Sandbox 51: Difference between revisions

Pancreatic lipase initiates the breakdown of triacylglycerols into 2-monoacylglycerols and fatty acids.  The digestion of triacylglycerols is a major source of energy storage in metabolism. Consequently, lipase hydrolyzes the ester bonds of the triglycerides.  Lipase, as a digestive enzyme, is soluble in water but the triacylglycerides it hydrolyzes are not.  In the duodenum, bile salts initiate lipase's mechanism by emulsification of the fatty acids.  Bile salts are usually sodium with the deprontated form of digestive acids (mostly derivatives of cholic acid).  Bile salts are stored by the gallbladder and released into the duodenum where they facilitate the formation of micelles.  Bile salts or acids are amphipathic.  Therefore, the hydrophobic region surrounds the fatty acids and the hydrophilic remains on the outside in the process of emulsification, creating smaller micelle molecules.  Micelle formation is essential to maximize the efficiency of lipase by increasing the hydrophilic surface area on which lipase will work.  For the hydrolysis reaction, lipase activity requires bile acids, its coenzyme (colipase), and calcium ions to achieve the correct orientation to hydrolyze the fats <ref>Fundamentals of Biochemistry...</ref>

==Mechanism==  

In addition to the effects of bile salts, Lipase is activated by the coenzyme colipase, which binds to the C-terminal non-catalytic domain.  Upon binding, active lipase is stabilized for the hydrophobic interaction with the triacylglycerides <ref>Fundamentals of Biochemistry...</ref>.  Colipase must be present for activation of lipase.  Lipase activation at the lipid-water interface of triacylglycerides, in the presence of colipase and bile salts, is known as interfacial activation. Colipase is also secreted in the pancreas, but in its inactive form, which must be activated by trypsin before interacting with lipase <ref>"Colipase". Wikipedia: The Free Encyclopedia. 5 July 2011 [http://en.wikipedia.org/wiki/Colipase]</ref>.  Colipase and lipase <scene name='Sandbox_51/Contacts/3'>contacts</scene> are at opposite of the active site on the C-terminal, including polar interactions such as <scene name='Sandbox_51/Salt_bridges/2'>salt bridges</scene> and van der waals forces which stabilize the interaction <ref>van Tilbeurgh H, etc."Structure of the pancreatic lipase-procolipase complex",  1992 Sep 10;359(6391):159-62. PMID:1522902.[http://www.proteopedia.org/wiki/index.php/1n8s]</ref>. <scene name='Sandbox_51/Lipase_and_colipase/1'>Colipase and lipase in complex with a triacylglyceride</scene> shows a unique feature of lipase is the lid over the active sight.  Once colipase has anchored lipase to the lipid-water membrane, a surface change occurs.  The lid of lipase is known to be essential to lipase action.  The 10 residue beta-5 loop changes confirmation exposing lipase's oxyanion hole and hydrophobic surface.  Before colipase binding, lipase is in the <scene name='Sandbox_51/Closed_lid/2'>closed confirmation</scene> where the beta-5 loop(residues 76-84, in pink) and lid (residues 237-261, yellow) protect the oxyanion hole from solvent interaction.  The <scene name='Sandbox_51/Mutated_open_ring/4'>open lid</scene> structure is accompanied by peptide shifts which increase hydrophobic surface area initiating the reaction with the lipid.  One such important shift is part of the lid at residues 240-252 (in yellow), very close to the active site.  Also, it is evident from the image that part of the beta-5 loop interacts with colipase in the open state.  The lid opening is accompanied by a change in secondary structure from a mostly beta-extended confirmation to a structure where more than half the active site is formed from alpha helices <ref>Thomas, A.etc. "Role of the Lid Hydrophobicity Pattern in Pancreatic