Family S8

Family

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

S8A

Summary Holotypes Alignment Tree Genomes Literature

S8B

Summary Holotypes Alignment Tree Genomes Literature

Summary for family S8

NamePeptidase family S8 (subtilisin family)
Family type peptidaseS08.001 - subtilisin Carlsberg (Bacillus licheniformis), MEROPS Accession MER0000309 (peptidase unit: 106-379)
Content of familyPeptidase 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 typeSerine
Active siteMembers 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 specificitiesMost 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.
InhibitorsMost 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 structureThe 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).
ClanSB
Basis of clan assignmentType family of clan SB.
Distribution of family Bacteria details  
Archaea details  
Protozoa details  
Fungi details  
Plants details  
Animals details  
Viruses details  
Biological functionsIn bacteria, archaea and fungi, family members are probably involved in nutrition. Most are secreted, but lactocepin (S08.018) is attached to the outer surface of the cell wall, and lantibiotic leader peptidases are intracellular. Lantibiotic leader peptidases, such as the CylP leader peptidase (S08.086), are required for the activation of lantibiotics and cytolysins. Subfamily S8A peptidases from Dichelobacter have been implicated in the pathogenesis of ovine foot-rot (Kortt & Stewart, 2004) and C5a peptidase (S08.020) from pathogenic streptococci destroys the complement chemotaxin C5a (Cleary & Matsuka, 2004). Site-1 protease (S08.063) is a mammalian member of subfamily S8A which catalyzes the first step in the proteolytic activation of sterol regulatory element-binding protein (Sakai et al., 1998). TPP-II (S08.090) is a mammalian cytoplasmic enzyme that degrades peptides and has a role in the processing of antigenic peptides and the degradation of cholecystokinin (Warburton & Bernardini, 2002). In subfamily S8B, kexin (S08.070) processes the yeast alpha-mating factor and killer toxin precursors, and furin (S08.071) is located in the mammalian trans-Golgi network and endosome membranes where is processes a variety of proproteins.
Pharmaceutical and biotech relevanceSubtilisin and proteinase K (S08.054) are used as reagents to make peptides from proteins. Subtilisin is an active agent in biological washing powder.
Statistics for family S8Sequences:28635
Identifiers:209
Identifiers with PDB entries:38
Downloadable files Sequence library (FastA format)
Sequence alignment (FastA format)
Phylogenetic tree (Newick format)
Subfamily S8A
Name Peptidase subfamily S8A
Subfamily type peptidase S08.001 - subtilisin Carlsberg (Bacillus licheniformis), MEROPS Accession MER0000309 (peptidase unit: 106-379)
Active site residues D137 H168 N259 S325 
Statistics Sequences: 26262
Identifiers: 185
Identifiers with PDB entries: 35
Other databases CATH 3.40.50.200
HOMSTRAD subt
HSSP 5sic
INTERPRO IPR000209
PFAM PF00082
SCOP 52744
Downloadable files Sequence library [FastA format]
Sequence alignment [FastA format]
Phylogenetic tree [Newick format]
