PROSITE documentation PDOC00129

Neutral zinc metallopeptidases, zinc-binding region signature

The majority of zinc-dependent metallopeptidases (with the notable exception of the carboxypeptidases) share a common pattern of primary structure [1,2,3] in the part of their sequence involved in the binding of zinc, and can be grouped together as a superfamily,known as the metzincins, on the basis of this sequence similarity. They can be classified into a number of distinct families [4,E1] which are listed below along with the proteases which are currently known to belong to these families.

 Family M1
 - Bacterial aminopeptidase N (EC 3.4.11.2) (gene pepN).
 - Mammalian aminopeptidase N (EC 3.4.11.2).
 - Mammalian glutamyl aminopeptidase (EC 3.4.11.7) (aminopeptidase A).  It may
   play a role in  regulating growth  and  differentiation  of early B-lineage
   cells.
 - Yeast aminopeptidase yscII (gene APE2).
 - Yeast alanine/arginine aminopeptidase (gene AAP1).
 - Yeast hypothetical protein YIL137c.
 - Leukotriene A-4 hydrolase (EC 3.3.2.6). This enzyme is responsible  for the
   hydrolysis of an  epoxide moiety of LTA-4 to form LTB-4;  it has been shown
   that it binds zinc and is capable of peptidase activity.

 Family M2
 - Angiotensin-converting enzyme (EC 3.4.15.1) (dipeptidyl carboxypeptidase I)
   (ACE) the enzyme  responsible  for hydrolyzing angiotensin I to angiotensin
   II. There  are  two  forms of ACE:  a testis-specific isozyme and a somatic
   isozyme which has two active centers.

 Family M3
 - Thimet  oligopeptidase  (EC 3.4.24.15),  a mammalian enzyme involved in the
   cytoplasmic degradation of small peptides.
 - Neurolysin (EC 3.4.24.16)  (also known as mitochondrial oligopeptidase M or
   microsomal endopeptidase).
 - Mitochondrial intermediate peptidase precursor (EC 3.4.24.59) (MIP).  It is
   involved the  second  stage  of processing of some proteins imported in the
   mitochondrion.
 - Yeast saccharolysin (EC 3.4.24.37) (proteinase yscD).
 - Escherichia   coli   and   related   bacteria  dipeptidyl  carboxypeptidase
   (EC 3.4.15.5) (gene dcp).
 - Escherichia coli and related bacteria oligopeptidase A (EC 3.4.24.70) (gene
   opdA or prlC).
 - Yeast hypothetical protein YKL134c.

 Family M4
 - Thermostable thermolysins (EC 3.4.24.27),  and related thermolabile neutral
   proteases (bacillolysins) (EC 3.4.24.28) from various species of Bacillus.
 - Pseudolysin (EC 3.4.24.26) from Pseudomonas aeruginosa (gene lasB).
 - Extracellular elastase from Staphylococcus epidermidis.
 - Extracellular protease prt1 from Erwinia carotovora.
 - Extracellular minor protease smp from Serratia marcescens.
 - Vibriolysin (EC 3.4.24.25) from various species of Vibrio.
 - Protease prtA from Listeria monocytogenes.
 - Extracellular proteinase proA from Legionella pneumophila.

 Family M5
 - Mycolysin (EC 3.4.24.31) from Streptomyces cacaoi.

 Family M6
 - Immune inhibitor A from Bacillus thuringiensis (gene ina). Ina degrades two
   classes of insect antibacterial proteins, attacins and cecropins.

 Family M7
 - Streptomyces extracellular small neutral proteases

 Family M8
 - Leishmanolysin (EC 3.4.24.36) (surface glycoprotein gp63),  a  cell surface
   protease from various species of Leishmania.

 Family M9
 - Microbial collagenase (EC 3.4.24.3) from Clostridium perfringens and Vibrio
   alginolyticus.

 Family M10A
 - Serralysin (EC 3.4.24.40), an extracellular metalloprotease from Serratia.
 - Alkaline metalloproteinase from Pseudomonas aeruginosa (gene aprA).
 - Secreted proteases A, B, C and G from Erwinia chrysanthemi.
 - Yeast hypothetical protein YIL108w.

