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https://ir.cnu.edu.tw/handle/310902800/32157
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| Title: | Hybrid Transcription Factor Engineering Activates the Silent Secondary Metabolite Gene Cluster for (+)-Asperlin in Aspergillus nidulans |
| Authors: | 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. |
| Contributors: | 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 |
| Keywords: | Dna-Binding
Polyketide Synthases
Biosynthetic-Pathway
Protein
Expression
Discovery
Asperlin
Facb
Regulator
Diversity |
| Date: | 2018-11 |
| Issue Date: | 2019-11-15 15:43:07 (UTC+8) |
| Publisher: | AMER CHEMICAL SOC |
| Abstract: | 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. |
| ???metadata.dc.relation.uri???: | http://dx.doi.org/10.1021/acschembio.8b00679 |
| Relation: | Langmuir, v.13, n.11, pp.3193-3205 |
| Appears in Collections: | [Dept. of Pharmacy] Periodical Articles
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| 10.1021-acschembio.8b00679.pdf | | 1052Kb | Adobe PDF | 397 | View/Open | | index.html | | 0Kb | HTML | 1299 | View/Open |
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