Sandbox 51: Difference between revisions

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==Introduction==

Pancreatic lipase 1hpl (EC 3.1.1.3) is a an enzyme involved with the digestion and absorption of triacylglycerols (fats) in the intestine. It is secreted by the pancreas into the duodenum where it participates in the initial stages of breaking down fats <ref>Voet, D.,etc. "Fundamentals of Biochemistry: Life at the Molecular Level" John Wiley and Sons, Inc: New Jersey, 2008.</ref>

Pancreatic lipase 1hpl (EC 3.1.1.3) is a an enzyme involved with the digestion and absorption of triacylglycerols (fats) in the intestine. It is secreted by the pancreas into the duodenum where it participates in the initial stages of breaking down fats into glyercol and three fatty acids. Lipase is a serine protease and a polar molecule. The mechanism of action requires Calcium ligands for stability and the coenzyme, colipase, for activation of the lipase mechanism. The hydrolysis products diffuse across enterocyte membrane and are absorbed into the blood <ref>Voet, D.,etc. "Fundamentals of Biochemistry: Life at the Molecular Level" John Wiley and Sons, Inc: New Jersey, 2008.</ref>. Due to that role lipase has in digestion of fat, and the growing problem of obesity, there has been increased effort to develop lipase inhibitors for weight loss supplements.

==Structure==

1hpl is the horse pancreatic lipase enzyme that is thought to have a similar structure and function to the human pancreatic lipase. The <scene name='Sandbox_51/Lipase_crystal_structure/1'> Crystal Structure</scene> of the human pancreatic lipase has not yet been published. Lipase is a dimer of two <scene name='Sandbox_51/Lipase_crystal_structure/3'>monomers</scene> with 449 amino acid residues interacting with one <scene name='Sandbox_51/Ligand_position/2'>Calcium Ligand</scene> each. The calcium ion <scene name='Sandbox_51/Calcium_orientation/2'>orientation</scene> shows that the molecule is located between acidic residues Arg, Asp and Glu. The enzyme has <scene name='Sandbox_51/Nc_terminal/1'>two domains</scene> of various composition specific for certain interactions, an N-terminal (blue) and a C-terminal (red). In the <scene name='Sandbox_51/Secondary_structure/2'>secondary structure</scene>, the N-terminal domain has the hydrolase alpha/beta folding structure, consisting of an 8 stranded alpha-beta sheet connected by helices. The C-terminal domain (where enzyme colipase binds) has a beta-sheet sandwich folding pattern <ref>Horse pancreatic lipase...</ref>. The enzyme has 13 alpha helices (pink) and 22 beta sheets (yellow) per subunit, as displayed in the <scene name='Sandbox_51/Secondary_structure/2'>secondary structure</scene> <ref>Egloff, M.P., etc. "The 2.46 angstroms resolution structure of the pancreatic lipase colipase complex inhibited by a C11 alkyl phosphonate."(1995) J. Biochemistry 34: 2751-2762 [http://www.pdb.org/pdb/explore/explore.do?structureId=1lpb]</ref>. At the <scene name='Sandbox_51/Monomer_interface/1'>interface</scene> of the two monomers, interactions include 4 hydrogen bonds and 4 salt bridges that stabilize the dimer <ref>"HORSE PANCREATIC LIPASE. THE CRYSTAL STRUCTURE AT 2.3 ANGSTROMS RESOLUTION." http://bisc.cse.ucsc.edu/pages/BiscHom/1hpl_AB.html</ref>. The molecule has a varying degree of <scene name='Sandbox_51/Polar_structure/3'>polar and hydrophobic residues</scene> interspersed within the protein(polar are shown in purple and hydrophobic in white) <ref>Bourne, Y., etc. "Horse pancreatic lipase..."(1994) J.Mol.Biol. 238: 709-732 [http://www.pdb.org/pdb/explore/explore.do?structureId=1HPL]</ref>. This is important because the enzyme actively digests at the lipid-water interface of the fatty micelles, requiring stability in both polar and non polar environments <ref>Fundamentals of Biochemistry...</ref>. Within each monomer and dimer structure, the molecules are held together by disulfide bonds, hydrogen bonding, and electrostatic interactions (salt bridges). The enzyme has six covalent <scene name='Sandbox_51/Disulfide_bons/1'>disulfide bonds</scene> per monomer. Also, the <scene name='Sandbox_51/Salt_bridges/3'>salt bridges</scene> stabilize the monomers and dimer of the enzyme at positively charged nitrogens (blue) in Arg and Lys, and negative oxygens (red) in Asp and Glu residues. <scene name='Sandbox_51/Hydrogen_bonds/2'>Hydrogen bonds</scene> are present within each monomer, as shown by the hydrogen bond forming residues (light gray), and the oxygen (red) and nitrogen (blue) atoms involved in the hydrogen bonding. Lipase is water soluble due to the polar residues on the surface, but has hydrophobic sequences on the interior. At enzyme activation and interaction with colipase, a confirmation change occurs to expose the more hydrophobic regions to the nonpolar lipid micelle.