 Family M10B
 - Mammalian extracellular matrix metalloproteinases (known as matrixins) [5]:
   MMP-1 (EC 3.4.24.7) (interstitial collagenase), MMP-2 (EC 3.4.24.24) (72 Kd
   gelatinase), MMP-9 (EC 3.4.24.35) (92 Kd gelatinase),  MMP-7 (EC 3.4.24.23)
   (matrylisin),   MMP-8  (EC 3.4.24.34)    (neutrophil  collagenase),   MMP-3
   (EC 3.4.24.17) (stromelysin-1),  MMP-10 (EC 3.4.24.22) (stromelysin-2), and
   MMP-11 (stromelysin-3), MMP-12 (EC 3.4.24.65) (macrophage metalloelastase).
 - Sea urchin hatching enzyme (envelysin)  (EC 3.4.24.12).   A  protease  that
   allows the embryo to digest  the  protective  envelope derived from the egg
   extracellular matrix.
 - Soybean metalloendoproteinase 1.

 Family M11
 - Chlamydomonas reinhardtii gamete lytic enzyme (GLE).

 Family M12A
 - Astacin (EC 3.4.24.21), a crayfish endoprotease.
 - Meprin A  (EC 3.4.24.18), a mammalian  kidney  and intestinal brush  border
   metalloendopeptidase.
 - Bone morphogenic protein 1 (BMP-1), a  protein which induces cartilage  and
   bone  formation  and   which  expresses  metalloendopeptidase activity. The
   Drosophila homolog  of BMP-1  is  the   dorsal-ventral  patterning  protein
   tolloid.
 - Blastula  protease  10  (BP10)  from  Paracentrotus lividus and the related
   protein SpAN from Strongylocentrotus purpuratus.
 - Caenorhabditis elegans protein toh-2.
 - Caenorhabditis elegans hypothetical protein F42A10.8.
 - Choriolysins  L  and  H  (EC  3.4.24.67)  (also known as embryonic hatching
   proteins LCE  and  HCE)  from  the  fish  Oryzias  lapides. These proteases
   participates in  the  breakdown  of the egg envelope, which is derived from
   the egg extracellular matrix, at the time of hatching.

 Family M12B
 - Snake venom metalloproteinases [6].  This subfamily mostly groups proteases
   that act  in  hemorrhage.  Examples  are:  adamalysin  II  (EC  3.4.24.46),
   atrolysin C/D    (EC  3.4.24.42),  atrolysin  E  (EC  3.4.24.44), fibrolase
   (EC 3.4.24.72), trimerelysin I (EC 3.4.24.52) and II (EC 3.4.24.53).
 - Mouse cell surface antigen MS2.

 Family M13
 - Mammalian neprilysin (EC 3.4.24.11) (neutral endopeptidase) (NEP).
 - Endothelin-converting enzyme 1 (EC 3.4.24.71)  (ECE-1), which  process  the
   precursor of endothelin to release the active peptide.
 - Kell  blood  group glycoprotein, a major antigenic protein of erythrocytes.
   The Kell protein is very probably a zinc endopeptidase.
 - Peptidase O from Lactococcus lactis (gene pepO).

 Family M27
 - Clostridial neurotoxins, including  tetanus  toxin (TeTx)  and  the various
   botulinum toxins  (BoNT).  These  toxins  are  zinc  proteases  that  block
   neurotransmitter release by proteolytic  cleavage of synaptic proteins such
   as synaptobrevins, syntaxin and SNAP-25 [7,8].

 Family M30
 - Staphylococcus hyicus neutral metalloprotease.

 Family M32
 - Thermostable carboxypeptidase 1  (EC 3.4.17.19)  (carboxypeptidase Taq), an
   enzyme from Thermus aquaticus which is most active at high temperature.

 Family M34
 - Lethal  factor  (LF)  from  Bacillus  anthracis,  one of the three proteins
   composing the anthrax toxin.

 Family M35
 - Deuterolysin (EC 3.4.24.39) from Penicillium citrinum and related proteases
   from various species of Aspergillus.

 Family M36
 - Extracellular elastinolytic metalloproteinases from Aspergillus.

From the tertiary structure of thermolysin, the position of the residues acting as zinc ligands and those involved in the catalytic activity are known. Two of the zinc ligands are histidines which are very close together in the sequence; C-terminal to the first histidine is a glutamic acid residue which acts as a nucleophile and promotes the attack of a water molecule on the carbonyl carbon of the substrate. A signature pattern which includes the two histidine and the glutamic acid residues is sufficient to detect this superfamily of proteins.