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Orlistat response to missense mutations in lipoprotein lipase
Chen, Huayou1,2,3; Jia, Jinru1; Ni, Zhong1; Vastermark, Ake3; Wu, Bangguo1; Le, Yilin1; Jawad, Ullah1
2017-07-01
发表期刊BIOTECHNOLOGY AND APPLIED BIOCHEMISTRY
ISSN0885-4513
卷号64期号:5页码:464-470
摘要The human lipoprotein lipase (LPL) is a therapeutic target for obesity, and inhibition of LPL with the approved small molecule agent orlistat has been widely used in clinic to treat obesity-related health problems such as diabetes and cardiovascular diseases. However, a variety of missense mutations in LPL protein have been observed, which may cause resistance or sensitization for orlistat, largely limiting the clinical applications of orlistat in obesity therapy. Here, we integrated molecular dynamics simulations and enzyme inhibition to investigate orlistat response to 16 disorder-associated missense mutations in LPL catalytic domain. It was found that most mutations have a modest effect on orlistat binding, and only few can exert strong impact to the binding. Three unfavorable (Trp86Arg, Ile194Thr, and Glu242Lys) and two favorable (His136Arg and Gly188Glu) mutations were identified, which can alter the binding affinity and inhibitory activity of orlistat considerably. Structural and energetic analysis revealed that these potent mutations induce orlistat resistance and sensitization by directly influencing the intermolecular interaction between LPL and orlistat or by indirectly addressing allosteric effect on LPL structure. (C) 2016 International Union of Biochemistry and Molecular Biology, Inc.
关键词Lipoprotein Lipase Orlistat Missense Mutation
文章类型Article
WOS标题词Science & Technology ; Life Sciences & Biomedicine
DOI10.1002/bab.1500
收录类别SCI
语种英语
关键词[WOS]FAMILIAL LPL DEFICIENCY ; MONOACYLGLYCEROL LIPASE ; ATOMIC CHARGES ; PLASMA-LIPIDS ; GENE ; TETRAHYDROLIPSTATIN ; ATHEROSCLEROSIS ; INHIBITORS ; DISEASE ; PATIENT
WOS研究方向Biochemistry & Molecular Biology ; Biotechnology & Applied Microbiology
WOS类目Biochemistry & Molecular Biology ; Biotechnology & Applied Microbiology
项目资助者Open Funding Project of the National Key Laboratory of Biochemical Engineering ; National Key Basic Research Program (973 Program) of China(2011CBA00800) ; Key Agriculture Support Project of Jiangsu Province, China(BE201340) ; National Natural Science Foundation of China(31200602)
WOS记录号WOS:000408126800002
引用统计
被引频次:2[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.ipe.ac.cn/handle/122111/23149
专题生化工程国家重点实验室
作者单位1.Jiangsu Univ, Inst Life Sci, 301 Xuefu Rd, Zhenjiang 212013, Peoples R China
2.Chinese Acad Sci, Inst Proc Engn, Natl Key Lab Biochem Engn, Beijing, Peoples R China
3.Univ Calif San Diego, Div Biol Sci, La Jolla, CA 92093 USA
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Chen, Huayou,Jia, Jinru,Ni, Zhong,et al. Orlistat response to missense mutations in lipoprotein lipase[J]. BIOTECHNOLOGY AND APPLIED BIOCHEMISTRY,2017,64(5):464-470.
APA Chen, Huayou.,Jia, Jinru.,Ni, Zhong.,Vastermark, Ake.,Wu, Bangguo.,...&Jawad, Ullah.(2017).Orlistat response to missense mutations in lipoprotein lipase.BIOTECHNOLOGY AND APPLIED BIOCHEMISTRY,64(5),464-470.
MLA Chen, Huayou,et al."Orlistat response to missense mutations in lipoprotein lipase".BIOTECHNOLOGY AND APPLIED BIOCHEMISTRY 64.5(2017):464-470.
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