Peptidases and Homologues MEROPS ID Structure
subtilisin CarlsbergS08.001Yes
mesentericopeptidaseS08.002Yes
subtilisin lentusS08.003Yes
wprA g.p. (Bacillus-type)S08.004-
endopeptidase QS08.005-
P69 peptidaseS08.006-
thermitaseS08.007Yes
Mername-AA053 peptidaseS08.008-
subtilisin Ak1S08.009Yes
M-peptidaseS08.010Yes
PfSUB1 peptidaseS08.012-
subtilisin-like peptidase 2 (Plasmodium-type)S08.013-
ALE1 peptidaseS08.014-
WF146 peptidase (Bacillus sp. WF146)S08.016-
bacillopeptidase FS08.017-
cell envelope-associated peptidase (Lactobacillus-type)S08.018-
lactocepin IS08.019-
C5a peptidaseS08.020Yes
fervidolysinS08.021Yes
bpr peptidase (Dichelobacter nodosus)S08.022Yes
apr5 peptidase (Dichelobacter nodosus)S08.023-
dentilisinS08.024-
allergen 13 (Penicillium sp.)S08.025-
nasp peptidaseS08.026-
cell envelope peptidase A (Streptococcus-type)S08.027-
high alkaline protease (Alkaliphilus transvaalensis)S08.028-
thermicinS08.029-
IspA peptidaseS08.030Yes
subtilisin BPN’S08.034Yes
subtilisin JS08.035-
subtilisin ES08.036Yes
subtilisin DYS08.037Yes
alkaline peptidase (Bacillus alcalophilus)S08.038Yes
PCSK9 peptidaseS08.039Yes
apr2 peptidase (Dichelobacter nodosus)S08.040-
perkinsinS08.041-
subtilisin amylosacchariticusS08.042-
subtilisin NATS08.044Yes
subtilisin ALP 1S08.045-
subtilisin aprMS08.046-
secreted peptidase AS08.050Yes
aqualysin 1S08.051Yes
cerevisinS08.052-
oryzinS08.053-
endopeptidase KS08.054Yes
alkaline peptidase (Yarrowia lipolytica)S08.055-
cuticle-degrading peptidase of parasitic fungusS08.056-
thermomycolinS08.057-
subtilisin-like peptidase (Ophiostoma sp.)S08.058-
NisP (Lactococcus lactis)-type lantibiotic leader peptidaseS08.059Yes
EpiP lantibiotic leader peptidaseS08.060-
peptidase TS08.061-
antigen Pen c 1-type peptidaseS08.062Yes
site-1 peptidaseS08.063-
PrtA (Streptococcus pneumoniae)-type peptidaseS08.064-
MutP (Streptococcus mutans)-type lantibiotic leader peptidaseS08.065-
Prb1 peptidaseS08.066-
Apr peptidaseS08.067-
SphB1 peptidaseS08.068-
SAM-P45 peptidaseS08.069-
Mername-AA210 peptidaseS08.082-
CP70 cold-active peptidase (Flavobacterium balustinum)S08.083-
SDD1 peptidaseS08.084-
PepP lantibiotic leader peptidaseS08.085-
CylA lantibiotic leader peptidaseS08.086-
tripeptidyl-peptidase IIS08.090Yes
tripeptidyl-peptidase SS08.091-
cucumisinS08.092Yes
extracellular subtilisin (Serratia marcescens)-like peptidaseS08.094-
ElkP lantibiotic leader peptidaseS08.095-
STABLE peptidase (Staphylothermus-type)S08.096-
peptidase C1S08.097-
subtilisin sendaiS08.098-
pyrolysinS08.100-
halolysin 1S08.101-
halolysin R4S08.102-
AF70 peptidaseS08.104-
aerolysinS08.105-
stetterlysinS08.106-
peptidase MprA (Burkholderia-type)S08.107-
CspB peptidase (Clostridium sp.)S08.108Yes
keratinase K1 (Stenotrophomonas maltophilia)S08.110-
AprP peptidaseS08.111-
ARA12 peptidaseS08.112-
sfericaseS08.113Yes
peptidase Vpr (Bacillus-type)S08.114-
subtilisin-like peptidase 3 (Microsporum-type)S08.115-
lactocepin-3S08.116-
FT peptidaseS08.117-
PrtB peptidase (Lactobacillus-type)S08.118-
AIR3 peptidaseS08.119-
cuticle-degrading peptidase of nematode-trapping fungusS08.120-
cytotoxin SubABS08.121-
subtilisin-like peptidase 3 (Plasmodium sp.)S08.122-
