英羧霉素的生物合成研究及恶唑类化合物的挖掘

	英羧霉素的生物合成研究及恶唑类化合物的挖掘; Study on the Biosynthesis of Inthomycin and the Discovery of Oxazole Compounds
	王永江
导师	黄胜雄
摘要	Natural products are an important source of modern drug discovery and have an important impact on the development of innovative drugs. Microbial secondary metabolites, especially antibiotics derived from Streptomyces, play an important role in drug discovery. Benefit from the rapid development of bioinformatics and sequencing technology, natural product chemists devote to the natural products biosynthesis, especially some natural products with significant biological activity and novel structural fragments. The oxazole ring is a five-membered ring with O and N atoms at 1 and 3 positions, respectively. They are rarely found in natural products and mostly exist in Streptomyces, Pseudomonas or marine organisms. According to the structural characteristics of oxazole ring, they can be divided into three groups: 2,4-disubstituted oxazole, 2,5-disubstituted oxazole and 5-monosubstituted oxazole. The biosynthetic formation mechanism of the first two groups of oxazole rings has been reported, while the formation mechanism of 5-monosubstituted oxazole ring is relatively vague. Inthomycin, a 5-monosubstituted oxazole natural product isolated from Streptomyces strains, had diverse functions including antibacterial, herbicidal and anti-cancer activities. However, its biosynthesis process is still unclear. In this dissertation, we tried to decipher the biosynthesis of inthomycin and discover more oxazole compounds. First, inthomycin and its two new analogues were isolated from the crude extract of Streptomyces pactum L8, which derived from the arid soil of Qinghai lake. And three oxazole-producing strains were screened by probe primers from the Streptomyces library. Oxazolomycin A, four virginiamycin analogues and conglobatin A were isolated from the crude extracts of S. sp. KIB-3099, S. sp. KIB-D158 and S. sp. KIB-2539, respectively. Preliminary activity screening showed that inthomycin showed an inhibitory effect on E. coli. Subsequently, the genome of S. pactum L8 was sequenced and two genomic libraries were constructed for gene interruption experiments and heterologous expression in Streptomyces. Based on bioinformatics analysis, the candidate gene cluster of inthomycin was found and confirmed. It contained eight genes: seven genes encoding PKSs or NRPSs and one putative functional gene. The formation process of inthomycin was predicted by analyzing the conserved site of each domain in PKSs or NRPSs. Its biosynthesis started with a formylated glycine and was then extended by 13 modules. As the carbon chain length in the predicated assembly chain is much longer than that in inthomycin. Two possible chain-tailored release pathways to form inthomycin were proposed. In one pathway, the assembly chain was hydrolyzed to form the acid-form inthomycin analogue, which could be transformed into inthomycin by a putative amidotransferase. In another pathway, a direct oxidative dealkylation reaction in the assembly chain led to the release of inthomycin. The 15N-glycine
	2021-05
文献类型	学位论文
条目标识符	http://ir.kib.ac.cn/handle/151853/74623
专题	昆明植物所硕博研究生毕业学位论文
推荐引用方式 GB/T 7714	王永江. 英羧霉素的生物合成研究及恶唑类化合物的挖掘, Study on the Biosynthesis of Inthomycin and the Discovery of Oxazole Compounds[D],2021.

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