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Operon for Biosynthesis of Lipstatin, the Beta-Lactone Inhibitor of Human Pancreatic Lipase
Alternative Title生物合成人胰脂肪酶抑制剂β-内酯lipstatin的操纵子
BAI TINGLI1; Zhang DZ(张道忠)1; LIN SHUANGJUN1; LONG QINGSHAN1; WANG YEMIN1; OU HONGYU1; KANG QIANJIN1; DENG ZIXIN1; Liu W(刘文)1; TAO MEIFENG1
2014
Source PublicationAppl. Environ. Microbiol.
Volume80Issue:24Pages:7473-7483
AbstractLipstatin, isolated from Streptomyces toxytricini as a potent and selective inhibitor of human pancreatic lipase, is a precursor for tetrahydrolipstatin (also known as orlistat, Xenical, and Alli), the only FDA-approved antiobesity medication for long-term use. Lipstatin features a 2-hexyl-3,5-dihydroxy-7,10-hexadecadienoic-beta-lactone structure with an N-formyl-L-leucine group attached as an ester to the 5-hydroxy group. It has been suggested that the alpha-branched 3,5-dihydroxy fatty acid beta-lactone moiety of lipstatin in S. toxytricini is derived from Claisen condensation between two fatty acid substrates, which are derived from incomplete oxidative degradation of linoleic acid based on feeding experiments. In this study, we identified a six-gene operon (lst) that was essential for the biosynthesis of lipstatin by large-deletion, complementation, and single-gene knockout experiments. lstA, lstB, and lstC, which encode two beta-ketoacyl-acyl carrier protein synthase III homologues and an acyl coenzyme A (acyl-CoA) synthetase homologue, were indicated to be responsible for the generation of the alpha-branched 3,5-dihydroxy fatty acid backbone. Subsequently, the nonribosomal peptide synthetase (NRPS) gene lstE and the putative formyltransferase gene lstF were involved in decoration of the alpha-branched 3,5-dihydroxy fatty acid chain with an N-formylated leucine residue. Finally, the 3 beta-hydroxysteroid dehydrogenase-homologous gene lstD might be responsible for the reduction of the beta-keto group of the biosynthetic intermediate, thereby facilitating the formation of the unique beta-lactone ring.
Subject Area生命有机化学
DOI10.1128/AEM.01765-14
URL查看原文
Indexed BySCI
Language英语
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Document Type期刊论文
Identifierhttp://ir.sioc.ac.cn/handle/331003/38963
Collection生命有机化学国家重点实验室
Corresponding AuthorTAO MEIFENG
Affiliation1.上海交通大学
2.中科院上海有机化学研究所
3.华中农业大学
Recommended Citation
GB/T 7714
BAI TINGLI,Zhang DZ,LIN SHUANGJUN,et al. Operon for Biosynthesis of Lipstatin, the Beta-Lactone Inhibitor of Human Pancreatic Lipase[J]. Appl. Environ. Microbiol.,2014,80(24):7473-7483.
APA BAI TINGLI.,张道忠.,LIN SHUANGJUN.,LONG QINGSHAN.,WANG YEMIN.,...&TAO MEIFENG.(2014).Operon for Biosynthesis of Lipstatin, the Beta-Lactone Inhibitor of Human Pancreatic Lipase.Appl. Environ. Microbiol.,80(24),7473-7483.
MLA BAI TINGLI,et al."Operon for Biosynthesis of Lipstatin, the Beta-Lactone Inhibitor of Human Pancreatic Lipase".Appl. Environ. Microbiol. 80.24(2014):7473-7483.
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