Lipase: Difference between revisions

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== '''Introduction''' ==

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Further breakdown ultimately results in 2-monoacylglycerols and free fatty acids <ref name= "A cross-linked complex between horse pancreatic lipase and colipase">[http://www.sciencedirect.com/science/article/pii/0014579389815923] A cross-linked complex between horse pancreatic lipase and colipase</ref>. An in depth discussion of the mechanism can be found in the Lipase Catalytic Mechanism section. The determination of the structure and function of lipase was a gradual process.  Lipase activity was first demonstrated in the pancreas by Claude Bernard in 1846.  However, it wasn't until 1955 that Mattson and Beck demonstrated a high-specificity of pancreatic lipase for triglyceride primary esters <ref name= "History of Lipids">[http://www.cyberlipid.org/history/history1.htm] History of Lipids</ref>.  In recent years, determination of the crystal structure of pancreatic lipase has become the primary focus as many scientists have worked to further this.<br />

* [[Molecular Playground/Pancreatic Lipase]]<br />

* [[Lipase lid morph]]<br />

* [[Hormone sensitive lipase]]<br />

== '''Structure''' ==

== '''Lipase Catalytic Mechanism''' ==

Lipase activation at the lipid-water interface of triacylglycerides, in the presence of colipase and bile salts, is known as interfacial activation.  For the hydroloysis reaction to take place, colipase anchors lipase to the lipid-water membrane of the micelle which causes a surface change on lipase.  Colipase's four hydrophobic loops interact with the hydrophobic atmosphere of the triacylglyceride. This initiates active site binding to the lipid, and lid opening to reveal a more hydrophobic environment for the triacylglycerol.  This in turn, allows the triacylglycerol to interact with key active site residues like the catalytic triad.  A diverse array of lipase enzymes can be found in nature. Though the different forms occupy diverse protein scaffolds, most are built upon an alpha/beta hydrolase fold<ref>PMID: 1678899</ref><ref>PMID:1409539 </ref>  and possess a [[chymotrypsin]]-like <scene name='Lipase/Catalytic_site_outerview/1'>catalytic triad </scene>comprised of an acidic residue, a histidine, and a serine nucleophile. In the case of horse pancreatic lipase, the catalytic triad is comprised of <scene name='Lipase/Catalytic_triad/4'>Ser 152, Asp 176 and His 263. </scene><ref>PMID:8182745</ref>.  This catalytic triad functions like most found in nature. First, aspartic acid forms a hydrogen bond with His 263, increasing the pKa of the histidine imidazole nitrogen. This allows the histidine to act as a powerful general base and deprotonate the serine. The deprotonated serine then can serve as a nucleophile and attack the ester carbonyl of one of the fatty acids on the 1 or 3 carbons of the glycerol backbone of the lipid substrate.  Upon attacking the lipid, a negatively charged tetrahedral intermediate is formed (Reaction 1).  It is stabilized in the oxyanion hole by two residues:  <scene name='Lipase/Catalytic_triad_with_oxyanion/2'>Phe 77 and Leu 153</scene>.   

The carbonyl reforms with the glycerol backbone segment acting as the leaving group (Reaction 2).   

A water molecule then donates a proton to the histidine, creating a reactive hydroxyl anion. The hydroxyl anion can then attack the carbonyl carbon of the lipid, forming another negatively charged tetrahedral intermediate which is stabilized in the oxyanion hole (Reaction 3).   

Upon reformation of the carbonyl, the catalytic serine is released and monoglyceride and fatty acid monomers diffuse away (Reaction 4).   

== '''Inhibition of Pancreatic Lipase''' ==

== '''Clinical Significance''' ==

Pancreatic lipase is secreted into the duodenum through the duct system of the pancreas. In a healthy individual, it is at very low concentration in serum. Under extreme disruption of pancreatic function, such as pancreatitis or pancreatic cancer, the pancreas may begin to digest itself and release pancreatic enzymes including pancreatic lipase into serum. Measurement of serum concentration of pancreatic lipase can therefore aid in diagnosis of acute pancreatitis.<ref>"Pancreatic lipase". Wikipedia: The Free Encyclopedia. 7 Nov 2011 [http://en.wikipedia.org/wiki/Pancreatic_lipase]</ref>.  Due to lipase's activity in the digestion and absorption of fat, there has been a growing market for lipase inhibitors for weight loss pharmaceuticals.  The most popular is Orlistat (or Xenical®) which is a natural product from ''Streptomyces toxytricini'' and is the hydrogenation product of lipostation- an irreversible lipase inhibitor.  This inhibitor also acts by binding Ser152, producing an ester which hydrolyzes so slow that it is practically irreversible <ref>Kordik, C., Reitz, A. "Pharmacological Treatment of Obesity: Therapeutic Strategies" Journal of Medicinal Chemistry, 1999 (42).</ref>.

== 3D Structures of Lipase ==

==References==

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