| Name | Peptidase family C1 (papain family) |
|---|
| Family type peptidase | C01.001 - papain (Carica papaya), MEROPS Accession MER0000647 (peptidase unit: 134-345) |
| Content of family | Peptidase family C1 contains many endopeptidases and a few exopeptidases. |
| History |
Identifier created: Biochem.J. 290:205-218 (1993)
The proteolytic activity of papaya latex has been known since at least 1880 (e.g. Martin, 1884). The active principle of the papaya latex is papain (C01.001), and a large family of peptidases that are homologous with papain is now recognised. |
| Catalytic type | Cysteine |
| Active site | The catalytic residues of family C1 have been identified as Cys and His, forming the catalytic dyad. Two other active site residues are found, a Gln residue preceding the catalytic Cys and an Asn residue following the catalytic His. The Gln is believed to help in the formation of the 'oxyanion hole' and the Asn to orientate the imidazolium ring of the catalytic His. There are a number of non-peptidase homologues in which catalytic residues have been replaced. |
| Activities and specificities | The family contains both endo- and exopeptidases. The dominant specificity subsite in most of the peptidases of subfamily C1A is S2. This commonly displays a preference for occupation by a bulky hydrophobic side chain, and not a charged one. Exceptionally, the S2 subsite of cathepsin B (C01.060) readily accepts Arg; this distinctive specificity of cathepsin B (C01.060) can be explained by the residue lying at the bottom of the S2 pocket, which in papain is Ser338, but in cathepsin B is Glu. Dipeptidyl-peptidase I (C01.070) is an exopeptidase, as its name indicates, and cathepsins B and H also exhibit strong exopeptidase activities. Cathepsin B acts as a peptidyl-dipeptidase (Aronson & Barrett, 1978) and cathepsin H as an aminopeptidase (Kirschke et al., 1977). Cathepsin X (C01.013) is almost exclusively a carboxypeptidase (Devanathan et al., 2005), and subfamily C1B contains aminopeptidases such as bleomycin hydrolase (C01.084) and aminopeptidase C (C01.086). |
| Inhibitors | E-64 is an irreversible inhibitor of peptidases in family C1 (Barrett et al., 1982) as well as family C2, and similarly broad, but reversible, inhibition is shown by leupeptin. Several members of the family are drug targets for the pharmaceutical industry, and potent inhibitors have been designed for these.
Proteins of the cystatin family (I25) inhibit papain and most of its homologues reversibly, but stem bromelain (C01.005) is not inhibited either by E-64 or the cystatins. Glycl endopeptidase (C01.004) is also not inhibited by cystatins. The proteins CTLA-2a and CTLA-2b (I29) of activated T cells are homologous to the papain propeptide, and have been shown to inhibit peptidases in this family (Delaria et al., 1994). |
| Molecular structure | Papain contains 3 disulfide bonds and its chain is folded to form a globular protein with two interacting domains delimiting a cleft at the surface of enzymes where substrates can be bind. Most members of subfamily C1A are monomeric, but dipeptidyl-peptidase I is a homotetramer in which each monomer consists of three chains as a result of proteolytic processing. Some peptidases of subfamily C1A have C-terminal extensions relative to papain. Cruzipain (C01.075) with 130 extensions is one of those. Inserts relative to papain occur within the catalytic domain in other members of the family. In cathepsin B, the 'occluding loop' that carries the histidine residues important for peptidyl-dipeptidase activity is inserted between the catalytic Cys and His residues.
The aminopeptidase C-like enzymes of subfamily C1B are oligomeric. The yeast bleomycin hydrolase is probably representative, and is a homohexamer, with the active sites arranged on the inner face of the central channel, in an arrangement reminiscent of that in the proteasome. This arrangement evidently allows only small molecules to interact with the catalytic site.
