Identification of a gene cluster for telomestatin biosynthesis and heterologous expression using a specific promoter in a clean host.
Identification of a gene cluster for telomestatin biosynthesis and heterologous expression using a specific promoter in a clean host.
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DOI：
10.1038/s41598-017-03308-5
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发表时间：
2017-06-13
影响因子：
4.6
通讯作者：
Shin-Ya K
中科院分区：
文献类型：
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作者：
Amagai K;Ikeda H;Hashimoto J;Kozone I;Izumikawa M;Kudo F;Eguchi T;Nakamura T;Osada H;Takahashi S;Shin-Ya K
端粒抑素是一种强端粒酶抑制剂，具有g -四联体稳定活性，是一种潜在的治疗癌症的药物。从微生物培养物中分离端粒抑素和化学合成的困难是阻碍其广泛应用的瓶颈。因此，为了进一步的利用和应用，需要提高端藻素的产量和结构多样化。本研究中，我们发现了负责端粒抑素生物合成的基因簇，并通过在工程型阿维链霉菌SUKA菌株中异源表达该基因簇实现了端粒抑素的生产。最佳促进剂的使用对生产的成功至关重要。基因破坏研究表明，tlsB、tlsC和tlsO-T基因在端粒抑素的生物合成中起着关键作用。此外，交换TlsC核心肽序列导致新的端粒抑素衍生物的产生。这项研究为药物开发提供了天然肽产品化学多样性的扩展。
Telomestatin, a strong telomerase inhibitor with G-quadruplex stabilizing activity, is a potential therapeutic agent for treating cancers. Difficulties in isolating telomestatin from microbial cultures and in chemical synthesis are bottlenecks impeding the wider use. Therefore, improvement in telomestatin production and structural diversification are required for further utilization and application. Here, we discovered the gene cluster responsible for telomestatin biosynthesis, and achieved production of telomestatin by heterologous expression of this cluster in the engineered Streptomyces avermitilis SUKA strain. Utilization of an optimal promoter was essential for successful production. Gene disruption studies revealed that the tlsB, tlsC, and tlsO–T genes play key roles in telomestatin biosynthesis. Moreover, exchanging TlsC core peptide sequences resulted in the production of novel telomestatin derivatives. This study sheds light on the expansion of chemical diversity of natural peptide products for drug development.