| Name | Peptidase family S8 (subtilisin family) |
|---|
| Family type peptidase | S08.001 - subtilisin Carlsberg (Bacillus licheniformis), MEROPS Accession MER0000309 (peptidase unit: 106-379) |
| Content of family | Peptidase family S8 contains the serine endopeptidase subtilisin and its homologues. |
| History |
Identifier created: Biochem.J. 290:205-218 (1993)
Until the determination of the sequence (Smith et al., 1966) and structure (Wright et al., 1969) of subtilisin (S08.001), it was thought that all serine-type peptidases would be homologous to chymotrypsin. Subtilisin was clearly very different and unrelated to chymotrypsin. Family S8, also known as the subtilase family, is the second largest family of serine peptidases, both in terms of number of sequences and characterized peptidases. The family is divided into two subfamilies, with subtilisin (S08.001) the type-example for subfamily S8A and kexin (S08.070) the type-example for subfamily S8B. Tripeptidyl-peptidase II (TPP-II; S08.090) was formerly considered to be the type-example of a third subfamily, but it was subsequently discovered that one of the catalytic residues had been misidentified because of a large insert, without which TPP-I resembles an S8A subfamily member. |
| Catalytic type | Serine |
| Active site | Members of family S8 have a catalytic triad in the order Asp, His and Ser in the sequence, which is a different order to that of families S1, S9 and S10. In subfamily S8A, the active site residues frequently occurs in the motifs Asp-Thr/Ser-Gly (which is similar to the sequence motif in families of aspartic endopeptidases in clan AA (AA)), His-Gly-Thr-His and Gly-Thr-Ser-Met-Ala-Xaa-Pro. In subfamily S8B, the catalytic residues frequently occur in the motifs Asp-Asp-Gly, His-Gly-Thr-Arg and Gly-Thr-Ser-Ala/Val-Ala/Ser-Pro. |
| Activities and specificities | Most members of the family are endopeptidases, but TPP-II is an exopeptidase releasing tripeptides from the N-terminus of peptides. Most members of the family are active at neutral-mildly alkali pH. Many peptidases in the family are thermostable. Casein is often used as a protein substrate and a typical synthetic substrate is Suc-Ala-Ala-Pro-Phe-NHPhNO2. Most members of the family are nonspecific peptidases with a preference to cleave after hydrophobic residues, but members of subfamily S8B, such as kexin (S08.070) and furin (S08.071), cleave after dibasic amino acids. |
| Inhibitors | Most members of the family are inhibited by general serine peptidase inhibitors such as DFP and PMSF, but kexin is resistant to PMSF and requires high concentrations of DFP (Fuller, 2004), which initially led its its misidentification as a cysteine peptidase. Cerevisin (S08.052) is inhibited by mercurial compounds because a cysteine residue is close to the active site His and was also initially misidentified as a cysteine peptidase. Because many members of the family bind calcium for stability, inhibition can be seen with EDTA and EGTA, which are often thought to be specific inhibitors of metallopeptidases. Protein inhibitors include turkey turkey ovomucoid third domain (I01.003), Streptomyces subtilisin inhibitor (I16.003), and members of family I13 such as eglin C (I13.001) and barley inhibitor CI-1A (I13.005), many of which also inhibit chymotrypsin (S01.001). The subtilisin propeptide is itself inhibitory, and the homologous proteinase B inhibitor from Saccharomyces inhibits cerevisin (S08.052). |
