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| - | == '''Pancreatic Lipase''' ==
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| - | == '''Introduction''' ==
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| - | <StructureSection load='1hpl' size='500' side='right' caption='Structure of Horse Pancreatic Lipase (PDB entry [[1hpl]])' scene=''>A subclass of esterases, pancreatic lipase (EC 3.1.1.3) is an enzyme that catalyzes the hydrolysis and formation of lipids. While produced in the pancreas, it is also present in the stomach and mouth. Due to its effective ester bond hydrolysis of lipids, lipase is essential for fat digestion, breaking lipids into monoglycerides and single fatty acids. If one is lipase deficient, it is hard to obtain adequate nutrition from food because the fats cannot be absorbed by the body. This results in diseases such as cystic fibrosis, Crohn's disease, and celiac disease.
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| - | == '''Structure''' ==
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| - | The <scene name='Sandbox_43/Quat_struc/2'>quaternary structure</scene> of horse pancreatic lipase contains two molecules which each contain 449 amino acid residues, 705 water molecules, and 1 calcium ion. These two identical molecules are connected by a two-fold symmetry axis. The tertiary structure of lipase is stabilized by <scene name='Sandbox_43/Disulfide/1'>disulfide bonds</scene> between cysteine residues. The <scene name='Sandbox_43/Interactions_between_chains/1'>interactions between the a chain and the b chain</scene> include <scene name='Sandbox_43/Hydogen_bonds/1'>hydrogen bonds</scene> and salt bridges. The secondary structure of lipase is composed of 102 residues that constitute 13 <scene name='Sandbox_43/Alpha_helixes/1'>alpha helices</scene> (22% helical) and 139 residues that constitute 28 <scene name='Sandbox_43/Beta_sheets/3'>beta sheet</scene> strands (30% beta sheets).<ref>http://www.pdb.org/pdb/explore.do?structureId=1HPL</ref> Lipase is essentially composed of two domains, as shown in the N-terminus to C-terminus <scene name='Sandbox_43/N-c_rainbow/1'>rainbow depiction</scene>. The <scene name='Sandbox_43/N_terminal/1'>N-terminal domain</scene>, which contains the <scene name='Sandbox_43/Active_site/8'>active site</scene> of lipase (consisting of three residues: Ser-152, Asp-176, and His-263).<ref>http://www.nature.com/nature/journal/v343/n6260/abs/343771a0.html</ref> The N-terminal domain also contains the <scene name='Sandbox_43/Active_site/3'>lid region</scene> (residues 216-239) which serves to block the active site, which is nestled in the <scene name='Sandbox_43/Hhhhhhhhhhhyrdop/1'>hydrophobic regions</scene>, (in red) from the solvent. Likewise, the active site does not have interactions with the polar, <scene name='Sandbox_43/Hhhhhyrdophilic/1'>hydrophilic regions</scene> (in orange). Additionally, the <scene name='Sandbox_43/C_terminal/1'>C-terminal domain</scene> is essential to the binding of lipase with colipase, an important cofactor for the catalysis of lipids. This forms the <scene name='Sandbox_43/Complex_with_colipase/1'>lipase-colipase complex</scene> pictured also with the triglyceride in the substrate binding site.<ref>http://en.wikipedia.org/wiki/Colipase</ref>
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| - | == '''Calcium Ligand''' ==
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| - | [[Image:Diag calcium 2.gif|150px|right|thumb| Calcium Ion <ref>http://www.bbc.co.uk/schools/gcsebitesize/science/images/diag_calcium_2.gif</ref>]]
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| - | The most significant ligand involved in the structure of lipase is the <scene name='Sandbox_43/Calcium_ligand/3'>calcium ion</scene>.<ref>http://www.sciencedirect.com/science/article/pii/S0268005X10000561</ref> This ion has been shown to promote the folding of lipase into its active dimer state, keeping in that state throughout the course of the lipase's hydrolysis of fat. As such, the calcium ion is extremely important in forming the lipase-fat complex, evidently necessary for the breakdown of lipids. Studies have shown that an increase in calcium concentration in a lipase catalyzed reaction results in an increase in the rate of the reaction, demonstrating the acute importance of the calcium ion. Furthermore, other ions such as magnesium have been tested and have been shown to not promote the folding of lipase into its dimer state, indicating the specificity of calcium in lipase.<ref>http://jb.oxfordjournals.org/content/72/6/1565.extract</ref>
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| - | == '''Colipase Cofactor''' ==
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| - | <scene name='Sandbox_43/Colipase/1'>Colipase</scene> is a small protein that is necessary for efficient lipid catalysis by lipase. It is secreted by the pancreas in its inactive form as procolipase which is converted into the active colipase by trypsin. It binds to the non-catalytic C-terminal domain of lipase and in so doing stabilizes its active conformation as it hydrolyzes lipids. Furthermore, it also binds to the lipid interface, increasing the affinity between lipase and the lipid.<ref>http://en.wikipedia.org/wiki/Colipase</ref>
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| - | == '''Mechanism of Triglyceride Hydrolysis''' ==
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| - | [[Image:Hydrolysis.gif|200px|right|thumb| Lipase-catalyzed hydrolysis of lipids. Notice the catalytic triad of Ser-152, Asp-176, and His-263 that constitute the active site.<ref>http://www.pnas.org/content/101/16/5716.full</ref>]]
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| - | After colipase binds to the C-terminus and the structural modifications of lipase take place (opening the "lipase lid"), the active site is exposed and the lipid binds, initiating its catalysis. <scene name='Sandbox_43/Asp_176/1'>Asp-176</scene> acts as a base and removes the proton from <scene name='Sandbox_43/Ser_152/3'>His-263</scene>. This allows His-263 to push electrons towards <scene name='Sandbox_43/Ser_152/2'>Ser-152</scene>, removing the hydrogen from serine's alcohol. Consequently, the nucleophilicity of the now-charged oxygen atom on Ser-152 is greatly increased, promoting its attack of one of the ester carbons of the triglyceride. Through the nucleophilic acyl substitution mechanism, Ser-152 forms a tertrahedral intermediate with the lipid, which consequently exposes the former carbonyl oxygen (now negatively charged) to the <scene name='Sandbox_45/Oxyhole/2'>oxyanion hole</scene>. Coming out of this stabilized transition state, the first product of the reaction (an alcohol) is pushed off the carbonyl carbon as the ester is reformed. Finally, hydrolysis can take place and the second product, the free fatty acid, leaves and the alcohol substituent of Ser-152 is reformed.<ref>http://www.pnas.org/content/101/16/5716.full</ref>
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| - | == '''C11 Alkyl Phosphonate Inhibitor''' ==
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| - | Lipase inhibitors are of medical importance because they can be used to block the absorption of fats by the body, aiding in weight loss.<ref>http://www.nature.com/ijo/journal/v24/n6/full/0801222a.html</ref> One such inhibitor is C11 alkyl phosphonate which <scene name='Sandbox_43/C11_inhibition/1'>interacts with lipase</scene> and inhibits its active site. This inhibitor forms a covalent bond with Ser-152 as well as forming hydrophobic interactions with the ampipathic lipase lid and mimicking the the interactions between the leaving fatty acid of triglyceride and lipase. Combined these successfully destroy the functionality of the active site while C11 is still bound. <ref>http://pubs.acs.org/doi/pdf/10.1021/bi00009a003</ref>
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| - | == '''References''' ==
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| - | <references />
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