Family S53

Family

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

Summary for family S53

Family type peptidaseS53.001 - sedolisin (Pseudomonas sp. 101), MEROPS Accession MER0000995 (peptidase unit: 216-585)
Content of familyPeptidase family S53 contains acid-acting endopeptidases and a tripeptidyl-peptidase.
History Identifier created: MEROPS 5.3 (4 December 2000)
Endopeptidases with acidic pH optima that differ from the majority of such enzymes in being resistant to inhibition by pepstatin were discovered by Murao, Oda and co-workers in the early 1980s (e.g. Terashita et al., 1981; Oda et al., 1998). Crystal structures have shown that many of these pepstatin-insensitive carboxyl proteinases are either glutamic peptidases in family G1 or sedolisins in family S53, both groups being unrelated to the aspartic peptidases of clan AA that are inhibited by pepstatin.
Catalytic typeSerine
Active site residuesE295 D299 D385 S502 
Active siteThe residues of the catalytic triad are Glu, Asp, Ser, and there is an additional acidic residue, Asp385 (numbering as in the Alignment) in the oxyanion hole (Wlodawer et al., 2003). The Ser residue is the nucleophile equivalent to Ser in the Asp, His, Ser triad of subtilisin, and the Glu of the triad is a substitution for the His general base in subtilisin. The residue that orients the general base side chain is quite different between the families, however, being Asp299 in family S53 (closely following Glu295 in the sequence), in contrast to Asp137 preceding His in the sequence of subtilisin. Asp385 of the oxyanion hole corresponds to Asn259 in subtilisin.
Activities and specificitiesThe specificities of sedolisin (S53.001) and sedolisin-B (S53.002) have been described by Narutaki et al. (1999) and Wlodawer et al. (2001). The specificities are broad, but there is an indication of preferences for hydrophobic residues in the P1 and P2 positions.
Having predominantly (though not exclusively) exopeptidase activity, tripeptidyl-peptidase I (S53.003) differs from the sedolisins. The structural basis of the specificity has been discussed by Wlodawer et al. (2003). Ala-Arg-PheNph-Arg-Leu has been described as a particularly sensitive substrate, with a specificity constant 40-fold that of Ala-Ala-PheNHMec, the substrate generally used for the enzyme (Wlodawer et al., 2001).
The peptidases of the sedolisin family tend to be most active at acidic pH (unlike the homologous subtilisins), and this can be attributed to the functional importance of carboxylic residues, notably Asp385 in the oxyanion hole.
InhibitorsMost known inhibitors are aldehydes containing large hydrophobic side chains, such as tyrostatin and chymostatin. These make covalent bonds to the active site Ser502 (numbering as in the Alignment) through their aldehyde moieties (Wlodawer et al., 2001).
Molecular structureHigh-resolution structures have been published for sedolisin (Wlodawer et al., 2001), kumamolisin (Comellas-Bigler et al., 2002), kumamolisin As (S53.009: Wlodawer et al., 2004) and prokumamolisin (Comellas-Bigler et al., 2004). The protein folds are clearly related to that of subtilisin (S08.001), but there are additional loops. The amino acid sequences are not closely similar to those in family S8, and this, taken together with the quite different active site residues and the resulting lower pH for maximal activity, justifies the separate families. However, it should be noted that some other databases choose to combine our families S8 and S53 in a single family.
ClanSB
Basis of clan assignmentProtein fold of the peptidase unit for members of this family resembles that of subtilisin, the type example of clan SB.
Distribution of family Bacteria details  
Archaea details  
Protozoa details  
Fungi details  
Plants details  
Animals details  
Viruses -  
Biological functionsThe proteins are secreted proteins, synthesised with signal peptides. The functions of the S53 peptidases in prokaryotic organisms are uncertain, although they probably contribute to the extracellular digestion of food proteins. Tripeptidyl-peptidase I is a lysosomal enzyme in eukaryotes, and its ability to function at acidic pH is doubtless an advantage in this location. Hereditary deficiency of tripeptidyl-peptidase I is the cause of an autosomal recessive neurodegenerative disease of children, classical late-infantile neuronal ceroid lipofuscinosis (cLINCL), and mice deficient in the enzyme display a similar syndrome(Sleat et al., 2004). The crucial natural substrates of tripeptidyl-peptidase I have yet to be conclusively identified.
Statistics for family S53Sequences:2643
Identifiers:13
Identifiers with PDB entries:4
Downloadable files Sequence library (FastA format)
Sequence alignment (FastA format)
Phylogenetic tree (Newick format)
Peptidases and Homologues MEROPS ID Structure
sedolisinS53.001Yes
sedolisin-BS53.002-
tripeptidyl-peptidase IS53.003Yes
kumamolisinS53.004Yes
kumamolisin-BS53.005-
physarolisinS53.006-
aorsinS53.007-
physarolisin IIS53.008-
kumamolisin-AsS53.009Yes
grifolisinS53.010-
scytalidolisinS53.011-
DDB_G0287357 g.p. (Dictyostelium discoideum)S53.A01-
V4-7 g.p. (Dictyostelium discoideum)S53.A02-
family S53 non-peptidase homologuesnon-peptidase homologue-
family S53 unassigned peptidasesunassigned-