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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
Ju XD(瞿旭东); JIANG NAN; XU FEI; Shao L(邵雷); Tang GL(唐功利); WILKINSON BARRIE; Liu W(刘文)
2011
发表期刊Mol. Biosyst.
ISSN1742-206X
卷号7期号:3页码:852-861
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.
学科领域生命有机化学
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
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收录类别SCI
语种英语
WOS记录号WOS:000287367100030
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被引频次:29[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.sioc.ac.cn/handle/331003/28469
专题生命有机化学国家重点实验室
通讯作者Liu W(刘文)
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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.
APA 瞿旭东.,JIANG NAN.,XU FEI.,邵雷.,唐功利.,...&刘文.(2011).Cloning, sequencing and characterization of the biosynthetic gene cluster of sanglifehrin A, a potent cyclophilin inhibitor.Mol. Biosyst.,7(3),852-861.
MLA 瞿旭东,et al."Cloning, sequencing and characterization of the biosynthetic gene cluster of sanglifehrin A, a potent cyclophilin inhibitor".Mol. Biosyst. 7.3(2011):852-861.
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