Family C1

Family

Summary Holotypes Alignment Tree Genomes Structure Literature H-seq M-seq Architecture

C1A

Summary Holotypes Alignment Tree Genomes Literature

C1B

Summary Holotypes Alignment Tree Genomes Literature

Summary for family C1

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.
Distribution of family Bacteria details  
Archaea details  
Protozoa details  
Fungi -  
Plants details  
Animals details  
Viruses details  
Biological functions Family C1 peptidases contribute proteolytic activity to the digestive vacuoles of protozoa and to the lysosomal system of eukaryotic cells, specific examples of lysosomal enzymes including cathepsin B (C01.060), cathepsin L (C01.032), cathepsin S (C01.034), cathepsin K (C01.036), cathepsin H (C01.040) and dipeptidyl-peptidase I (C01.070).
Pharmaceutical and biotech relevance Family C1 contains many possible drug targets. Examples are cathepsin B for cancer (Podgorski & Sloane, 2003), cathepsin S for control of antigen presentation (Driessen et al., 1999) and potentially for attenuation of the immune response, cathepsin K for the control of osteoporosis, and cathepsin L for roles in antigen processing and tumour cell metabolism. Chymopapain (C01.002) is used in the treatment of herniated intervertebral disks. Stem bromelain and ananain (C01.026) have potential for use in the treatment of burns.
Reviews Gutierrez-Gonzalez et al. (2005)
Statistics for family C1 Sequences: 21368
Identifiers: 232
Identifiers with PDB entries: 44
Downloadable files Sequence library (FastA format)
Sequence alignment (FastA format)
Phylogenetic tree (Newick format)
Subfamily C1A
Name Peptidase subfamily C1A
Subfamily type peptidase C01.001 - papain (Carica papaya), MEROPS Accession MER0000647 (peptidase unit: 134-345)
Active site residues Q152 C158 H292 Q,N308 
Statistics Sequences: 17392
Identifiers: 225
Identifiers with PDB entries: 42
Other databases CATH 3.90.70.10
INTERPRO IPR000668
PANTHER PTHR12411
PFAM PF00112
SCOP 54002
Downloadable files Sequence library [FastA format]
Sequence alignment [FastA format]
Phylogenetic tree [Newick format]
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
Subfamily C1B
Name Peptidase subfamily C1B
Subfamily type peptidase C01.085 - bleomycin hydrolase (yeast) (Saccharomyces cerevisiae), MEROPS Accession MER0000727 (peptidase unit: 31-471)
Active site residues Q96 C102 H398 N421 
Statistics Sequences: 3913
Identifiers: 6
Identifiers with PDB entries: 2
Other databases CATH 3.90.70.10
INTERPRO IPR004134
PANTHER PTHR10363
PFAM PF00112
PFAM PF03051
SCOP 54002
Downloadable files Sequence library [FastA format]
Sequence alignment [FastA format]
Phylogenetic tree [Newick format]
Peptidases and Homologues MEROPS ID Structure
bleomycin hydrolase (animal) C01.084 Yes
bleomycin hydrolase (yeast) C01.085 Yes
aminopeptidase C C01.086 -
oligopeptidase E C01.088 -
peptidase G C01.089 -
peptidase W C01.091 -
Subfamily C1B non-peptidase homologues non-peptidase homologue -
Subfamily C1B unassigned peptidases unassigned -
Peptidases not assigned to subfamily
Peptidases and Homologues MEROPS ID Structure
At5g17080 (Arabidopsis thaliana) C01.A23 -
Family C1 non-peptidase homologues non-peptidase homologue -
Family C1 unassigned peptidases unassigned -