似物可以与 LysRNt 相互作用，进而影响其 DNA 结合活性。