Unlike papain and cathepsin B, the aminopeptidases of family C1B do not contain disulfide bonds and are synthesized without propeptides. The mature bleomycin hydrolase subunit consists of three domains, the peptidase domain, an oligomerization (or 'hook') domain, and a helical domain. Half of the hook domain is N-terminal to the catalytic domain, but the other half is an insert (relative to papain) preceding the catalytic His. The helical domain corresponds to two inserts in the catalytic domain with respect to papain. |
| Clan | CA |
| Basis of clan assignment | Type family of clan CA. |
| Peptidases and Homologues |
MEROPS ID |
Structure |
| papain | C01.001 | Yes |
| chymopapain | C01.002 | Yes |
| caricain | C01.003 | Yes |
| glycyl endopeptidase | C01.004 | Yes |
| stem bromelain | C01.005 | Yes |
| ficin | C01.006 | - |
| actinidin | C01.007 | Yes |
| asclepain A | C01.008 | - |
| cathepsin V | C01.009 | Yes |
| vignain | C01.010 | Yes |
| calotropain | C01.011 | Yes |
| cathepsin X | C01.013 | Yes |
| cathepsin-1 | C01.016 | - |
| zingipain | C01.017 | Yes |
| cathepsin F | C01.018 | Yes |
| CC-I peptidase (Vasconcellea sp.) | C01.019 | - |
| CC-III peptidase (Vasconcellea-type) | C01.020 | - |
| brassicain | C01.021 | - |
| glycinain | C01.022 | - |
| cathepsin M | C01.023 | - |
| endopeptidase-B (Hordeum-type) | C01.024 | Yes |
| ananain | C01.026 | Yes |
| comosain | C01.027 | - |
| fruit bromelain | C01.028 | - |
| pseudotzain | C01.029 | - |
| crustapain | C01.030 | - |
| cathepsin-2 | C01.031 | - |
| cathepsin L | C01.032 | Yes |
| cathepsin L1 (Fasciola sp.) | C01.033 | Yes |
| cathepsin S | C01.034 | Yes |
| cathepsin O | C01.035 | - |
| cathepsin K | C01.036 | Yes |
| cathepsin W | C01.037 | - |
| cathepsin P | C01.038 | - |
| cathepsin Q | C01.039 | - |
| cathepsin H | C01.040 | Yes |
| aleurain | C01.041 | - |
| cathepsin R | C01.042 | - |
| SmCL2 peptidase | C01.044 | - |
| cathepsin-6 | C01.045 | - |
| falcipain-2 | C01.046 | Yes |
| granulovirus cathepsin | C01.047 | - |
| cathepsin B, plant form | C01.049 | - |
| histolysain | C01.050 | - |
| Mername-AA069 putative peptidase | C01.051 | - |
| cathepsin Q-like peptidase (Rattus norvegicus) | C01.052 | - |
| cathepsin-3 | C01.053 | - |
| 2310051m13rik protein | C01.054 | - |
| papain homologue (nematode) | C01.055 | - |
| RCR3 peptidase | C01.056 | - |
| vinckepain-2 | C01.057 | - |
| peptidase similar to cathepsin 7 | C01.058 | - |
| cathepsin B | C01.060 | Yes |
| SmCB2 peptidase (Schistosoma-type) | C01.061 | - |
| cathepsin B-like peptidase (platyhelminth) | C01.062 | Yes |
| falcipain-3 | C01.063 | Yes |
| RD21 peptidase | C01.064 | - |
| XCP1 peptidase (Arabidopsis-type) | C01.065 | - |
| CPL-1 peptidase (Caenorhabditis elegans-type) | C01.066 | - |
| insect 26/29 kDa peptidase | C01.067 | - |
