Family M13


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

Summary for family M13

NamePeptidase family M13 (neprilysin family)
Family type peptidaseM13.001 - neprilysin (Homo sapiens), MEROPS Accession MER0001050 (peptidase unit: 52-750)
Content of familyPeptidase family M13 contains metalloendopeptidases restricted to action on substrates smaller than proteins.
History Identifier created: Biochem.J. 290:205-218 (1993)
Neprilysin (M13.001), a neutral-acting metalloendopeptidase, was discovered in brush border membranes by Kenny and colleagues (e.g. Kerr & Kenny, 1974; Kerr & Kenny, 1974). It was for a long time the only known peptidase in family M13, but additional homologues are now known, principally from animals and bacteria.
Catalytic typeMetallo
Active site residuesH584 E585 H588 E647 D651 
Active siteThere is a HEXXH motif, in which the His residues are ligands of a zinc atom and the Glu has a catalytic role. There is also a more C-terminal Glu residue that is the third ligand of the zinc atom (see the Alignment). Residues involved in substrate binding in neprilysin are Val541, Asn542, Ala543, His711 and Arg717 (Oefner et al., 2000).
Activities and specificitiesThe enzymes appear to be synthesised in active form; there are no proenzymes. Probably all peptidases in family M13 are restricted to acting on substrates of not more than about 40 residues. Substrates of neprilysin include bioactive peptides such as the enkephalins, substance P, endothelin, bradykinin and atrial natriuretic factor, but the other mammalian enzymes have more restricted activities. For example, endothelin-converting enzyme 1 (M13.002) is very selective for the cleavage of TrpVal/Ile in the 'big endothelin' precursors of endothelin 1 (Turner & Murphy, 1996; Ahn & Johnson, 2004), and human recombinant endopeptidase PHEX (M13.091) has a strict S1" specificity for acidic residues, preferably Asp (Campos et al., 2003).
InhibitorsMetal chelating agents such as 1,10-phenanthroline inhibit, as is expected for metallopeptidases. Phosphoramidon is a potent inhibitor. There has been much work towards the development of selective inhibitors of neprilysin and endothelin-converting enzyme as possible drugs (see Literature for the individual enzymes). There is little evidence of physiological inhibitors of these peptidases.
Molecular structureThe structure of neprilysin may be typical for the family. From the N-terminus, there is a short (27 residues) cytoplasmic tail followed by a hydrophobic segment (23 residues) that anchors the enzyme to the cell membrane. The bulk of the protein, located extracellularly, comprises two domains that enclose a large central cavity containing the active site. The more N-terminal of the domains has a fold reminiscent of that of thermolysin and contains the active site residues. The second domain may well serve to control access of substrates to the active site and prevent cleavage of proteins. The thermolysin-like fold of the catalytic domain is the reason for the assignment ot clan MA (subclan E). Neprilysin is glycosylated.
Basis of clan assignmentProtein fold of the peptidase unit for members of this family resembles that of thermolysin, the type example for clan MA.
Distribution of family Bacteria details  
Archaea details  
Protozoa details  
Fungi details  
Plants details  
Animals details  
Viruses details  
Biological functionsThe enzymes act outside animal cells to degrade or convert polypeptide substrates. In bacteria they are presumed to have a nutritional role.
Pharmaceutical and biotech relevanceActivities of neprilysin such as the destruction of enkephalins, and the generation of endothelin 1 by endothelin-converting enzyme 1, make these enzymes potential drug targets, and there has been a great deal of work on the development of inhibitors.
Statistics for family M13Sequences:8062
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
endothelin-converting enzyme 1M13.002Yes
endothelin-converting enzyme 2M13.003Yes
oligopeptidase O1M13.004-
oligopeptidase O3M13.005-
endothelin-converting enzyme-like 1 endopeptidaseM13.007-
Zmp1 peptidase (Mycobacterium-type)M13.009Yes
oligopeptidase O2M13.010-
MEP peptidase (nematode)M13.011-
Nep2 peptidase (insect)M13.012-
NEP-1 peptidase (Caenorhabditis sp.)M13.013-
neprilysin-4 (Drosophila melanogaster)M13.014-
NEP-2 peptidase (Caenorhabditis sp.)M13.015-
T25B6.2 g.p. (Caenorhabditis elegans)M13.016-
Kell blood-group peptidaseM13.090-
PHEX peptidaseM13.091-
similar to Kell blood group protein (Rattus norvegicus)M13.950-
CG3775 protein (Drosophila melanogaster)M13.A01-
CG6265 (Drosophila melanogaster)M13.A02-
CG8550 protein (Drosophila melanogaster)M13.A03-
CG14526 protein (Drosophila melanogaster)M13.A04-
CG14527 protein (Drosophila melanogaster)M13.A05-
CG14528 protein (Drosophila melanogaster)M13.A06-
CG14529 protein (Drosophila melanogaster)M13.A07-
CG5527 protein (Drosophila melanogaster)M13.A08-
CG8358 protein (Drosophila melanogaster)M13.A09-
CG9508 protein (Drosophila melanogaster)M13.A10-
CG9507 protein (Drosophila melanogaster)M13.A11-
CG9505 protein (Drosophila melanogaster)M13.A12-
CG3239 protein (Drosophila melanogaster)M13.A13-
Nep3 protein (Drosophila melanogaster)M13.A14-
CG5894 protein (Drosophila melanogaster)M13.A15-
F18A12.8 g.p. (Caenorhabditis elegans)M13.A16-
K02F6.9 g.p. (Caenorhabditis elegans)M13.A17-
T06D4.3 g.p. (Caenorhabditis elegans)M13.A18-
F54F11.2 g.p. domain 1 (Caenorhabditis elegans)M13.A19-
F54F11.2 g.p. domain 2 (Caenorhabditis elegans)M13.A20-
C49D10.10 g.p. (Caenorhabditis elegans)M13.A21-
F18A12.6 g.p. (Caenorhabditis elegans)M13.A22-
F18A12.4 g.p. (Caenorhabditis elegans)M13.A23-
F18A12.1 g.p. (Caenorhabditis elegans)M13.A24-
F39E9.4 g.p. (Caenorhabditis elegans)M13.A25-
F26G1.6 g.p. (Caenorhabditis elegans)M13.A26-
ZK1248.1 g.p. (Caenorhabditis elegans)M13.A27-
ZK970.1 g.p. (Caenorhabditis elegans)M13.A28-
Y116A8C.5 g.p. (Caenorhabditis elegans)M13.A29-
Y116A8C.4 g.p. (Caenorhabditis elegans)M13.A30-
T16A9.4 g.p. (Caenorhabditis elegans)M13.A31-
family M13 non-peptidase homologuesnon-peptidase homologue-
family M13 unassigned peptidasesunassigned-