title: Computational analysis and enzyme assay of inhibitor response to disease single nucleotide polymorphisms (SNPs) in lipoprotein lipase.
abstract: 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.
authors.affiliation: * School of Chemistry and Chemical Engineering, Jinggangshan, University, No. 28 Xueyuan Road, Ji'an 343009, China.
authors.forename: Deyong
authors.initials: D
authors.lastname: He
authors.affiliation: * School of Chemistry and Chemical Engineering, Jinggangshan, University, No. 28 Xueyuan Road, Ji'an 343009, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Huang
authors.affiliation: * School of Chemistry and Chemical Engineering, Jinggangshan, University, No. 28 Xueyuan Road, Ji'an 343009, China.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Xu
authors.affiliation: † School of Mechanical Engineering, Jinggangshan University, No.28 Xueyuan Road, Ji'an 343009, China.
authors.forename: Xiaoliang
authors.initials: X
authors.lastname: Pan
authors.affiliation: * School of Chemistry and Chemical Engineering, Jinggangshan, University, No. 28 Xueyuan Road, Ji'an 343009, China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Liu
mesh_terms: D019440:Anti-Obesity Agents / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D020022:Genetic Predisposition to Disease; D006801:Humans; D007783:Lactones / Q000737:chemistry / Q000494:pharmacology; D008071:Lipoprotein Lipase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics*; D008958:Models, Molecular; D020125:Mutation, Missense; D009765:Obesity / Q000188:drug therapy / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011487:Protein Conformation
chemical_list: D019440:Anti-Obesity Agents; D004791:Enzyme Inhibitors; D007783:Lactones; C054164:lipstatin; D008071:Lipoprotein Lipase
keywords: Lipoprotein lipase; drug response; lipase inhibitor; missense mutation; single nucleotide polymorphism