Introduction
Pancreatic (EC 3.1.1.3) is an esterase enzyme that catalyzes the break down of lipids in the digestive system. It is secreted from the pancreas and converts triglyceride substrates to monoglycerides and free fatty acids by ester hydrolysis.[1] Pancreatic triglyceride lipase is critical for the efficient absorption of dietary fats.[2]
Structure
Horse pancreatic lipase (PDB ID 1hpl) is an asymmetrical molecule that consists of two subunits, each of which contain 449 amino acids and 705 well-defined water molecules. The two subunits, and , interact through a variety of . The subunits are related by a 2-fold non-crystallographic symmetry axis. Lipase also binds two as ligands through a variety of . Its consists of 22% and 30% . It contains both (red) and (blue). The overall molecular structure of horse lipase has two well-defined domains. The domain (residues 1-336) contains the and has a typical alpha/beta hydrolase fold topology. The active site contains a catalytic triad (Ser-152, Asp-176, and His-263) that closely resembles that of serine proteases. The N-terminal domain also contains a that blocks solvent from entering the active site. The domain (residues (337-449), for colipase binding, has a beta-sheet sandwich topology.[3]
Function
Most lipases act at a specific position on the glycerol backbone of the lipid substrate.[4] Pancreatic lipase catalyzes the hydrolysis of triacylglycerols at their 1 and 3 positions to form 1,2-diacylglycerols and 2-acylglycerols together with the Na+ and K+ salts of fatty acids. The enzymatic activity of pancreatic lipase increases when it contacts the lipid-water interface. Binding to the lipid-water interface requries mixed micelles of phosphatidylcholine and bile acids as well as colipase.[5]
Colipase
Unlike many proteases, pancreatic lipase is secreted in its final form. However, it is only active in the presence of in the duodenum. Colipase is a 90-residue protein that forms a 1:1 .[6][7] Colipase is also secreted in the pancreas, but in its inactive form, procolipase, which is activated by trypsin in the intestinal lumen. Colipase prevents the inhibitory effect of bile salts on the lipase-catalyzed intraduodenal hydrolysis of dietary long-chain triglycerides. Colipase binds to the C-terminal, non-catalytic domain of lipase, which stabilizes the active conformation and increases the hydrophobicity of the binding site.[8] In other words, colipase activates the enzyme through the movement of the N-terminal domain loop or lid. Here, lipase and colipase can be seen .[9]
Mechanism
The mechanism of pancreatic lipase begins with His263 deprotonating Ser152, which attacks the carboxy carbon of the triacylglycerol substrate in a nucleophilic addition. In the second step, the oxyanion collapses, initiating an elimination of the diacylglycerol product, which deprotonates His263 and acylated Ser152. Next, His263 deprotonates water, which attacks the carboxyl carbon of the acylated Ser152 in a nucleophilic addition. Finally, the oxyanion collapses, initiating an elimination of the carboxylate product, and Ser152, which deprotonates His263.[10]
Inhibition
C11 alkyl phosphonate is an effective inhibitor of pancreatic lipase. The binding of the ligand induces rearrangements of two surface loops in comparison with the closed structure of the enzyme. The inhibitor covalently binds to the active site serine Ser152, as seen in this image of the . Evidence exists that the active site binds both of the enantiomers of C11 phosphonate. The C11 alkyl chain of the first enantiomer fits into a hydrophobic groove and is thought to mimic the interaction between the leaving fatty acid of a triglyceride substrate and the protein. The alkyl chain of the second enantiomer also has an elongated conformation and interacts with hydrophobic patches on the surface of the open amphipathic lid. This may indicate the location of a second alkyl chain of a triglyceride substrate.[11]
Clinical Significance
Pancreatic lipase is secreted into the duodenum through the duct system of the pancreas. In a healthy individual, it is in very low concentration in serum. Under extreme disruption of pancreatic function, such as pancreatitis or pancreatic cancer, the pancreas may begin to digest itself and release pancreatic enzymes including pancreatic lipase into serum. Measurement of serum concentration of pancreatic lipase can therefore aid in diagnosis of acute pancreatitis.[12]
References
- ↑ "Pancreatic lipase". Wikipedia: The Free Encyclopedia. 7 Nov 2011 [1]
- ↑ "Colipase". Wikipedia: The Free Encyclopedia. 5 July 2011 [2]
- ↑ Bourne Y, Martinez C, Kerfelec B, Lombardo D, Chapus C, Cambillau C. 1994. Horse pancreatic lipase. J. mol Biol. 238: 709-732.
- ↑ "Lipase". Wikipedia: The Free Encyclopedia. 6 Nov 2011 [3]
- ↑ Voet D, Voet JG, Pratt CW. "Fundamentals of Biochemistry: Life at the Molecular Level" John Wiley and Sons, Inc: New Jersey, 2008..
- ↑ Voet D, Voet JG, Pratt CW. "Fundamentals of Biochemistry: Life at the Molecular Level" John Wiley and Sons, Inc: New Jersey, 2008..
- ↑ "van Tilbeurgh H, Sarda L, Verger R, Cambillau C. 1992. Structure of the pancreatic lipase-procolipase complex. Nature 359: 159-162.
- ↑ "Colipase". Wikipedia: The Free Encyclopedia. 5 July 2011 [4]
- ↑ Hermoso J, Pignol D, Kerfelec B, Crenon I, Chapus C, Fontecilla-Camps JC. 1996. Lipase activation by nonionic detergents. J. Biol. Chem. 271: 18007-18016.
- ↑ "Overview for MACiE Entry M0218". EMBL-EBI. 17 June 2008. [5]
- ↑ Egloff MP, Marguet F, Buono G, Verger R, Cambillau C, van Tilbeurgh H. 1995. The 2.46 A resolution structure of the pancreatic lipase-colipase complex inhibited by a C11 phosphonate. Biochemistry 34: 2751-2762.
- ↑ "Pancreatic lipase". Wikipedia: The Free Encyclopedia. 7 Nov 2011 [6]
