Sandbox Wabash28

Trypsin is a digestive enzyme synthesized by the pancreas and secreted into the duodenum. Its purpose is to catalyze the peptide bonds, but with specificity for positively charged residues (lysine and arginine). It also activates hydrolytic enzymes and other enzymes in the pancreas. Its structure is very similar to chymotrypsin and elastase. Its substrate binding site contains two glycines and an aspartic acid. This binding site's glycines permit the bulkier lysine and arginine residues to nestle within the pocket and interact ionically with the aspartate residue thereby holding the peptide in place for hydrolysis. Trypsin is inactivated by the lysine-mimicking tosyl-L-lysine chloromethylketone as well as by enzymes trypsin activates within the body.

First, the substrate peptide binds to trypsin. Specifically, a lysine or arginine binds to the binding pocket's aspartate (Asp 189).

Made more nucleophilic by a base attack from His 57 (a residue itself stabilized via hydrogen bonding with Asp 102), Ser 195 attacks the scissile bond at the carbonyl forming a tetrahedral intermediate. These three residues (Asp 102, His 57, and Ser 195) form a conserved active site among serine proteases called the catalytic triad.

His 57 donates its proton to the forming amine making it a good leaving group. Simultaneously, the carbonyl reforms by kicking off the amine. The ester formed between Ser 195 and the N-terminus is known as the acyl-enzyme intermediate. The C-terminus leaves the active site and water enters.

As before, His 57 again attacks a proton (this time from water) supported by Asp 102. The more nucleophilic water attacks the ester forming a second tetrahedral intermediate.

The protonated His 57 donates that proton to the Ser 195 oxygen making it a stable leaving group as the carbonyl reforms as a carboxylic acid. The N-terminus leaves the active site and trypsin is ready to repeat the process.

Function

Disease

Relevance

Structural highlights

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