Sandbox 51: Difference between revisions

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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. Bile salts surround the fatty acid globules to make them more soluble. Lipase activity requires bile acids, its coenzyme, and calcium ions to acheive 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 that the lid over the active sight is lifted and a 10 residue beta-5 loops changes confirmation exposing lipase's oxyanion hole and hydrophobic surface. Before colipase binding, the beta-5 loop serves to protect the oxyanion hole from solvent interaction Colipase hydrophobic loops interact with the hydrophobic atmosphere of the triacylglyceride initiating lipase active site binding to the lipid. Once bound, lipase initiates a serine-like hydrolysis involving His, Asp, Ser residues in the catalytic triad releasing the lipid products <ref>Fundamentals of Biochemistry...</ref>. [[Image:F6.medium.gif]]

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 that the lid over the active sight is lifted and a 10 residue beta-5 loops changes confirmation exposing lipase's oxyanion hole and hydrophobic surface. Before colipase binding, the beta-5 loop serves to protect the oxyanion hole from solvent interaction Colipase hydrophobic loops interact with the hydrophobic atmosphere of the triacylglyceride initiating lipase active site binding to the lipid. Once bound, lipase initiates a serine-like hydrolysis involving His, Asp, Ser residues in the catalytic triad releasing the lipid products <ref>Fundamentals of Biochemistry...</ref>. In the reaction, serine attacks the ester, forming an acyl-enzyme intermediate. The His and Asp residues help to stabilize the oxyanion intermediate. Water enters the active site and reacts to release lipase and free the fatty acid. [[Image:F6.medium.gif]] <ref> Reetz, Manfield F. Controlling the enantioselectivity of enzymes by directed evolution: Practical and theoretical ramifications. PNAS: 12 April 2004 [http://www.pnas.org/content/101/16/5716.full]</ref>.

==Inhibition==

Sandbox 51: Difference between revisions

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 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.  Bile salts surround the fatty acid globules to make them more soluble.  Lipase activity requires bile acids, its coenzyme, and calcium ions to acheive 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 that the lid over the active sight is lifted and a 10 residue beta-5 loops changes confirmation exposing lipase's oxyanion hole and hydrophobic surface.  Before colipase binding, the beta-5 loop serves to protect the oxyanion hole from solvent interaction Colipase hydrophobic loops interact with the hydrophobic atmosphere of the triacylglyceride initiating lipase active site binding to the lipid. Once bound, lipase initiates a serine-like hydrolysis involving His, Asp, Ser residues in the catalytic triad releasing the lipid products <ref>Fundamentals of Biochemistry...</ref>. [[Image:F6.medium.gif]]
+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 that the lid over the active sight is lifted and a 10 residue beta-5 loops changes confirmation exposing lipase's oxyanion hole and hydrophobic surface.  Before colipase binding, the beta-5 loop serves to protect the oxyanion hole from solvent interaction Colipase hydrophobic loops interact with the hydrophobic atmosphere of the triacylglyceride initiating lipase active site binding to the lipid. Once bound, lipase initiates a serine-like hydrolysis involving His, Asp, Ser residues in the catalytic triad releasing the lipid products <ref>Fundamentals of Biochemistry...</ref>. In the reaction, serine attacks the ester, forming an acyl-enzyme intermediate.  The His and Asp residues help to stabilize the oxyanion intermediate.   Water enters the active site and reacts to release lipase and free the fatty acid. [[Image:F6.medium.gif]] <ref> Reetz, Manfield F. Controlling the enantioselectivity of enzymes by directed evolution: Practical and theoretical ramifications. PNAS: 12 April 2004 [http://www.pnas.org/content/101/16/5716.full]</ref>.
 ==Inhibition==