KP-43 peptidaseS08.123Yes
ASUB peptidaseS08.124-
AspA (Aeromonas sobria)-type peptidaseS08.125Yes
EPR peptidase (Bacillus sp.)S08.126-
TagC peptidase (Dictyostelium discoideum)S08.127-
TagA peptidase (Dictyostelium discoideum)S08.128-
Tk-subtilisinS08.129Yes
MCP-01 peptidaseS08.130-
mycosin-1S08.131Yes
subtilisin LD-1S08.133-
Apa1 peptidase (Pseudoalteromonas sp. strain AS-11)S08.134-
tengconlysinS08.135-
BdSUB1 peptidase (Babesia divergens)S08.136-
AprX peptidase (Bacillus sp.)S08.137-
SufA peptidase (Finegoldia sp.)S08.138-
PoSl (Pleurotus ostreatus)-type peptidaseS08.139-
subtilisin S41S08.140Yes
TgSUB1 peptidaseS08.141-
collagenolytic endopeptidase (Geobacillus sp. MO-1)S08.142-
PopC peptidase (Myxococcus xanthus)S08.143-
AasP peptidase (Actinobacillus pleuropneumoniae)S08.144-
sporanginS08.145-
PatG peptidaseS08.146Yes
prtH2 peptidase (Lactobacillus helveticus)S08.147-
keratinase (Doratomyces microsporus)S08.148-
CDF peptidaseS08.149-
phytaspaseS08.150-
SlSBT3 g.p. (Solanum lycopersicum)S08.151Yes
prtR peptidase (Lactobacillus rhamnosus)S08.153-
SUB2 g.p. (Toxoplasma gondii)S08.154-
AtSBT1 peptidase (Arabidopsis thaliana)S08.155-
PatA peptidase (Prochloron didemni )S08.156Yes
subtilisin YaBS08.157-
CspC peptidase (Clostridium sp.)S08.158-
CspA peptidase (Clostridium perfringens)S08.159-
NalP g.p. (Neisseria meningitidis)S08.160Yes
EprS g.p. (Pseudomonas aeruginosa)S08.162-
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 homologuesnon-peptidase homologue-
subfamily S8A unassigned peptidasesunassignedYes
Subfamily S8B
Name Peptidase subfamily S8B
Subfamily type peptidase S08.070 - kexin (Saccharomyces cerevisiae), MEROPS Accession MER0000364 (peptidase unit: 144-439)
Active site residues D175 H213 D,N314 S385 
Statistics Sequences: 2317
Identifiers: 21
Identifiers with PDB entries: 3
Other databases CATH 3.40.50.200
HOMSTRAD hs1ot5a
INTERPRO IPR000209
PANTHER PTHR10795
PFAM PF00082
SCOP 52744
Downloadable files Sequence library [FastA format]
Sequence alignment [FastA format]
Phylogenetic tree [Newick format]
Peptidases and Homologues MEROPS ID Structure
kexin-like peptidse (Pneumocystis-type)S08.011-
bli-4 g.p. (Caenorhabditis sp.)S08.031-
Psp3 peptidaseS08.032-
HreP peptidase (Yersinia enterocolitica)S08.043-
KPC1-type peptidaseS08.047-
furin-1 (arthropod-type)S08.048-
furin-2 (insect)S08.049-
kexinS08.070Yes
furinS08.071Yes
PCSK1 peptidaseS08.072Yes
PCSK2 peptidaseS08.073-
PCSK4 peptidaseS08.074-
PCSK6 peptidaseS08.075-
PCSK5 peptidaseS08.076-
PCSK7 peptidaseS08.077-
PrcA peptidaseS08.079-
KPC2-type peptidaseS08.109-
KPC-3 peptidase (Caenorhabditis sp.)S08.132-
furin A (Brachydanio rerio)S08.152-
FurinB g.p. (Brachydanio rerio)S08.161-
krp1 g.p. (Schizosaccharomyces pombe)S08.A55-
subfamily S8B non-peptidase homologuesnon-peptidase homologue-
subfamily S8B unassigned peptidasesunassigned-
Peptidases not assigned to subfamily
Peptidases and Homologues MEROPS ID Structure
EciP lantibiotic leader peptidase (Staphylococcus epidermidis)S08.087-
LasP lantibiotic leader peptidase (Lactobacillus sakei)S08.093-
family S8 non-peptidase homologuesnon-peptidase homologue-
family S8 unassigned peptidasesunassigned-