| vitellogenic cathepsin B | C01.068 | Yes |
| Mername-AA203 peptidase | C01.069 | - |
| dipeptidyl-peptidase I | C01.070 | Yes |
| toxopain-1 | C01.071 | - |
| rhodesain | C01.072 | Yes |
| peptidase 1 (mite) | C01.073 | Yes |
| CPB peptidase | C01.074 | Yes |
| cruzipain | C01.075 | Yes |
| CPA peptidase | C01.076 | - |
| falcipain-1 | C01.077 | - |
| papain homologue (Theileria-type) | C01.079 | - |
| papain homologue (Dictyostelium-type) | C01.081 | - |
| Mername-AA287 peptidase | C01.082 | - |
| V-cath peptidase | C01.083 | - |
| L3 cysteine peptidase (Onchocerca volvulus-type) | C01.087 | - |
| cathepsin L1 (arthropod-type) | C01.092 | - |
| miltpain | C01.093 | - |
| giardain | C01.094 | - |
| papain homologue (Archaeoglobus-type) | C01.095 | - |
| melain G | C01.096 | - |
| phytolacain | C01.097 | - |
| CPC peptidase | C01.098 | Yes |
| ervatamin B | C01.099 | Yes |
| cruzipain 2 | C01.100 | - |
| cathepsin B-like peptidase, nematode | C01.101 | Yes |
| encystation-specific peptidase (Giardia sp.) | C01.102 | - |
| SPG31-like peptidase | C01.104 | - |
| maize insect resistant 1 g.p. (Zea mays) | C01.105 | - |
| papain homologue (Rattus-type) | C01.107 | - |
| Mername-AA301 peptidase | C01.108 | - |
| Mername-AA302 peptidase | C01.109 | - |
| cathepsin Q2 (Rattus norvegicus) | C01.111 | - |
| tetrain | C01.113 | - |
| testin-3 | C01.114 | - |
| fascipain B | C01.115 | - |
| ervatamin C | C01.116 | Yes |
| senescence-associated gene 12 | C01.117 | - |
| EhCP112 peptidase (Entamoeba sp.) | C01.119 | - |
| Mername-AA249 peptidase | C01.120 | - |
| EhCP-B peptidase (Entamoeba histolytica) | C01.123 | - |
| dipeptidylpeptidase I (Plasmodium-type) | C01.124 | - |
| Cwp84 peptidase | C01.125 | Yes |
| ECP-1 peptidase | C01.126 | - |
| TsCL-1 peptidase | C01.127 | - |
| xylellain | C01.128 | Yes |
| cathepsin L3 (Fasciola sp.) | C01.129 | - |
| CSCP3 peptidase (Clonorchis-type) | C01.130 | - |
| WCP2 peptidase | C01.131 | - |
| Mername-AA303 peptidase | C01.132 | - |
| CmCatB (Callosobruchus maculatus)-type peptidase | C01.133 | - |
| mexicain | C01.134 | Yes |
| Mername-AA250 peptidase | C01.135 | - |
| ervatamin A | C01.137 | Yes |
| Kth-CL peptidase (Kudoa sp.) | C01.138 | - |
| dipeptidylaminopeptidase 3 (Plasmodium sp.) | C01.139 | - |
| PIP1 peptidase (Solanum sp.) | C01.140 | - |
| GsCL1 peptidase (Gnathostoma spinigerum) | C01.141 | - |
| cathepsin L2 (Fasciola sp.) | C01.142 | - |
| intestain D4 (Leptinotarsa decemlineata) | C01.143 | - |
| cathepsin B-like cysteine peptidase (Raphanus sativus) | C01.144 | - |
| hieronymain I | C01.145 | - |
| hieronymain II | C01.146 | - |
| hieronymain III | C01.147 | - |
| cryptopain-1 | C01.148 | - |
| TgCPL peptidase (Toxoplasma-type) | C01.149 | Yes |
| asclepain f (Asclepias fruticosa) | C01.150 | - |
