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首页> 外文期刊>Applied Microbiology >Activation of a Silent Fungal Polyketide Biosynthesis Pathway through Regulatory Cross Talk with a Cryptic Nonribosomal Peptide Synthetase Gene Cluster
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Activation of a Silent Fungal Polyketide Biosynthesis Pathway through Regulatory Cross Talk with a Cryptic Nonribosomal Peptide Synthetase Gene Cluster

机译：通过与隐性非核糖体肽合成酶基因簇的调控串扰激活沉默的真菌聚酮化合物的生物合成途径。

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Filamentous fungi produce numerous natural products that constitute a consistent source of potential drug leads, yet it seems that the majority of natural products are overlooked since most biosynthesis gene clusters are silent under standard cultivation conditions. Screening secondary metabolite genes of the model fungus Aspergillus nidulans , we noted a silent gene cluster on chromosome II comprising two nonribosomal peptide synthetase (NRPS) genes, inpA and inpB , flanked by a regulatory gene that we named scpR for secondary metabolism cross-pathway regulator. The induced expression of the scpR gene using the promoter of the alcohol dehydrogenase AlcA led to the transcriptional activation of both the endogenous scpR gene and the NRPS genes. Surprisingly, metabolic profiling of the supernatant of mycelia overexpressing scpR revealed the production of the polyketide asperfuranone. Through transcriptome analysis we found that another silent secondary metabolite gene cluster located on chromosome VIII coding for asperfuranone biosynthesis was specifically induced. Quantitative reverse transcription-PCR proved the transcription not only of the corresponding polyketide synthase (PKS) biosynthesis genes, afoE and afoG , but also of their activator, afoA , under alcAp - scpR -inducing conditions. To exclude the possibility that the product of the inp cluster induced the asperfuranone gene cluster, a strain carrying a deletion of the NRPS gene inpB and, in addition, the alcAp - scpR overexpression cassette was generated. In this strain, under inducing conditions, transcripts of the biosynthesis genes of both the NRPS-containing gene cluster inp and the asperfuranone gene cluster except gene inpB were detected. Moreover, the existence of the polyketide product asperfuranone indicates that the transcription factor ScpR controls the expression of the asperfuranone biosynthesis gene cluster. This expression as well as the biosynthesis of asperfuranone was abolished after the deletion of the asperfuranone activator gene afoA , indicating that ScpR binds to the afoA promoter. To the best of our knowledge, this is the first report of regulatory cross talk between two biosynthesis gene clusters located on different chromosomes.
机译：丝状真菌产生大量天然产物，构成了潜在的潜在药物线索的一致来源，但是由于大多数生物合成基因簇在标准栽培条件下沉默，因此似乎大多数天然产物被忽略了。筛选模式真菌构巢曲霉的次级代谢产物基因时，我们注意到染色体II上的一个沉默基因簇包含两个非核糖体肽合成酶（NRPS）基因inpA和inpB，侧翼是一个调控基因，我们将其命名为scpR用于次级代谢交叉途径调控子。使用醇脱氢酶AlcA的启动子诱导的scpR基因的表达导致内源性sppR基因和NRPS基因的转录激活。出人意料的是，过表达scpR的菌丝体上清液的代谢谱分析揭示了聚酮化合物阿斯呋喃酮的产生。通过转录组分析，我们发现特异诱导了位于VIII染色体上的另一个沉默的次生代谢产物基因簇，该簇编码阿斯呋喃酮的生物合成。定量逆转录-PCR证明不仅在alcAp-scpR诱导的条件下，相应的聚酮化合物合酶（PKS）生物合成基因afoE和afoG转录，而且还在其激活剂afoA转录。为了排除inp簇的产物诱导阿斯呋喃酮基因簇的可能性，产生了带有NRPS基因inpB的缺失以及另外的alcAp-scpR过表达盒的菌株。在该菌株中，在诱导条件下，检测到含有NRPS的基因簇inp和除呋喃酮基因簇以外的生物合成基因的转录本，而基因inpB除外。此外，聚酮化合物阿斯呋喃酮的存在表明转录因子ScpR控制阿斯呋喃酮生物合成基因簇的表达。删除了阿斯呋喃酮激活基因afoA后，该表达以及阿斯呋喃酮的生物合成均被取消，这表明ScpR与afoA启动子结合。据我们所知，这是位于不同染色体上的两个生物合成基因簇之间调节性串扰的首次报道。

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