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Overexpression of a type III PKS gene affording novel violapyrones with enhanced anti-influenza A virus activity
Hou, LK; Huang, HM; Li, HY; Wang, SY; Ju, JH; Li, WL;
AbstractBackground: Type III polyketide synthases (PKSs) are simple homodimer ketosynthases that distribute across plants, fungi, and bacteria, catalyzing formation of pyrone-and resorcinol-types aromatic polyketides with various bioactivities. The broad substrate promiscuity displayed by type III PKSs makes them wonderful candidates for expanding chemical diversity of polyketides. Results: Violapyrone B (VLP B, 10), an alpha-pyrone compound produced by deepsea-derived Streptomyces somaliensis SCSIO ZH66, is encoded by a type III PKS VioA. We overexpressed VioA in three different hosts, including Streptomyces coelicolor M1146, Streptomyces sanyensis FMA as well as the native producer S. somaliensis SCSIO ZH66, leading to accumulation of different violapyrone compounds. Among them, S. coelicolor M1146 served as the host producing the most abundant violapyrones, from which five new (2-4, 7 and 12) and nine known (1, 5, 6, 8-11, 13 and 14) compounds were identified. Anti-influenza A (H1N1) virus activity of these compounds was then evaluated using ribavirin as a positive control (IC50 = 112.9 mu M), revealing that compounds 11-14 showed considerable activity with IC50 values of 112.7, 26.9, 106.7 and 28.8 mu M, respectively, which are significantly improved as compared to that of VLP B (10) (IC50 > 200 mu M). The productions of 10 and 13 were increased by adding P450 inhibitor metyrapone. In addition, site-directed mutagenesis experiment led to demonstration of the residue S242 to be essential for the activity of VioA. Conclusions: Biological background of the expression hosts is an important factor impacting on the encoding products of type III PKSs. By using S. coelicolor M1146 as cell factory, we were able to generate fourteen VLPs compounds. Anti-H1N1 activity assay suggested that the lipophilic nature of the alkyl chains of VLPs plays an important role for the activity, providing valuable guidance for further structural optimization of VLPs.
Department[Hou, Lukuan; Huang, Huiming; Li, Huayue; Wang, Shuyao; Li, Wenli] Ocean Univ China, Sch Med & Pharm, Minist Educ China, Key Lab Marine Drugs, Qingdao 266003, Peoples R China; [Li, Huayue; Li, Wenli] Qingdao Natl Lab Marine Sci & Technol, Lab Marine Drugs & Bioprod, Qingdao 266237, Peoples R China; [Ju, Jianhua] Chinese Acad Sci, CAS Key Lab Marine Bioresources Sustainable Utili, RNAM Ctr Marine Microbiol South China, Guangdong Key Lab Marine Mat Med,Sea Inst Oceanol, 164 West Xingang Rd, Guangzhou 510301, Guangdong, Peoples R China
Subject AreaBiotechnology & Applied Microbiology
WOS KeywordViolapyrones (VLPs) ; Overexpression ; Type III polyketide synthase (PKS) ; Anti-influenza A (H1N1) virus activity
Funding ProjectLMB
Document Type期刊论文
Recommended Citation
GB/T 7714
Hou, LK,Huang, HM,Li, HY,et al. Overexpression of a type III PKS gene affording novel violapyrones with enhanced anti-influenza A virus activity[J]. MICROBIAL CELL FACTORIES,2018,17:-61.
APA Hou, LK.,Huang, HM.,Li, HY.,Wang, SY.,Ju, JH.,...& of a type III PKS gene affording novel violapyrones with enhanced anti-influenza A virus activity.MICROBIAL CELL FACTORIES,17,-61.
MLA Hou, LK,et al."Overexpression of a type III PKS gene affording novel violapyrones with enhanced anti-influenza A virus activity".MICROBIAL CELL FACTORIES 17(2018):-61.
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