EC 3.4 Acting on peptide bonds (peptidases)
It is recommended that the term "peptidase" be used as being synonymous with "peptide hydrolase" for any enzyme that hydrolyses peptide bonds. Peptidases are recommended to be further divided into "exopeptidases" that act only near a terminus of a polypeptide chain and "endopeptidases" that act internally in polypeptide chains. The types of exopeptidases and endopeptidases are described more fully below. The usage of "peptidase", which is now recommended, is synonymous with "protease" as it was originally used  as a general term for both exopeptidases and endopeptidases, but it should be noted that previously, in Enzyme Nomenclature (1984), "peptidase" was restricted to the enzymes included in sub-subclasses EC 3.4.11 and EC 3.4.13-19, the exopeptidases. Also, the term "proteinase" used previously for the enzymes included in sub-subclasses EC 3.4.21-25 carried the same meaning as "endopeptidase", and has been replaced by "endopeptidase", for consistency.
The nomenclature of the peptidases is troublesome. Their specificity is commonly difficult to define, depending upon the nature of several amino-acid residues around the peptide bond to be hydrolysed and also on the conformation of the substrate's polypeptide chain. A classification involving the additional criterion of catalytic mechanism is therefore used.
Two sets of sub-subclasses of peptidases are recognized, those of the exopeptidases (EC 3.4.11 and EC 3.4.13-19) and those of the endopeptidases (EC 3.4.21-25). The exopeptidases act only near the ends of polypeptide chains, and those acting at a free N-terminus liberate a single amino-acid residue (aminopeptidases; EC 3.4.11), or a dipeptide or a tripeptide (dipeptidyl-peptidases and tripeptidyl-peptidases; EC 3.4.14). The exopeptidases that act at a free C-terminus liberate a single residue (carboxypeptidases, EC 3.4.16-18), or a dipeptide (peptidyl-dipeptidases; EC 3.4.15). The carboxypeptidases are allocated to three groups on the basis of catalytic mechanism: the serine-type carboxypeptidases (EC 3.4.16), the metallocarboxypeptidases (EC 3.4.17) and the cysteine-type carboxypeptidases (EC 3.4.18). Other exopeptidases are specific for dipeptides (dipeptidases, EC 3.4.13), or for removal of terminal residues that are substituted, cyclized or linked by isopeptide bonds (peptide linkages other than those of alpha-carboxyl to alpha-amino groups) (omega peptidases; EC 3.4.19).
The endopeptidases are divided into sub-subclasses on the basis of catalytic mechanism, and specificity is used only to identify individual enzymes within the groups. The sub-subclasses are: serine endopeptidases (EC 3.4.21), cysteine endopeptidases (EC 3.4.22), aspartic endopeptidases (EC 3.4.23), metalloendopeptidases (EC 3.4.24) and threonine endopeptidases (EC 3.4.25).
There are characteristic inhibitors of the members of each catalytic type of endopeptidase; to save space, these have not been listed separately for each individual enzyme but are reviewed in  and . A general source of information on peptidases that similarly has not been cited for each individual enzyme is reference .
In describing the specificity of peptidases, use is made of a model in which the catalytic site is considered to be flanked on one or both sides by specificity subsites, each able to accommodate the sidechain of a single amino-acid residue (based on ). These sites are numbered from the catalytic site, S1...Sn towards the N-terminus of the substrate, and S1'...Sn' towards the C-terminus. The residues they accommodate are numbered P1...Pn, and P1'...Pn', respectively, as follows:
Substrate: - P3 - P2 - P1 ┼ P1'- P2'- P3'-
Enzyme: - S3 - S2 - S1 * S1'- S2'- S3'-
In this representation, the catalytic site of the enzyme is marked by an asterisk (*). The peptide bond cleaved (the scissile bond) is indicated by the symbol '┼' or a hyphen in the structural formula of the substrate, or a hyphen in the name of the enzyme.
Finally, in describing the specificity of endopeptidases, the term oligopeptidase' is used to refer to those that act optimally on substrates smaller than proteins.
Families of peptidases are referred to by use of the numbering system of Rawlings & Barrett [6,7].
1. Grassmann, W. & Dyckerhoff, H. Über die Proteinase und die Polypeptidase der Hefe. 13. Abhandlung über Pflanzenproteasen in der von R. Willstätter und Mitarbeitern begonnenen Untersuchungsreihe. Hoppe-Seyler's Z. Physiol. Chem. 179 (1928) 41-78.
2. Barrett, A. J. & Salvesen, G. S. (eds) Proteinase Inhibitors, Elsevier Science Publishers, Amsterdam (1986).
3. Beynon, R. J. & Bond, J. S. Proteolytic Enzymes. A Practical Approach. IRL Press, Oxford (1989).
4. Barrett, A. J., Rawlings, N. D. & Woessner, J. F. (eds) Handbook of Proteolytic Enzymes, Academic Press, London (1998).
5. Berger, A. and Schechter, I. Mapping the active site of papain with the aid of peptide substrates and inhibitors. Philos. Trans. R. Soc. London, Ser. B Biol. Sci. 257 (1970) 249-264.
6. Rawlings, N.D. and Barrett, A.J. In: Methods Enzymol. 244 (1994) 19-61 and 461-486; Methods Enzymol. 248 (1995) 105-120 and 183-228.
7. Rawlings, N. D. and Barrett, A. J. MEROPS: the peptidase database. Nucleic Acids Res. 27 (1999) 325-331.