| Molecular structure | The tertiary structures for several members of family S8 have now been determined. A typical S8 protein structure consists of three layers with a seven-stranded β sheet sandwiched between two layers of helices. Subtilisin (S08.001) is the type structure for clan SB (SB). Despite the different structure, the active sites of subtilisin and chymotrypsin (S01.001) can be superimposed, which suggests the similarity is the result of convergent rather than divergent evolution. Two calcium-binding sites contribute to the thermal stability of many members of the family. Unlike members of family S1, most members of the family are not multidomain proteins; however, some homologues have large inserts within the peptidase unit, especially lactocepin (S08.019), with the insert between the active site His and Ser, and tripeptidyl-peptidase II (S08.090), with the insert between the active site Asp and His. Some bacterial members of the family have a C-terminal domain essential for secretion that is also found in peptidases from other families such as vibriolysin (M04.003) and lysyl endopeptidase (S01.280). |
| Clan | SB |
| Basis of clan assignment | Type family of clan SB. |
| Peptidases and Homologues |
MEROPS ID |
Structure |
| subtilisin Carlsberg | S08.001 | Yes |
| mesentericopeptidase | S08.002 | Yes |
| subtilisin lentus | S08.003 | Yes |
| wprA g.p. (Bacillus-type) | S08.004 | - |
| endopeptidase Q | S08.005 | - |
| P69 peptidase | S08.006 | - |
| thermitase | S08.007 | Yes |
| Mername-AA053 peptidase | S08.008 | - |
| subtilisin Ak1 | S08.009 | Yes |
| M-peptidase | S08.010 | Yes |
| PfSUB1 peptidase | S08.012 | Yes |
| subtilisin-like peptidase 2 (Plasmodium-type) | S08.013 | - |
| ALE1 peptidase | S08.014 | - |
| WF146 peptidase (Bacillus sp. WF146) | S08.016 | - |
| bacillopeptidase F | S08.017 | - |
| cell envelope-associated peptidase (Lactobacillus-type) | S08.018 | - |
| lactocepin I | S08.019 | - |
| C5a peptidase | S08.020 | Yes |
| fervidolysin | S08.021 | Yes |
| bpr peptidase (Dichelobacter nodosus) | S08.022 | Yes |
| apr5 peptidase (Dichelobacter nodosus) | S08.023 | - |
| dentilisin | S08.024 | - |
| allergen 13 (Penicillium sp.) | S08.025 | - |
| nasp peptidase | S08.026 | - |
| cell envelope peptidase A (Streptococcus-type) | S08.027 | Yes |
| high alkaline protease (Alkaliphilus transvaalensis) | S08.028 | - |
| thermicin | S08.029 | - |
| IspA peptidase | S08.030 | Yes |
| subtilisin BPN' | S08.034 | Yes |
| subtilisin J | S08.035 | - |
| subtilisin E | S08.036 | Yes |
| subtilisin DY | S08.037 | Yes |
| alkaline peptidase (Bacillus alcalophilus) | S08.038 | Yes |
| PCSK9 peptidase | S08.039 | Yes |
| apr2 peptidase (Dichelobacter nodosus) | S08.040 | Yes |
| perkinsin | S08.041 | - |
| subtilisin amylosacchariticus | S08.042 | - |
| subtilisin NAT | S08.044 | Yes |
| subtilisin ALP 1 | S08.045 | - |
| subtilisin aprM | S08.046 | - |
| secreted peptidase A | S08.050 | Yes |
| aqualysin 1 | S08.051 | Yes |
| cerevisin | S08.052 | - |
| oryzin | S08.053 | - |
| endopeptidase K | S08.054 | Yes |
| alkaline peptidase (Yarrowia lipolytica) | S08.055 | - |
| cuticle-degrading peptidase of parasitic fungus | S08.056 | Yes |
| thermomycolin | S08.057 | - |
| subtilisin-like peptidase (Ophiostoma sp.) | S08.058 | - |
| NisP (Lactococcus lactis)-type lantibiotic leader peptidase | S08.059 | Yes |
