Computational analysis and enzyme assay of inhibitor response to disease single nucleotide polymorphisms (SNPs) in lipoprotein lipase
Computational analysis and enzyme assay of inhibitor response to disease single nucleotide polymorphisms (SNPs) in lipoprotein lipase
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脂蛋白脂肪酶中疾病单核苷酸多态性 (SNP) 抑制剂反应的计算分析和酶测定
DOI：
10.1142/s0219720016500281
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发表时间：
2016-11
影响因子：
1
通讯作者：
刘丽君
中科院分区：
文献类型：
--
作者：
何德勇;黄玲;许亚萍;潘晓亮;刘丽君
脂蛋白脂肪酶（LPL）是一种限速酶，用于水解循环中富含TG的脂蛋白、乳糜微粒和极低密度脂蛋白的甘油三酯（TG）核心。该酶已被确定为一种有效和安全的治疗肥胖的靶点。本文通过综合复杂结构建模、虚拟诱变、分子动力学（MD）模拟、结合能分析和放射性标记TG水解分析，建立了三种抗肥胖药物（奥利司他、利司他汀和西替司他）对由疾病单核苷酸多态性（snp）引起的临床LPL错义突变的脂肪酶抑制剂反应的系统描述。该基因图谱随后被用来表征系统突变抑制剂对的耐药性和敏感性。这表明奥利司他和利司他汀由于具有同源的化学结构，对所研究的突变具有相似的反应谱，但与西替司他表现出不同的反应谱。大多数突变预测对抑制剂结合有适度或中等的影响；它们位于远离酶活性位点的位置，因此只能有限地影响结合。许多突变被发现通过直接与抑制剂配体相互作用或通过间接处理酶活性位点的变构效应而使脂肪酶抑制剂增敏或引起抗性。长期MD模拟显示，奥利司他与野生型LPL及其致敏突变体H163R和耐药突变体I221T的复杂界面存在不同的非共价相互作用网络。
Lipoprotein lipase (LPL) is the rate-limiting enzyme for the hydrolysis of the triglyceride (TG) core of circulating TG-rich lipoproteins, chylomicrons, and very low-density lipoproteins. The enzyme has been established as an efficacious and safe therapeutic target for the management of obesity. Here, a systematic profile of the lipase inhibitor response of three anti-obesity agents (Orlistat, Lipstatin, and Cetilistat) to clinical LPL missense mutations arising from disease single nucleotide polymorphisms (SNPs) was established by integrating complex structure modeling, virtual mutagenesis, molecular dynamics (MD) simulations, binding energy analysis, and radiolabeled TG hydrolysis assays. The profile was then used to characterize the resistance and sensitivity of systematic mutation-inhibitor pairs. It is suggested that the Orlistat and Lipstatin have a similar response profile to the investigated mutations due to their homologous chemical structures, but exhibit a distinct profile to that of Cetilistat. Most mutations were predicted to have a modest or moderate effect on inhibitor binding; they are located far away from the enzyme active site and thus can only influence the binding limitedly. A number of mutations were found to sensitize or cause resistance for lipase inhibitors by directly interacting with the inhibitor ligands or by indirectly addressing allosteric effect on enzyme active site. Long-term MD simulations revealed a different noncovalent interaction network at the complex interfaces of Orlistat with wild-type LPL as well as its sensitized mutant H163R and resistant mutant I221T.
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DOI：
10.1073/pnas.87.9.3474
发表时间：
1990-05
影响因子：
11.1
作者：
O. Beg;M. Meng;S. Skarlatos;L. Previato;J. Brunzell;H. Brewer;S. Fojo
通讯作者：
O. Beg;M. Meng;S. Skarlatos;L. Previato;J. Brunzell;H. Brewer;S. Fojo
影响因子：
14.8
作者：
Kumar, Prateek;Henikoff, Steven;Ng, Pauline C.
通讯作者：
Ng, Pauline C.
影响因子：
3.7
作者：
Wang Z;Li S;Sun L;Fan J;Liu Z
通讯作者：
Liu Z
DOI：
10.1016/s0021-9258(19)39449-9
发表时间：
1990-04
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Mitsuru Emi;Dana E. Wilson;P. Iverius;Lily L. Wu;Aaron N. Hata;Robert A. Hegele;Roger R. Williams;J. Lalouel
通讯作者：
Mitsuru Emi;Dana E. Wilson;P. Iverius;Lily L. Wu;Aaron N. Hata;Robert A. Hegele;Roger R. Williams;J. Lalouel
影响因子：
2.8
作者：
Guo, Xinchun;He, Deyong;Yang, Huijuan
通讯作者：
Yang, Huijuan