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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

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.

KeywordLipoprotein Lipase Orlistat Missense Mutation
WOS HeadingsScience & Technology ; Life Sciences & Biomedicine
Indexed BySCI
WOS KeywordFamilial Lpl Deficiency ; Monoacylglycerol Lipase ; Atomic Charges ; Plasma-lipids ; Gene ; Tetrahydrolipstatin ; Atherosclerosis ; Inhibitors ; Disease ; Patient
WOS Research AreaBiochemistry & Molecular Biology ; Biotechnology & Applied Microbiology
WOS SubjectBiochemistry & Molecular Biology ; Biotechnology & Applied Microbiology
Funding OrganizationOpen 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 IDWOS:000408126800002
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Cited Times:3[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Affiliation1.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
Recommended Citation
GB/T 7714
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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