| EpiP lantibiotic leader peptidase | S08.060 | - |
| peptidase T | S08.061 | - |
| antigen Pen c 1-type peptidase | S08.062 | Yes |
| site-1 peptidase | S08.063 | - |
| PrtA (Streptococcus pneumoniae)-type peptidase | S08.064 | - |
| MutP (Streptococcus mutans)-type lantibiotic leader peptidase | S08.065 | - |
| Prb1 peptidase | S08.066 | - |
| Apr peptidase | S08.067 | - |
| SphB1 peptidase | S08.068 | - |
| SAM-P45 peptidase | S08.069 | - |
| Mername-AA210 peptidase | S08.082 | - |
| CP70 cold-active peptidase (Flavobacterium balustinum) | S08.083 | - |
| SDD1 peptidase | S08.084 | - |
| PepP lantibiotic leader peptidase | S08.085 | - |
| CylA lantibiotic leader peptidase | S08.086 | Yes |
| tripeptidyl-peptidase II | S08.090 | Yes |
| tripeptidyl-peptidase S | S08.091 | - |
| cucumisin | S08.092 | Yes |
| extracellular subtilisin (Serratia marcescens)-like peptidase | S08.094 | - |
| ElkP lantibiotic leader peptidase | S08.095 | - |
| STABLE peptidase (Staphylothermus-type) | S08.096 | - |
| peptidase C1 | S08.097 | - |
| subtilisin sendai | S08.098 | - |
| pyrolysin | S08.100 | - |
| halolysin 1 | S08.101 | - |
| halolysin R4 | S08.102 | - |
| AF70 peptidase | S08.104 | - |
| aerolysin | S08.105 | - |
| stetterlysin | S08.106 | - |
| peptidase MprA (Burkholderia-type) | S08.107 | - |
| CspB peptidase (Clostridium sp.) | S08.108 | Yes |
| keratinase K1 (Stenotrophomonas maltophilia) | S08.110 | - |
| AprP peptidase | S08.111 | - |
| ARA12 peptidase | S08.112 | - |
| sfericase | S08.113 | Yes |
| peptidase Vpr (Bacillus-type) | S08.114 | - |
| subtilisin-like peptidase 3 (Microsporum-type) | S08.115 | - |
| lactocepin-3 | S08.116 | - |
| FT peptidase | S08.117 | - |
| PrtB peptidase (Lactobacillus-type) | S08.118 | - |
| AIR3 peptidase | S08.119 | - |
| cuticle-degrading peptidase of nematode-trapping fungus | S08.120 | - |
| cytotoxin SubAB | S08.121 | Yes |
| subtilisin-like peptidase 3 (Plasmodium sp.) | S08.122 | - |
| KP-43 peptidase | S08.123 | Yes |
| ASUB peptidase | S08.124 | - |
| AspA (Aeromonas sobria)-type peptidase | S08.125 | Yes |
| minor extracellular protease (Bacillus licheniformis) | S08.126 | - |
| TagC peptidase (Dictyostelium discoideum) | S08.127 | - |
| TagA peptidase (Dictyostelium discoideum) | S08.128 | - |
| Tk-subtilisin | S08.129 | Yes |
| MCP-01 peptidase | S08.130 | Yes |
| mycosin-1 | S08.131 | Yes |
| subtilisin LD-1 | S08.133 | - |
| Apa1 peptidase (Pseudoalteromonas sp. strain AS-11) | S08.134 | - |
| tengconlysin | S08.135 | - |
| BdSUB1 peptidase (Babesia divergens) | S08.136 | - |
| AprX peptidase (Bacillus sp.) | S08.137 | - |
| SufA peptidase (Finegoldia sp.) | S08.138 | - |
| PoSl (Pleurotus ostreatus)-type peptidase | S08.139 | - |
| subtilisin S41 | S08.140 | Yes |
| TgSUB1 peptidase | S08.141 | - |
| collagenolytic endopeptidase (Geobacillus sp. MO-1) | S08.142 | - |
| PopC peptidase (Myxococcus xanthus) | S08.143 | - |
| AasP peptidase (Actinobacillus pleuropneumoniae) | S08.144 | - |
| sporangin | S08.145 | - |
| PatG peptidase | S08.146 | Yes |
| prtH2 peptidase (Lactobacillus helveticus) | S08.147 | - |
| keratinase (Doratomyces microsporus) | S08.148 | - |
| CDF peptidase | S08.149 | - |
| phytaspase | S08.150 | - |
| SlSBT3 g.p. (Solanum lycopersicum) | S08.151 | Yes |
| prtR peptidase (Lactobacillus rhamnosus) | S08.153 | - |
| SUB2 g.p. (Toxoplasma gondii) | S08.154 | - |
