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学科主题: 生命有机化学
题名: Cloning, sequencing and characterization of the biosynthetic gene cluster of sanglifehrin A, a potent cyclophilin inhibitor
其他题名: Cloning, sequencing and characterization of the biosynthetic gene cluster of sanglifehrin A, a potent cyclophilin inhibitor
作者: Ju XD(瞿旭东) ; JIANG NAN ; XU FEI ; Shao L(邵雷) ; Tang GL(唐功利) ; WILKINSON BARRIE ; Liu W(刘文)
通讯作者: 刘文
刊名: Mol. Biosyst.
发表日期: 2011
卷: 7, 期:3, 页:852-861
收录类别: SCI
部门归属: 中科院上海有机化学研究所; 英国剑桥生物技术有限公司
英文摘要: Sanglifehrin A (SFA), a potent cyclophilin inhibitor produced by Streptomyces flaveolus DSM 9954, bears a unique [5.5] spirolactam moiety conjugated with a 22-membered, highly functionalized macrolide through a linear carbon chain. SFA displays a diverse range of biological activities and offers significant therapeutic potential. However, the structural complexity of SFA poses a tremendous challenge for new analogue development via chemical synthesis. Based on a rational prediction of its biosynthetic origin, herein we report the cloning, sequencing and characterization of the gene cluster responsible for SFA biosynthesis. Analysis of the 92 776 bp contiguous DNA region reveals a mixed polyketide synthase (PKS)/non-ribosomal peptide synthetase (NRPS) pathway which includes a variety of unique features for unusual PKS and NRPS building block formation. Our findings suggest that SFA biosynthesis requires a crotonyl-CoA reductase/carboxylase (CCR) for generation of the putative unusual PKS starter unit (2R)-2-ethylmalonamyl-CoA, an iterative type I PKS for the putative atypical extender unit (2S)-2-(2-oxo-butyl) malonyl-CoA and a phenylalanine hydroxylase for the NRPS extender unit (2S)-m-tyrosine. A spontaneous ketalization of significant note, may trigger spirolactam formation in a stereo-selective manner. This study provides a framework for the application of combinatorial biosynthesis methods in order to expand the structural diversity of SFA.
语种: 英语
相关网址: 查看原文
WOS记录号: WOS:000287367100030
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内容类型: 期刊论文
URI标识: http://ir.sioc.ac.cn/handle/331003/28469
Appears in Collections:生命有机化学国家重点实验室_期刊论文

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Recommended Citation:
Ju XD,JIANG NAN,XU FEI,et al. Cloning, sequencing and characterization of the biosynthetic gene cluster of sanglifehrin A, a potent cyclophilin inhibitor[J]. Mol. Biosyst.,2011,7(3):852-861.
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