| asclepain B | C01.151 | - |
| SmCL3 peptidase (Schistosoma-type) | C01.152 | - |
| araujiain (Araujia sp.) | C01.153 | - |
| Ta.61026 peptidase (Triticum aestivum) | C01.154 | - |
| EhCP4 peptidase (Entamoeba histolytica) | C01.155 | - |
| CysP peptidase (Mycoplasma sp.) | C01.156 | - |
| vivapain-4 (Plasmodium vivax) | C01.157 | - |
| asclepain cI (Asclepias curassavica) | C01.158 | - |
| asclepain cII (Asclepias curassavica) | C01.159 | - |
| morrenain b I (Morrenia brachystephana) | C01.160 | - |
| morrenain b II (Morrenia brachystephana) | C01.161 | - |
| At3g45310-type peptidase | C01.162 | - |
| At5g60360-type peptidase | C01.163 | - |
| CPXaC peptidase (Xanthomonas sp.) | C01.164 | - |
| TgCPC1 (Toxoplasma gondii) | C01.165 | - |
| SmCL1 peptidase (Schistosoma mansoni and similar) | C01.166 | - |
| Cwp13 (Clostridium difficile) | C01.167 | - |
| endopeptidase-A (Hordeum-type) | C01.168 | - |
| SERA6 (Plasmodium sp.) | C01.169 | - |
| macrodontain | C01.170 | - |
| Pd_dinase (Parabacteroides distasonis) | C01.171 | Yes |
| endopeptidase (bacterium symbiont of Theonella swinhoei) | C01.172 | - |
| testin | C01.972 | - |
| tubulointerstitial nephritis antigen | C01.973 | - |
| Mername-AA140 protein | C01.974 | - |
| tubulointerstitial nephritis antigen-related protein | C01.975 | - |
| protein similar to testin 1/2 precursor (Rattus norvegicus) | C01.977 | - |
| Mername-AA305 nonpeptidase homologue | C01.978 | - |
| LOC311491 protein (Rattus norvegicus) | C01.979 | - |
| serine-repeat antigen (Plasmodium sp.) | C01.984 | Yes |
| papain-like protein SPE31 (Pachyrhizus erosus) | C01.987 | Yes |
| silicatein | C01.988 | - |
| Mername-AA300 peptidase | C01.989 | - |
| allergen Blo t 1 (Blomia tropicalis-type) | C01.990 | - |
| AtCEP2 peptidase (Arabidopsis thaliana) | C01.A01 | - |
| AtCEP3 peptidase (Arabidopsis thaliana) | C01.A02 | - |
| AtCEP1 peptidase (Arabidopsis thaliana) | C01.A03 | - |
| At2g21430 (Arabidopsis thaliana) | C01.A04 | - |
| At3g54940 (Arabidopsis thaliana) | C01.A05 | - |
| At4g16190 (Arabidopsis thaliana)-type peptidase | C01.A06 | - |
| At5g43060 (Arabidopsis thaliana)-type peptidase | C01.A12 | - |
| CP14 peptidase | C01.A13 | - |
| At1g29080 (Arabidopsis thaliana) | C01.A14 | - |
| At1g29090 (Arabidopsis thaliana) | C01.A15 | - |
| At2g27420 (Arabidopsis thaliana) | C01.A16 | - |
| At2g34080 (Arabidopsis thaliana) | C01.A17 | - |
| At3g43960 (Arabidopsis thaliana) | C01.A18 | - |
| At3g49340 (Arabidopsis thaliana) | C01.A19 | - |
| At4g11310 (Arabidopsis thaliana) | C01.A20 | - |
| At4g11320 (Arabidopsis thaliana) | C01.A21 | - |
| At4g23520 (Arabidopsis thaliana) | C01.A22 | - |
| At5g17140 (Arabidopsis thaliana) | C01.A24 | - |
| At1g06260 (Arabidopsis thaliana) | C01.A26 | - |
| CG12163 g.p. (Drosophila melanogaster) | C01.A27 | - |
