Production of the antibiotic FR-008/candicidin in Streptomyces sp. FR-008 is co-regulated by two regulators, FscRI and FscRIV, from different transcription factor families.
Production of the antibiotic FR-008/candicidin in Streptomyces sp. FR-008 is co-regulated by two regulators, FscRI and FscRIV, from different transcription factor families.
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DOI：
10.1099/mic.0.000033
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发表时间：
2015-03
期刊：
影响因子：
1.5
通讯作者：
Peipei Zhang;Zhilong Zhao;Hao Li;Xiulan Chen;Z. Deng;Linquan Bai;Xiuhua Pang
中科院分区：
文献类型：
--
作者：
Peipei Zhang;Zhilong Zhao;Hao Li;Xiulan Chen;Z. Deng;Linquan Bai;Xiuhua Pang
在链霉菌FR-008中，多烯抗生素FR-008（也称为杀念菌素）的生物合成基因簇由21个基因组成，包括4个调控基因fscRI-fscRIV。我们的生物信息学分析表明，FscRI有一个N-末端PAS结构域，而其他三个监管机构有N-末端AAA结构域，是LAL（大ATP结合调节LuxR型）家族的成员。fscRI的缺失消除了FR-008的产生，在补充的菌株中恢复了产生，支持FscRI在FR-008生物合成中的关键作用。与这些发现一致，参与FR-008生物合成和流出的基因的转录在ΔfscRI突变体中被大大下调。有趣的是，调控基因fscRIV在ΔfscRI突变体中也下调。在fscRIV缺失突变体中，FR-008的产生减少，但没有消失，尽管ΔfscRIV中的结构基因下调，但变化远不如ΔfscRI显著，表明FscRI的调节作用更强。值得注意的是，在ΔfscRIV中fscRI的转录也减少。在ΔfscRIV突变体中，fscRI的表达恢复了抗生素的产生，但反之亦然。在fscRIV和编码大模块聚酮酶的三个结构基因fscA、fscB和fscD的上游鉴定了FscRI的推定结合序列。我们的研究结果表明，fscRI和fscRIV是相互调节的，而fscRII和fscRIII的表达似乎独立于fscRI和fscRIV。这项研究表明，多烯抗生素合成的调节可能涉及相互调节的转录激活因子，属于不同的家庭。
In Streptomyces sp. FR-008, the biosynthetic gene cluster of the polyene antibiotic FR-008, also known as candicidin, consists of 21 genes, including four regulatory genes, fscRI-fscRIV. Our bioinformatics analyses indicate that FscRI has an N-terminal PAS domain, whereas the other three regulators have N-terminal AAA domains and are members of the LAL (large ATP-binding regulators of the LuxR type) family. Deletion of fscRI abolished the production of FR-008, with production restored in the complemented strain, supporting a critical role for FscRI in FR-008 biosynthesis. Consistent with these findings, transcription of genes involved in the biosynthesis and efflux of FR-008 was greatly downregulated in a ΔfscRI mutant. Interestingly, the regulatory gene fscRIV was also downregulated in the ΔfscRI mutant. Production of FR-008 was reduced, but not abrogated, in an fscRIV deletion mutant, and although structural genes were downregulated in ΔfscRIV, the changes were much less dramatic than in ΔfscRI, suggesting a stronger regulatory role for FscRI. Remarkably, transcription of fscRI was also decreased in ΔfscRIV. Expression of fscRI restored antibiotic production in a ΔfscRIV mutant, but not vice versa. Putative binding sequences for FscRI were identified upstream of fscRIV and the three structural genes fscA, fscB and fscD, which encode large modular polyketide synthases. Our findings suggest that fscRI and fscRIV are interregulatory, whereas expression of fscRII and fscRIII appears to be independent of fscRI and fscRIV. This study demonstrates that the regulation of polyene antibiotic synthesis can involve mutually regulated transcriptional activators that belong to different families.