| AtSBT1 peptidase (Arabidopsis thaliana) | S08.155 | - |
| PatA peptidase (Prochloron didemni ) | S08.156 | Yes |
| subtilisin YaB | S08.157 | - |
| CspC peptidase (Clostridium sp.) | S08.158 | - |
| CspA peptidase (Clostridium sp.) | S08.159 | - |
| NalP g.p. (Neisseria meningitidis) | S08.160 | Yes |
| EprS g.p. (Pseudomonas aeruginosa) | S08.162 | - |
| keratinase (Brevibacillus parabrevis) | S08.163 | - |
| At4g20430 (Arabidopsis thaliana) | S08.A01 | - |
| At2g19170/At4g30020/At2g19170 (Arabidopsis thaliana) | S08.A02 | - |
| At1g30600 (Arabidopsis thaliana) | S08.A03 | - |
| At5g44530 (Arabidopsis thaliana) | S08.A04 | - |
| At5g45640 (Arabidopsis thaliana) | S08.A05 | - |
| At3g46850 (Arabidopsis thaliana) | S08.A06 | - |
| At5g58840 (Arabidopsis thaliana) | S08.A07 | - |
| At5g59190 (Arabidopsis thaliana) | S08.A09 | - |
| At5g58810 (Arabidopsis thaliana) | S08.A10 | - |
| At5g58820 (Arabidopsis thaliana) | S08.A11 | - |
| At5g58830 (Arabidopsis thaliana) | S08.A12 | - |
| At5g03620 (Arabidopsis thaliana) | S08.A13 | - |
| At4g00230 (Arabidopsis thaliana) | S08.A14 | - |
| At5g59130 (Arabidopsis thaliana) | S08.A15 | - |
| At5g67090 (Arabidopsis thaliana) | S08.A16 | - |
| At4g15040 (Arabidopsis thaliana) | S08.A17 | - |
| At3g46840 (Arabidopsis thaliana) | S08.A18 | - |
| At5g59100 (Arabidopsis thaliana) | S08.A19 | - |
| At5g59090 (Arabidopsis thaliana) | S08.A20 | - |
| At5g59120 (Arabidopsis thaliana) | S08.A21 | - |
| AtSBT5.2 g.p. (Arabidopsis thaliana) | S08.A22 | - |
| At1g20150 (Arabidopsis thaliana) | S08.A23 | - |
| At2g05920 (Arabidopsis thaliana) | S08.A24 | - |
| At5g51750 (Arabidopsis thaliana) | S08.A25 | - |
| At5g59810 (Arabidopsis thaliana) | S08.A26 | - |
| At1g32950 (Arabidopsis thaliana) | S08.A27 | - |
| At3g14067 (Arabidopsis thaliana) | S08.A28 | - |
| At4g21326 (Arabidopsis thaliana) | S08.A30 | - |
| At1g32980 (Arabidopsis thaliana) | S08.A31 | - |
| At4g21323 (Arabidopsis thaliana) | S08.A32 | - |
| At1g66220 (Arabidopsis thaliana) | S08.A33 | - |
| At1g66210 (Arabidopsis thaliana) | S08.A34 | - |
| At1g32960 (Arabidopsis thaliana) | S08.A35 | - |
| At1g32940 (Arabidopsis thaliana) | S08.A36 | - |
| At5g11940 (Arabidopsis thaliana) | S08.A37 | - |
| At4g10530/At4g10520 (Arabidopsis thaliana) | S08.A38 | - |
| At4g34980 (Arabidopsis thaliana) | S08.A39 | - |
| At4g26330 (Arabidopsis thaliana) | S08.A40 | - |
| At1g32970 (Arabidopsis thaliana) | S08.A41 | - |
| At4g21640 (Arabidopsis thaliana) | S08.A42 | - |
| At4g10550 (Arabidopsis thaliana) | S08.A43 | - |
| At3g14240 (Arabidopsis thaliana) | S08.A44 | - |
| At4g10540 (Arabidopsis thaliana) | S08.A45 | - |
| At2g39850 (Arabidopsis thaliana) | S08.A46 | - |
| At4g21630 (Arabidopsis thaliana) | S08.A47 | - |
| At4g21650 (Arabidopsis thaliana) | S08.A48 | - |
| At4g10510 (Arabidopsis thaliana) | S08.A49 | - |
| OSW3 peptidase (Saccharomyces cerevisiae) | S08.A50 | - |
| hypothetical protein SCRG_01405 (Saccharomyces cerevisiae) | S08.A51 | - |
| isp6 g.p. (Schizosaccharomyces pombe) | S08.A54 | - |
| SPAP8A3.12c g.p. (Schizosaccharomyces pombe) | S08.A56 | - |
| tagB g.p. (Dictyostelium discoideum) | S08.A57 | - |
| mbtps1 g.p. (Dictyostelium discoideum) | S08.A58 | - |
| BSn5_12555 (Bacillus subtilis) | S08.A60 | - |
| Subfamily S8A non-peptidase homologues | non-peptidase homologue | Yes |
| Subfamily S8A unassigned peptidases | unassigned | Yes |