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 <applet load='1hpl' size='500' frame='true' align='right' caption='Lipase' />
 ==Introduction==
-Pancreatic lipase 1hpl (EC 3.1.1.3)  is a an enzyme involved with the digestion and absorption of triacylglycerols (fats) in the intestine.  It is secreted by the pancreas into the duodenum where it participates in the initial stages of breaking down fats <ref>Voet, D.,etc. "Fundamentals of Biochemistry: Life at the Molecular Level" John Wiley and Sons, Inc: New Jersey, 2008.</ref>
+Pancreatic lipase 1hpl (EC 3.1.1.3)  is a an enzyme involved with the digestion and absorption of triacylglycerols (fats) in the intestine.  It is secreted by the pancreas into the duodenum where it participates in the initial stages of breaking down fats into glyercol and three fatty acids.  Lipase is a serine protease and a polar molecule.  The mechanism of action requires Calcium ligands for stability and the coenzyme, colipase, for activation of the lipase mechanism.  The hydrolysis products diffuse across enterocyte membrane and are absorbed into the blood <ref>Voet, D.,etc. "Fundamentals of Biochemistry: Life at the Molecular Level" John Wiley and Sons, Inc: New Jersey, 2008.</ref>.  Due to that role lipase has in digestion of fat, and the growing problem of obesity, there has been increased effort to develop lipase inhibitors for weight loss supplements.
 ==Structure==
 hpl is the horse pancreatic lipase enzyme that is thought to have a similar structure and function to the human pancreatic lipase.  The  <scene name='Sandbox_51/Lipase_crystal_structure/1'> Crystal Structure</scene> of the human pancreatic lipase has not yet been published.   Lipase is a dimer of two <scene name='Sandbox_51/Lipase_crystal_structure/3'>monomers</scene> with 449 amino acid residues interacting with one <scene name='Sandbox_51/Ligand_position/2'>Calcium Ligand</scene> each.  The calcium ion <scene name='Sandbox_51/Calcium_orientation/2'>orientation</scene> shows that the molecule is located between acidic residues Arg, Asp and Glu.  The enzyme has <scene name='Sandbox_51/Nc_terminal/1'>two domains</scene> of various composition specific for certain interactions, an N-terminal (blue) and a C-terminal (red).  In the <scene name='Sandbox_51/Secondary_structure/2'>secondary structure</scene>, the N-terminal domain has the hydrolase alpha/beta folding structure, consisting of an 8 stranded alpha-beta sheet connected by helices. The C-terminal domain (where enzyme colipase binds) has a beta-sheet sandwich folding pattern <ref>Horse pancreatic lipase...</ref>. The enzyme has 13 alpha helices (pink) and 22 beta sheets (yellow) per subunit, as displayed in the <scene name='Sandbox_51/Secondary_structure/2'>secondary structure</scene> <ref>Egloff, M.P., etc. "The 2.46 angstroms resolution structure of the pancreatic lipase colipase complex inhibited by a C11 alkyl phosphonate."(1995) J. Biochemistry 34: 2751-2762 [http://www.pdb.org/pdb/explore/explore.do?structureId=1lpb]</ref>.  At the <scene name='Sandbox_51/Monomer_interface/1'>interface</scene> of the two monomers, interactions include 4 hydrogen bonds and 4 salt bridges that stabilize the dimer <ref>"HORSE PANCREATIC LIPASE. THE CRYSTAL STRUCTURE AT 2.3 ANGSTROMS RESOLUTION." http://bisc.cse.ucsc.edu/pages/BiscHom/1hpl_AB.html</ref>.  The molecule has a varying degree of <scene name='Sandbox_51/Polar_structure/3'>polar and hydrophobic residues</scene> interspersed within the protein(polar are shown in purple and hydrophobic in white) <ref>Bourne, Y., etc. "Horse pancreatic lipase..."(1994) J.Mol.Biol. 238: 709-732 [http://www.pdb.org/pdb/explore/explore.do?structureId=1HPL]</ref>.  This is important because the enzyme actively digests at the lipid-water interface of the fatty micelles, requiring stability in both polar and non polar environments <ref>Fundamentals of Biochemistry...</ref>. Within each monomer and dimer structure, the molecules are held together by disulfide bonds, hydrogen bonding, and electrostatic interactions (salt bridges).  The enzyme has six covalent <scene name='Sandbox_51/Disulfide_bons/1'>disulfide bonds</scene> per monomer.  Also, the <scene name='Sandbox_51/Salt_bridges/3'>salt bridges</scene> stabilize the monomers and dimer of the enzyme at positively charged nitrogens (blue) in Arg and Lys, and negative oxygens (red) in Asp and Glu residues.  <scene name='Sandbox_51/Hydrogen_bonds/2'>Hydrogen bonds</scene> are present within each monomer, as shown by the hydrogen bond forming residues (light gray), and the oxygen (red) and nitrogen (blue) atoms involved in the hydrogen bonding. Lipase is water soluble due to the polar residues on the surface, but has hydrophobic sequences on the interior.  At enzyme activation and interaction with colipase, a confirmation change occurs to expose the more hydrophobic regions to the nonpolar lipid micelle.