Sandbox 78: Difference between revisions

Human gastric lipase (HGL, E.C. 3.1.1.3) (PBD ID: 1hlg) is the [[lipase]] that is responsible for initiating the digestion of dietary fats in the stomach <ref name="armand">PMID:7598069</ref>. This acid-stable enzyme <ref name="gastritis">PMID:23899880</ref> is secreted by the fundic chief cells of the human stomach and catalyzes 10-20% of total lipolytic processes (i.e., those involving fat breakdown) in healthy adults <ref name="armand" />. HGL specifically catalyzes the hydrolysis of triacylglycerol in order to produce diacylglycerol and a carboxylate byproduct <ref name="roussel">PMID:10358049</ref>, a process that facilitates subsequent fat breakdown by pancreatic lipase <ref name="dogs">PMID:20965171</ref>. In terms of disease implications, there is evidence to suggest that HGL secretion is altered in individuals with gastritis (the most common gastric condition, in which the stomach lining is inflamed) <ref name="gastritis" />.

HGL, a dimeric [[hydrolase]] enzyme consisting of two 379 amino acid residue-long subunits, possesses a <scene name='72/728060/Catalytic_elbow/3'>Catalytic Arm</scene> that contains residues Ser-153, His-353, and Asp-324. This structure is essential to the breakdown of lipids, coordinated with an <scene name='72/728060/Arm_and_hole/1'>Oxyanion Hole</scene> at Leu-67 and Gln-154 <ref name="dogs">PMID:20965171</ref>, that serves to stabilize the transition state. Structurally, the human gastric lipase exhibits a complex <scene name='72/728060/Secondary_structure/1'>Secondary Structure</scene> (beta sheets shown in yellow, alpha helices shown in orange, coiled coils shown in green, and amino acid side chains shown as purple). The <scene name='72/728060/1hlg_lid/5'>"Lid"</scene> of HGL at residues 215-244 <ref name="dogs">PMID:20965171</ref> gives way to the <scene name='72/728060/Hydrophobic_regions/1'>Hydrophobic Areas</scene> (hydrophobic regions noted in red) both surrounding the active site and interfacing the lid. These areas are thought to draw lipids and promote docking <ref name="roussel" />.  

 

 

As an esterase with a catalytically active serine, HGL exhibits a mechanism resembling the established serine esterase mechanism. The active site serine, located within the <scene name='72/728060/Catalytic_elbow/3'>Catalytic Arm</scene>, is facilitated first by the neighboring formation of a salt bridge between Asp-136 and His-152, which induces the appropriation of a proton from Ser-153. The now highly nucleophilic Ser-153 will attack the carbonyl carbon of the acetate group in a triacylglycerol molecule. The tetrahedral species is stabilized by the oxyanion hole. However, as soon as the species disassembles into the covalently bonded acetate and lipase, the serine undergoes deacylation in which water acts as the nucleophile. This final step restores Ser-153 to its protonated state <ref name="esterase">PMID:23209280</ref>.  

Tomasik et al. (2013) <ref name="gastritis" /> investigated the hormonal regulation of HGL secretion in children and adolescents with gastritis. HGL activity was compared across three groups: one experimental group consisting of adolescents diagnosed with ''Helicobacter pylori'' gastritis (''n'' = 10), another experimental group consisting of adolescents with a non-''H. pylori'' induced form of gastritis (''n'' = 10), and one control group of healthy adolescents (''n'' = 14). HGL activity, in addition to plasma concentrations of glucagon-like peptide-1, cholecystokinin, and glucose-dependent insulinotropic peptide, were observed through analysis of gastric juice samples that had been collected via endoscopic measurements from each patient.

Patients whose superficial gastritis was induced by pathogens other than ''H. pylori'' exhibited lower levels of HGL activity compared to both healthy adolescents (''p'' < .005) and those who were diagnosed with ''H. pylori'' gastritis (''p'' < .005). Mean plasma concentrations of glucose-dependent insulinotropic peptide were lower in healthy patients (''p'' < 0.005) than in those with non-''H. pylori'' gastritis (''p'' < .003) and those with ''H. pylori'' gastritis (''p'' < 0.01).  Regulation of HGL secretion by glucagon-like peptide-1 and cholecystokinin was therefore found to be altered in adolescents with gastritis. In addition, glucose-dependent insulinotropic peptide was found to be a powerful activator of human gastric lipase activity in all experimental and control groups <ref name="gastritis" />.