Sandbox 44

There are two main chains in human pancreatic lipase, shown here as Chain A and Chain B. (in blue) is exactly identical to (in green), and each chain has two domains which can be identified through . This rainbow labeling displays the N-terminus domain of each chain in blue, leading in a color spectrum fashion to the C-terminus domain of each chain in red. These two sections of each chain are not identical in composition, however, as the N-terminus 337 residues long, comprised mainly in a 3 layer sandwich known as alpha, beta, alpha sandwich. The C-terminus, in comparison, contains a mere 112 residues that are ordered primarily in beta sandwich fashion. The C-terminus of lipase is where its enzyme colipase binds.

The is seen here highlighted in yellow, located within the N-terminus in residues 1-336. This active site contains a catalytic triad of Ser 152, His 263, and Asp 176 that facilitate the ester hydrolysis reaction carried out by lipase. This catalytic triad is very similar to that in a serine protease enzyme. However, if no lipid micelles are present for digestion, the active site of lipase (containing this catalytic triad of Ser, His, and Asp) is covered with a "lid" composed of 25 residues in a helical fashion.

The identical is shown here in red, also facilitating the reaction, the mechanism of which will be discussed below.

Each of the two chains of pancreatic lipase interact with one calcium ligand. A close look at the shows these calcium ligands to be located between the acidic residues Glu, Arg, and Asp. These four residues (Glu 187, Arg 190, Asp 195, and Asp 192) interact specifically with the calcium ligand in each chain.

Within the lipase molecule there are various hydrophilic (polar) and hydrophobic residues to account for the molecules amphiphilic properties, where stability within the molecule in both polar and non polar environments is of utmost importance. All of triacylglycerol digestion occurs at lipid-water interfaces; therefore, it is easy to understand why lipase must be stable in either environment. The of pancreatic lipase can be seen here in grey, while the polar residues of pancreatic lipase are shown in purple. Again, a fairly even distribution of polar to nonpolar residues are seen so as to most effectively stabilize the molecule under whatever conditions are encountered in digestion.

When colipase binds to the nonactive site of the C-terminal domain of lipase, then, the lipase enzyme is stabilized enough so that it may proceed with any hydrophobic interactions between itself and the triacylglycerides. This binding of colipase essentially activates lipase so that it can effectively break down fats in the body; the association of colipase and lipase is what makes lipase a true catalyst.

When lipid micelles are present, the 25-residue "lid" over the active site undergoes a conformational changes in order that the active site may be exposed. At the same time, the beta 5 loop (consisting of 10 residues) also undergoes a conformational change to make an oxyanion hole for the enzyme, thereby creating a hydrophobic surface close to the active site entryway. This beta 5 loop had previously (before the coenzyme's binding) served to protect the oxyanion hole, but now it can reveal the hole for the reaction to proceed. As colipase binds, it forms three additional hydrogen bonds to the recently opened "lid" of the active site so as to most effectively stabilize the lid in its open position. After the binding of colipase, lipase completes a hydrolysis very similar to that of a serine protease through the use of its catalytic triad. This hydrolysis eventually releases the desired broken-down lipid products.