Sandbox 51
From Proteopedia
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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 [1]
Structure
1hpl is the horse pancreatic lipase enzyme that is thought to have a similar structure and function to the human pancreatic lipase. The of the human pancreatic lipase has not yet been published. Lipase has two of 449 amino acid residues interacting with one each. The calcium ion shows that the molecule is located between acidic residues Arg, Asp and Glu. The enzyme has 13 alpha helices (pink) and 22 beta sheets (yellow)per subunit as displayed in the [2]. The molecule has a varying degree of interspersed within the molecules [3]. 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 [4]. The enzyme has of various composition specific for certain interaction, an N-terminal (blue) and a C-terminal (red). In the , the N-terminal domain has the hydrolase alpha/beta folding structure, consisting of an alpha-beta sheet consisting of 8 strands connected by helices. The C-terminal domain (enzyme colipase binds) has a beta-sheet sand which folding pattern [5] The of the lipase molecule is found in the N-terminal domain (residues 1-336) and contains a consisting of a Ser-His-Arg for the ester hydrolysis reaction (similar to that of a serine protease). The active site is covered by a 25-residue helical 'lid' blocking the binding site, unless appropriate conditions [6].
Function
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 [7]
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 [8]. 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 [9]. Colipase and lipase are at opposite of the active site on the C-terminal, including polar interactions such as and van der waals forces which stabilize the interaction [10]. 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 [11]. 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. 
[12].
Inhibition
The inhibition of pancreatic lipase has serious effects on storage and absorption of fats taken in by the body. Inhibition of the enzyme reduces the amount of fat stored and absorbed by the body, and is therefore a potentially strong basis for pharmaceuticals to combat obesity. Because lipase is a part of the serine esterase family, it is inhibited in a similar manner. One such compound is a inhibitor (shown interacting with the lipase-coplipase structure). The inhibitor acts by binding Ser 152 in the active site inducing confirmational changes in the beta-5 loop structures. The alkyl chain fits into the hydrophobic portion of the active lipase-colipase complex mimicking the fatty acid produced through hydrolysis in the normal enzymatic reaction [13].
References
- ↑ Voet, D.,etc. "Fundamentals of Biochemistry: Life at the Molecular Level" John Wiley and Sons, Inc: New Jersey, 2008.
- ↑ 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 [1]
- ↑ Bourne, Y., etc. "Horse pancreatic lipase..."(1994) J.Mol.Biol. 238: 709-732 [2]
- ↑ Fundamentals of Biochemistry...
- ↑ Horse pancreatic lipase...
- ↑ Fundamentals of Biochemistry...
- ↑ Fundamentals of Biochemistry...
- ↑ Fundamentals of Biochemistry...
- ↑ "Colipase". Wikipedia: The Free Encyclopedia. 5 July 2011 [3]
- ↑ van Tilbeurgh H, etc."Structure of the pancreatic lipase-procolipase complex", 1992 Sep 10;359(6391):159-62. PMID:1522902.[4]
- ↑ Fundamentals of Biochemistry...
- ↑ Reetz, Manfield F. Controlling the enantioselectivity of enzymes by directed evolution: Practical and theoretical ramifications. PNAS: 12 April 2004 [5]
- ↑ 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 [6]
