Proteases, or peptidases, are enzymes that hydrolyze proteins
- They are classified as endo or exo based on whether they cleave internal peptide bonds or terminal ones
- They were the first enzymes to be studied because of their abundance in the digestive system
- In fact they have a wide range of protein processing functions:
- modulating hormone activity; for example, angiotensin converting enzyme
- modulating blood clotting activity
- activation of the immune system
- destruction of cells
- punching holes in cell walls for such processes as fertilization
Four major groups of proteases exist:
- Serine proteases, which have a reactive serine residue, and act optimally at neutral pH
- The carboxyl or aspartyl proteases, which have catalytically important carboxyls and act at relatively low pH
- Thiol proteases have reactive cysteine residues
- Zinc proteases, which have a zinc in the active site and function at neutral pH
We will take a look at examples of each of these, beginning with the serine proteases: chymotrypsin, trypsin, and elastase, which catalyze the hydrolysis of peptides in the intestines.
- Like all known proteolytic enzymes, the serine proteases are synthesized and stored as inactive forms called zymogens: chymotrypsinogen, trypsinogen, and proelastase
- An enteropeptidase found in the duodenum activates trypsinogen by cleaving off the first six residues at the N-terminal end of the protein.
- The trypsin thus produced then activates chymotrypsinogen and proelastase by hydrolysis at several points.
- It also can activate other trypsinogens in the same way. Here is an oversimplified picture of the activation cascade:
The enteropeptidase is itself a serine protease; the catalytic His and Ser are picked out in the picture.
- Enteropeptidase is membrane-bound; two Zn ions assist in binding to trypsinogen
- Note the inhibitor (magenta); a short peptide that prevents binding to trypsinogen
- The cleavage point follows the Lys of the sequence Val(Asp)4Lys
| Enteropeptidase (1ekb) |
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The activated chymotrypsin also can cleave chymotrypsinogen if insufficient trypsin is available to facilitate the activation
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This produces an equilibrium mixture of some 7 or 8 neochymotrypsinogens that ultimately are converted to chymotrypsin itself.