Hybrid Transcription Factor Engineering Activates the Silent Secondary Metabolite Gene Cluster for (+)-Asperlin in Aspergillus nidulans

doi:10.1021/acschembio.8b00679

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標題:	Hybrid Transcription Factor Engineering Activates the Silent Secondary Metabolite Gene Cluster for (+)-Asperlin in Aspergillus nidulans
作者:	Grau, Michelle F. Entwistle, Ruth Chiang, Yi-Ming Ahuja, Manmeet Oakley, C. Elizabeth Akashi, Tomohiro Wang, Clay C. C. Todd, Richard B. Oaldey, Berl R.
貢獻者:	Univ Southern Calif, Sch Pharm, Dept Pharmacol & Pharmaceut Sci Univ Kansas, Dept Mol Biosci Chia Nan Univ Pharm & Sci, Dept Pharm Nagoya Univ, Grad Sch Med, Ctr Neurol Dis & Canc, Div OMICS Anal Univ Southern Calif, Dept Chem, Dornsife Coll Letters Arts & Sci Kansas State Univ, Dept Plant Pathol Reliance Ind Ltd, Reliance Technol Grp, Ind Biotechnol Div, Reliance Corp Pk
關鍵字:	Dna-Binding Polyketide Synthases Biosynthetic-Pathway Protein Expression Discovery Asperlin Facb Regulator Diversity
日期:	2018-11
上傳時間:	2019-11-15 15:43:07 (UTC+8)
出版者:	AMER CHEMICAL SOC
摘要:	Fungi are a major source of valuable bioactive secondary metabolites (SMs). These compounds are synthesized by enzymes encoded by genes that are clustered in the genome. The vast majority of SM biosynthetic gene clusters are not expressed under normal growth conditions, and their products are unknown. Developing methods for activation of these silent gene clusters offers the potential for discovering many valuable new fungal SMs. While a number of useful approaches have been developed, they each have limitations, and additional tools are needed. One approach, upregulation of SM gene cluster-specific transcription factors that are associated with many SM gene clusters, has worked extremely well in some cases, but it has failed more often than it has succeeded. Taking advantage of transcription factor domain modularity, we developed a new approach. We fused the DNA-binding domain of a transcription factor associated with a silent SM gene cluster with the activation domain of a robust SM transcription factor, AfoA. Expression of this hybrid transcription factor activated transcription of the genes in the target cluster and production of the antibiotic (+)-asperlin. Deletion of cluster genes confirmed that the cluster is responsible for (+)-asperlin production, and we designate it the aln cluster. Separately, coinduction of expression of two aln cluster genes revealed the pathway intermediate (2Z,4Z,6E)-octa-2,4,6-trienoic acid, a compound with photoprotectant properties. Our findings demonstrate the potential of our novel synthetic hybrid transcription factor strategy to discover the products of other silent fungal SM gene clusters.
link:	http://dx.doi.org/10.1021/acschembio.8b00679
關聯:	Langmuir, v.13, n.11, pp.3193-3205
显示于类别:	[藥學系(所)] 期刊論文

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