Peptidases are catalytically active proteins (enzymes) that cleave peptide bonds in proteins and peptides by hydrolysis. Not only do peptidases break down proteins and peptides so that the amino acids can be recycled and used during growth and remodelling, but they are also important for modifying proteins. These processing events ensure proteins are sent to the correct cellular or extracellular locations, are activated or inactivated when required, and that biologically important peptides are excised. There are six catalytic types (serine, cysteine, threonine, aspartic, glutamic and metallo). Peptidases can be classified by sequence similarities into approximately 250 families, and these in turn can be arranged into approximately 60 clans by comparing tertiary structures.

Key Concepts:

  • A peptidase is a catalytically active protein that cleaves one or more peptide bonds in a protein or peptide by hydrolysis.

  • There are six different catalytic types of peptidases.

  • Comparison of the amino acid sequences of peptidases allows them to be classified into about 250 families.

  • Comparison of the structural folds of peptidases allows them to be classified into about 60 clans.

  • A peptidase that acts only within three residues of the amino or carboxyl termini of a substrate protein is known as an exopeptidase.

  • A peptidase that cleaves any bond in a substrate protein that is more than three residues from the amino or carboxyl termini is known as an endopeptidase.

  • A peptidase has an active site containing amino acids that are important for catalysis and which are usually conserved in all active members of a family.

  • The active site of a peptidase is flanked by substrate binding pockets, each of which accommodates one residue from the substrate.

  • Some peptidases have additional substrate binding sites remote from the active site that are known as exosites.

Keywords: aminopeptidase; carboxypeptidase; endopeptidase; exopeptidase; peptidase; proteinase

Figure 1.

Positional specificity of peptidase activity. Peptidases can be divided into exopeptidases and endopeptidases. The exopeptidases act only near the ends of polypeptide chains. Those acting at a free N‐terminus may liberate a single amino acid residue (aminopeptidases), a dipeptide (dipeptidyl‐peptidases) or a tripeptide (tripeptidyl‐peptidases). Those acting at a free C‐terminus liberate a single residue (carboxypeptidases) or a dipeptide (peptidyldipeptidases). Other exopeptidases are specific for dipeptides (dipeptidases), or remove terminal residues that are substituted, cyclised or linked by isopeptide bonds (peptide linkages other than those of α‐carboxyl to α‐amino groups) (ω peptidases). In the figure, the circles represent amino acid residues, the down‐arrows show the bonds that are hydrolysed, and the brackets attached to the arrows indicate the part of the substrate molecule typically recognised by the specificity sites of the enzymes before catalysis, and thus directing specificity. Peptidases that act internally in polypeptide chains (usually whole protein molecules) are called endopeptidases. Primary determinants of endopeptidase specificity are amino acids near the scissile peptide bond on either side.

Figure 2.

Scheme for the specificity subsites of peptidases that dictate their sequence specificity. It can be seen that the specificity subsites are numbered from the catalytic site, S1, S2, …, Sn towards the N‐terminus of the substrate, and S1′,S2′, …, Sn′ towards the C‐terminus. The amino acids they accommodate are numbered P1, P2, …, Pn and P1′, P2′, …, Pn′, respectively.



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Further Reading

Beynon R and Bond JS (eds) (2001) Proteolytic Enzymes. A Practical Approach, 2nd edn. Oxford: Oxford University Press.

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Rawlings, Neil D, and Barrett, Alan J(Jul 2014) Peptidases. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0000670.pub3]