Comparative Analyses of Lipoprotein Lipase, Hepatic Lipase, and Endothelial Lipase, and Their Binding Properties with Known Inhibitors

PLOS ONE, Dec 2019

The triglyceride lipase gene subfamily plays a central role in lipid and lipoprotein metabolism. There are three members of this subfamily: lipoprotein lipase, hepatic lipase, and endothelial lipase. Although these lipases are implicated in the pathophysiology of hyperlipidemia and atherosclerosis, their structures have not been fully solved. In the current study, we established homology models of these three lipases, and carried out analysis of their activity sites. In addition, we investigated the kinetic characteristics for the catalytic residues using a molecular dynamics simulation strategy. To elucidate the molecular interactions and determine potential key residues involved in the binding to lipase inhibitors, we analyzed the binding pockets and binding poses of known inhibitors of the three lipases. We identified the spatial consensus catalytic triad “Ser-Asp-His”, a characteristic motif in all three lipases. Furthermore, we found that the spatial characteristics of the binding pockets of the lipase molecules play a key role in ligand recognition, binding poses, and affinities. To the best of our knowledge, this is the first report that systematically builds homology models of all the triglyceride lipase gene subfamily members. Our data provide novel insights into the molecular structures of lipases and their structure-function relationship, and thus provides groundwork for functional probe design towards lipase-based therapeutic inhibitors for the treatment of hyperlipidemia and atherosclerosis.

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Comparative Analyses of Lipoprotein Lipase, Hepatic Lipase, and Endothelial Lipase, and Their Binding Properties with Known Inhibitors

and Their Binding Properties with Known Inhibitors. PLoS ONE 8(8): e72146. doi:10.1371/journal.pone.0072146 Comparative Analyses of Lipoprotein Lipase, Hepatic Lipase, and Endothelial Lipase, and Their Binding Properties with Known Inhibitors Ziyun Wang 0 Shen Li 0 Lidan Sun 0 Jianglin Fan 0 Zhenming Liu 0 Paul Taylor, University of Edinburgh, United Kingdom 0 1 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University , Beijing , P. R. China , 2 Department of Molecular Pathology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi , Yamanashi , Japan The triglyceride lipase gene subfamily plays a central role in lipid and lipoprotein metabolism. There are three members of this subfamily: lipoprotein lipase, hepatic lipase, and endothelial lipase. Although these lipases are implicated in the pathophysiology of hyperlipidemia and atherosclerosis, their structures have not been fully solved. In the current study, we established homology models of these three lipases, and carried out analysis of their activity sites. In addition, we investigated the kinetic characteristics for the catalytic residues using a molecular dynamics simulation strategy. To elucidate the molecular interactions and determine potential key residues involved in the binding to lipase inhibitors, we analyzed the binding pockets and binding poses of known inhibitors of the three lipases. We identified the spatial consensus catalytic triad ''Ser-Asp-His'', a characteristic motif in all three lipases. Furthermore, we found that the spatial characteristics of the binding pockets of the lipase molecules play a key role in ligand recognition, binding poses, and affinities. To the best of our knowledge, this is the first report that systematically builds homology models of all the triglyceride lipase gene subfamily members. Our data provide novel insights into the molecular structures of lipases and their structure-function relationship, and thus provides groundwork for functional probe design towards lipase-based therapeutic inhibitors for the treatment of hyperlipidemia and atherosclerosis. - Funding: This work was supported by the National Natural Science Foundation of China (Grant No. 21272017, 20802006) and National High Technology Research and Development Program of China (Grant No. 2012AA020308). These funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. The triglyceride lipase gene subfamily (TLGS) is comprised of three evolutionarily related lipases: lipoprotein lipase (LPL), hepatic lipase (HL), and endothelial lipase (EL), and plays a central role in plasma lipoprotein metabolism and homeostasis [1]. These lipases are differentiated by their tissue-specific gene expression, and substrate specificity. LPL is mainly expressed in adipose and muscle tissues, while HL is specifically expressed in the liver [2,3]. In contrast, EL is a newly identified lipase that is synthesized by vascular endothelial cells, thyroid epithelial cells, and hepatocytes [4]. LPL mainly hydrolyzes the triglycerides of chylomicrons and very low-density lipoproteins, whereas EL exerts significant phospholipase activity on high-density lipoprotein (HDL) particles, but has less triglyceride lipase activity [2,46]. HL seems to have equal hydrolytic activity on triglycerides, phospholipids of remnant lipoproteins, and HDL particles [7]. Furthermore, all lipases are expressed in macrophages and have been implicated in the pathogenesis of atherosclerosis [710]. Because of their diverse range of important functions in maintaining lipoprotein homeostasis and their involvement in the pathophysiology of hyperlipidemia and atherosclerosis, the TLGS members are attractive biomarkers and potential therapeutic targets for the treatment of metabolic diseases [11]. For example, the up-regulation of LPL activity may be beneficial in obesity and diabetes, whereas inhibition of EL may increase plasma HDL levels [12,13]. It is therefore essential to obtain molecular structural information to elucidate how these lipases exert their effects, and how they interact with their ligands. Previous studies have revealed that these lipases share common motifs, including a heparin-binding domain, and key active site residues (called the a/b hydrolase fold) [14]. The active site residues are responsible for maintaining the juxtaposition of the conserved residues in the active site pentapeptide, and evolved independently from the forces that constrained and molded the analogous pentapeptide of serine proteases [15]. It is likely that these two motifs are a result of convergent evolution [16]. Each lipase molecule has a lid element, which blocks the enzymatic active site, and cofactors that are required for enzymatic activation. For example, apolipoprotei (...truncated)


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Ziyun Wang, Shen Li, Lidan Sun, Jianglin Fan, Zhenming Liu. Comparative Analyses of Lipoprotein Lipase, Hepatic Lipase, and Endothelial Lipase, and Their Binding Properties with Known Inhibitors, PLOS ONE, 2013, 8, DOI: 10.1371/journal.pone.0072146