Coordinate Regulation of Antimycin and Candicidin Biosynthesis.
Coordinate Regulation of Antimycin and Candicidin Biosynthesis.
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DOI：
10.1128/msphere.00305-16
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发表时间：
2016-11
期刊：
影响因子：
4.8
通讯作者：
Seipke RF
中科院分区：
文献类型：
--
作者：
McLean TC;Hoskisson PA;Seipke RF
由放线菌门成员产生的天然产物支撑许多工业和医学上重要的化合物;然而，平均物种所包含的约30种生物合成途径中的大多数在实验室中不表达。因此，了解控制这些途径表达的调控策略的多样性是至关重要的，如果要探索其生物合成潜力的新药物线索。我们的研究结果表明，candicidin集群位于调节FscRI协调控制candicidin和抗霉素的生物合成，这是第一次观察到指定不相关的天然产物的不同的生物合成基因簇的交叉调节。我们预计，这将成为一个主要的策略，其中放线菌门的成员协调生产天然产物，这将促进我们的理解如何表达的次级代谢的控制，并将有助于追求“沉默”的生物合成途径激活。链霉菌产生一系列令人难以置信的高价值特种化学品和药物治疗剂。一个物种通常含有约30种生物合成途径，但只有少数在实验室中表达;因此，对天然产物生物合成如何调节的理解不足是药物发现的主要瓶颈。抗霉素是由链霉菌属物种广泛产生的抗癌化合物的大家族，并且与大多数其他天然产物相比，它们的调节是非典型的。在这里，我们表明，由白色链霉菌S4的抗霉素生产的FscRI，PAS-LuxR家族簇位于多烯抗真菌剂杀念菌素的调节调节。我们报道天蓝色链霉菌异源生产抗霉素依赖于FscRI，并表明FscRI激活关键生物合成基因的转录。我们还证明，通过染色质免疫沉淀测序FscRI调控是直接的，我们提供的证据表明，这种调控策略是保守的，独特的短形式的抗霉素基因簇。我们的研究提供了直接在体内的证据表明，指定不相关的天然产物的不同的生物合成基因簇的交叉调节，并扩大了对次生代谢调节的范式理解。重要性放线菌门成员产生的天然产物是许多工业和医学重要化合物的基础;然而，平均物种所包含的约30种生物合成途径中的大多数在实验室中不表达。因此，了解控制这些途径表达的调控策略的多样性是至关重要的，如果要探索其生物合成潜力的新药物线索。我们的研究结果表明，candicidin集群位于调节FscRI协调控制candicidin和抗霉素的生物合成，这是第一次观察到指定不相关的天然产物的不同的生物合成基因簇的交叉调节。我们预计，这将成为一个主要的策略，其中放线菌门的成员协调生产天然产物，这将促进我们的理解如何表达的次级代谢的控制，并将有助于追求“沉默”的生物合成途径激活。
Natural products produced by members of the phylum Actinobacteria underpin many industrially and medically important compounds; however, the majority of the ~30 biosynthetic pathways harbored by an average species are not expressed in the laboratory. Understanding the diversity of regulatory strategies controlling the expression of these pathways is therefore critical if their biosynthetic potential is to be explored for new drug leads. Our findings reveal that the candicidin cluster-situated regulator FscRI coordinately controls the biosynthesis of both candicidin and antimycin, which is the first observation of cross-regulation of disparate biosynthetic gene clusters specifying unrelated natural products. We anticipate that this will emerge as a major strategy by which members of the phylum Actinobacteria coordinately produce natural products, which will advance our understanding of how the expression of secondary metabolism is controlled and will aid the pursuit of “silent” biosynthetic pathway activation. Streptomyces species produce an incredible array of high-value specialty chemicals and medicinal therapeutics. A single species typically harbors ~30 biosynthetic pathways, but only a few them are expressed in the laboratory; thus, poor understanding of how natural-product biosynthesis is regulated is a major bottleneck in drug discovery. Antimycins are a large family of anticancer compounds widely produced by Streptomyces species, and their regulation is atypical compared to that of most other natural products. Here we demonstrate that antimycin production by Streptomyces albus S4 is regulated by FscRI, a PAS-LuxR family cluster-situated regulator of the polyene antifungal agent candicidin. We report that heterologous production of antimycins by Streptomyces coelicolor is dependent on FscRI and show that FscRI activates the transcription of key biosynthetic genes. We also demonstrate through chromatin immunoprecipitation sequencing that FscRI regulation is direct, and we provide evidence that this regulation strategy is conserved and unique to short-form antimycin gene clusters. Our study provides direct in vivo evidence of the cross-regulation of disparate biosynthetic gene clusters specifying unrelated natural products and expands the paradigmatic understanding of the regulation of secondary metabolism. IMPORTANCE Natural products produced by members of the phylum Actinobacteria underpin many industrially and medically important compounds; however, the majority of the ~30 biosynthetic pathways harbored by an average species are not expressed in the laboratory. Understanding the diversity of regulatory strategies controlling the expression of these pathways is therefore critical if their biosynthetic potential is to be explored for new drug leads. Our findings reveal that the candicidin cluster-situated regulator FscRI coordinately controls the biosynthesis of both candicidin and antimycin, which is the first observation of cross-regulation of disparate biosynthetic gene clusters specifying unrelated natural products. We anticipate that this will emerge as a major strategy by which members of the phylum Actinobacteria coordinately produce natural products, which will advance our understanding of how the expression of secondary metabolism is controlled and will aid the pursuit of “silent” biosynthetic pathway activation.