Family C1


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


Summary Holotypes Alignment Tree Genomes Literature


Summary Holotypes Alignment Tree Genomes Literature

Summary for family C1

NamePeptidase family C1 (papain family)
Family type peptidaseC01.001 - papain (Carica papaya), MEROPS Accession MER0000647 (peptidase unit: 134-345)
Content of familyPeptidase 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 typeCysteine
Active siteThe 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 specificitiesThe 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).
InhibitorsE-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 structurePapain 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.
Basis of clan assignmentType family of clan CA.
Distribution of family Bacteria details  
Archaea details  
Protozoa details  
Fungi details  
Plants details  
Animals details  
Viruses details  
Biological functionsFamily 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 relevanceFamily 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.
ReviewsGutierrez-Gonzalez et al. (2005)
Statistics for family C1Sequences:15685
Identifiers with PDB entries:42
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 N,Q308 
Statistics Sequences: 13984
Identifiers: 219
Identifiers with PDB entries: 40
Other databases CATH
HSSP 9pap
PFAM PF00112
SCOP 54002
Downloadable files Sequence library [FastA format]
Sequence alignment [FastA format]
Phylogenetic tree [Newick format]
Peptidases and Homologues MEROPS ID Structure
glycyl endopeptidaseC01.004Yes
stem bromelainC01.005Yes
asclepain AC01.008-
cathepsin VC01.009Yes
cathepsin XC01.013Yes
cathepsin FC01.018Yes
CC-I peptidase (Vasconcellea sp.)C01.019-
CC-III peptidase (Vasconcellea-type)C01.020-
cathepsin MC01.023-
endopeptidase-B (Hordeum-type)C01.024Yes
fruit bromelainC01.028-
cathepsin LC01.032Yes
cathepsin L1 (Fasciola sp.)C01.033Yes
cathepsin SC01.034Yes
cathepsin OC01.035-
cathepsin KC01.036Yes
cathepsin WC01.037-
cathepsin PC01.038-
cathepsin QC01.039-
cathepsin HC01.040Yes
cathepsin RC01.042-
SmCL2 peptidaseC01.044-
granulovirus cathepsinC01.047-
cathepsin B, plant formC01.049-
Mername-AA069 putative peptidaseC01.051-
cathepsin Q-like peptidase (Rattus norvegicus)C01.052-
2310051m13rik proteinC01.054-
papain homologue (nematode)C01.055-
RCR3 peptidaseC01.056-
peptidase similar to cathepsin 7C01.058-
cathepsin BC01.060Yes
SmCB2 peptidase (Schistosoma-type)C01.061-
cathepsin B-like peptidase (platyhelminth)C01.062Yes
RD21 peptidaseC01.064-
XCP1 peptidase (Arabidopsis-type)C01.065-
CPL-1 peptidase (Caenorhabditis elegans-type)C01.066-
insect 26/29 kDa peptidaseC01.067-
vitellogenic cathepsin BC01.068Yes
Mername-AA203 peptidaseC01.069-
dipeptidyl-peptidase IC01.070Yes
peptidase 1 (mite)C01.073Yes
CPB peptidaseC01.074Yes
CPA peptidaseC01.076-
papain homologue (Theileria-type)C01.079-
papain homologue (Dictyostelium-type)C01.081-
Mername-AA287 peptidaseC01.082-
V-cath peptidaseC01.083-
L3 cysteine peptidase (Onchocerca volvulus-type)C01.087-
cathepsin L1 (arthropod-type)C01.092-
papain homologue (Archaeoglobus-type)C01.095-
melain GC01.096-
CPC peptidaseC01.098Yes
ervatamin BC01.099Yes
cruzipain 2C01.100-
cathepsin B-like peptidase, nematodeC01.101Yes
encystation-specific peptidase (Giardia sp.)C01.102-
SPG31-like peptidaseC01.104-
maize insect resistant 1 g.p. (Zea mays)C01.105-
papain homologue (Rattus-type)C01.107-
Mername-AA301 peptidaseC01.108-
Mername-AA302 peptidaseC01.109-
cathepsin Q2 (Rattus norvegicus)C01.111-
fascipain BC01.115-
ervatamin CC01.116Yes
senescence-associated gene 12C01.117-
EhCP112 peptidase (Entamoeba sp.)C01.119-
Mername-AA249 peptidaseC01.120-
EhCP-B peptidase (Entamoeba histolytica)C01.123-
dipeptidylpeptidase I (Plasmodium-type)C01.124-
Cwp84 peptidaseC01.125Yes
ECP-1 peptidaseC01.126-
TsCL-1 peptidaseC01.127-
cathepsin L3 (Fasciola sp.)C01.129-
CSCP3 peptidase (Clonorchis-type)C01.130-
WCP2 peptidaseC01.131-
Mername-AA303 peptidaseC01.132-
CmCatB (Callosobruchus maculatus)-type peptidaseC01.133-
Mername-AA250 peptidaseC01.135-
ervatamin AC01.137Yes
Kth-CL peptidase (Kudoa sp.)C01.138-
dipeptidylpeptidase 3 (Plasmodium sp.)C01.139-
PIP1 peptidase (Lycopersicon 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 IC01.145-
hieronymain IIC01.146-
hieronymain IIIC01.147-
TgCPL peptidase (Toxoplasma-type)C01.149Yes
asclepain f (Asclepias fruticosa)C01.150-
asclepain BC01.151-
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 peptidaseC01.162-
At5g60360-type peptidaseC01.163-
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-
tubulointerstitial nephritis antigenC01.973-
Mername-AA140 proteinC01.974-
tubulointerstitial nephritis antigen-related proteinC01.975-
protein similar to testin 1/2 precursor (Rattus norvegicus)C01.977-
Mername-AA305 nonpeptidase homologueC01.978-
LOC311491 protein (Rattus norvegicus)C01.979-
serine-repeat antigen (Plasmodium sp.)C01.984Yes
papain-like protein SPE31 (Pachyrhizus erosus)C01.987Yes
Mername-AA300 peptidaseC01.989-
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 peptidaseC01.A06-
At5g43060 (Arabidopsis thaliana)-type peptidaseC01.A12-
CP14 peptidaseC01.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 protein (Drosophila melanogaster)C01.A27-
CG4847 protein (Drosophila melanogaster)C01.A28-
CG6347 protein (Drosophila melanogaster)C01.A29-
CG5367 protein (Drosophila melanogaster)C01.A30-
CG11459 protein (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 homologuesnon-peptidase homologue-
subfamily C1A unassigned peptidasesunassignedYes
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: 1679
Identifiers: 6
Identifiers with PDB entries: 2
Other databases CATH
HOMSTRAD Pept_C1-like
HSSP 1gcb
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)C01.084Yes
bleomycin hydrolase (yeast)C01.085Yes
aminopeptidase CC01.086-
oligopeptidase EC01.088-
peptidase GC01.089-
peptidase WC01.091-
subfamily C1B non-peptidase homologuesnon-peptidase homologue-
subfamily C1B unassigned peptidasesunassigned-
Peptidases not assigned to subfamily
Peptidases and Homologues MEROPS ID Structure
At5g17080 (Arabidopsis thaliana)C01.A23-
family C1 non-peptidase homologuesnon-peptidase homologue-
family C1 unassigned peptidasesunassigned-