| CG4847 g.p. (Drosophila melanogaster) | C01.A28 | - |
| CG6347 g.p. (Drosophila melanogaster) | C01.A29 | - |
| CG5367 g.p. (Drosophila melanogaster) | C01.A30 | - |
| CG11459 g.p. (Drosophila melanogaster) | C01.A31 | - |
| cpr-1 g.p. (Caenorhabditis elegans) | C01.A32 | - |
| cathepsin B-like cysteine peptidase 3 (Caenorhabditis elegans) | C01.A33 | - |
| cathepsin B-like cysteine peptidase 4 (Caenorhabditis elegans) | C01.A34 | - |
| cathepsin B-like cysteine peptidase 5 (Caenorhabditis elegans) | C01.A35 | - |
| tag-329 g.p. (Caenorhabditis elegans) | C01.A36 | - |
| Y51A2D.1 g.p. (Caenorhabditis elegans) | C01.A37 | - |
| cpz-1 g.p. (Caenorhabditis elegans) | C01.A38 | - |
| W07B8.4 g.p (Caenorhabditis elegans) | C01.A39 | - |
| cpr-2 g.p. (Caenorhabditis elegans) | C01.A40 | - |
| cpz-2 g.p. (Caenorhabditis elegans) | C01.A41 | - |
| F57F5.1 g.p. (Caenorhabditis elegans) | C01.A42 | - |
| R07E3.1 g.p. (Caenorhabditis elegans) | C01.A43 | - |
| R09F10.1 g.p. (Caenorhabditis elegans) | C01.A44 | - |
| F15D4.4 g.p. (Caenorhabditis elegans) | C01.A45 | - |
| Y65B4A.2 g.p. (Caenorhabditis elegans) | C01.A46 | - |
| Y113G7B.15 g.p. (Caenorhabditis elegans) | C01.A47 | - |
| Y40H7A.10 g.p. (Caenorhabditis elegans) | C01.A48 | - |
| Y51A2D.8 g.p. (Caenorhabditis elegans) | C01.A49 | - |
| cathepsin B-like cysteine peptidase 6 (Caenorhabditis elegans) | C01.A51 | - |
| gmsA (Dictyostelium discoideum) | C01.A52 | - |
| DDB_0203746 (Dictyostelium discoideum) | C01.A53 | - |
| DDB_G0274385 (Dictyostelium discoideum) | C01.A54 | - |
| cprC (Dictyostelium discoideum) | C01.A55 | - |
| DDB_G0292462 (Dictyostelium discoideum) | C01.A56 | - |
| cysteine proteinase 5 (Dictyostelium discoideum) | C01.A57 | - |
| DDB_G0288563 (Dictyostelium discoideum) | C01.A58 | - |
| ctsB (Dictyostelium discoideum) | C01.A59 | - |
| ctsZ (Dictyostelium discoideum) | C01.A60 | - |
| DDB_G0280187 (Dictyostelium discoideum) | C01.A61 | - |
| DDB_G0278401 (Dictyostelium discoideum) | C01.A62 | - |
| Cysteine endopeptidase 2 (Dictyostelium discoideum) | C01.A63 | - |
| PFB0335c g.p. (Plasmodium falciparum) | C01.A64 | - |
| ctsl1b g.p. (Brachydanio rerio) | C01.A65 | - |
| pseudogene similar to cathepsin M (Mus musculus) | C01.P01 | - |
| cathepsin L-like pseudogene 1 (Homo sapiens) | C01.P02 | - |
| cathepsin B-like pseudogene (chromosome 4, Homo sapiens) | C01.P03 | - |
| cathepsin B-like pseudogene (chromosome 1, Homo sapiens) | C01.P04 | - |
| cathepsin 1 pseudogene (Mus musculus) | C01.P05 | - |
| pseudogene (Mus musculus mouse chromosome X) | C01.P06 | - |
| CTSLL2 g.p. (Homo sapiens) | C01.P07 | - |
| CTSLL3 g.p. (Homo sapiens) | C01.P08 | - |
| Subfamily C1A non-peptidase homologues | non-peptidase homologue | - |
| Subfamily C1A unassigned peptidases | unassigned | Yes |
