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. This results in diseases such as cystic fibrosis, Crohn's disease, and celiac disease. Furthermore, this deficiency can also lead to high cholesterol and difficulty losing weight as the body breaks down fats at a much slower rat.
Structure
The quaternary structure of horse pancreatic lipase (as featured right) 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 include and salt bridges. The secondary structure of lipase is composed of 102 residues that constitute 13 (22% helical) and 139 residues that constitute 28 strands (30% beta sheets). Lipase is essentially composed of two domains, the , which contains the of lipase (consisting of three residues: Ser-152, Asp-176, and His-263). The N-terminal domain also contains the (residues 216-239) which serves to block the active site, which is nestled in the , from the solvent. Additionally, the is essential to the binding of lipase with colipase, an important cofactor for the catalysis of lipids. This forms the .
Calcium Ligand
The most prominent ligand involved in the structure of lipase is the . This ion has been shown to promote the folding of lipase into its active dimer state. As such, the calcium ion is extremely important in forming the lipase-fat complex, necessary for the breakdown of lipids. Studies have shown that an increase in calcium concentration in a lipase catalyzed reaction resulted in an increase in the rate of the reaction.
Colipase Cofactor
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.
Mechanism
Image:Hydrolysis.gif Lipase-catalyzed hydrolysis of lipids. Notice the catalytic triad (as seen in serine proteases) of Ser-152, Asp-176, and His-263 that constitute the active site.
Once the lipid has bound to the active site of pancreatic lipase, the catalysis begins. acts as a base and removes the proton from . This allows His-263 to push electrons towards , 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 oxyanion hole.
