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Activation and characterization of a cryptic gene cluster reveals a cyclization cascade for polycyclic tetramate macrolactams
Saha, S; Zhang, WJ; Zhang, GT; Zhu, YG; Chen, YC; Liu, W; Yuan, CS; Zhang, QB; Zhang, HB; Zhang, LP; Zhang, WM; Zhang, CS; czhang2006@gmail.com
2017
Source PublicationCHEMICAL SCIENCE
Volume8Issue:2Pages:1607-1612
AbstractPolycyclic tetramate macrolactams (PTMs) are a growing class of natural products and are derived from a hybrid polyketide synthase (PKS)/non-ribosomal peptide synthetase (NRPS) pathway. PTM biosynthetic gene clusters are conserved and widely distributed in bacteria, however, most of them remain silent. Herein we report the activation of a PTM gene cluster in marine-derived Streptomyces pactum SCSIO 02999 by promoter engineering and heterologous expression, leading to the discovery of six new PTMs, pactamides A-F (11-16), with potent cytotoxic activity upon several human cancer cell lines. In vivo gene disruption experiments and in vitro biochemical assays reveal a reductive cyclization cascade for polycycle formation, with reactions sequentially generating the 5, 5/5 and 5/5/6 carbocyclic ring systems, catalysed by the phytoene dehydrogenase PtmB2, the oxidoreductase PtmB1, and the alcohol dehydrogenase PtmC, respectively. Furthermore, PtmC was demonstrated as a bifunctional cyclase for catalyzing the formation of the inner five-membered ring in ikarugamycin. This study suggests the possibility of finding more bioactive PTMs by genome mining and discloses a general mechanism for the formation of 5/5/6-type carbocyclic rings in PTMs.
Department[Saha, Subhasish; Zhang, Wenjun; Zhang, Guangtao; Zhu, Yiguang; Liu, Wei; Yuan, Chengshan; Zhang, Qingbo; Zhang, Haibo; Zhang, Liping; Zhang, Changsheng] Chinese Acad Sci, CAS Key Lab Trop Marine Bioresources & Ecol, Guangdong Key Lab Marine Mat Med, South China Sea Inst Oceanol, 164 West Xingang Rd, Guangzhou 510301, Guangdong, Peoples R China; [Chen, Yuchan; Zhang, Weimin] Guangdong Inst Microbiol, State Key Lab Appl Microbiol Southern China, 100 Cent Xianlie Rd, Guangzhou 510070, Guangdong, Peoples R China; [Liu, Wei; Zhang, Changsheng] South China Sea Resource Exploitat & Protect Coll, State Key Lab Appl Microbiol Southern China, Guangzhou, Guangdong, Peoples R China
Funding ProjectLMB
Document Type期刊论文
Identifierhttp://ir.scsio.ac.cn/handle/344004/16219
Collection中科院海洋生物资源可持续利用重点实验室
Corresponding Authorczhang2006@gmail.com
Recommended Citation
GB/T 7714
Saha, S,Zhang, WJ,Zhang, GT,et al. Activation and characterization of a cryptic gene cluster reveals a cyclization cascade for polycyclic tetramate macrolactams[J]. CHEMICAL SCIENCE,2017,8(2):1607-1612.
APA Saha, S.,Zhang, WJ.,Zhang, GT.,Zhu, YG.,Chen, YC.,...&czhang2006@gmail.com.(2017).Activation and characterization of a cryptic gene cluster reveals a cyclization cascade for polycyclic tetramate macrolactams.CHEMICAL SCIENCE,8(2),1607-1612.
MLA Saha, S,et al."Activation and characterization of a cryptic gene cluster reveals a cyclization cascade for polycyclic tetramate macrolactams".CHEMICAL SCIENCE 8.2(2017):1607-1612.
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