A metalloproteinase, or metalloprotease, is any
protease
A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the ...
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
whose
catalytic
Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...
mechanism involves a
metal
A metal (from Greek μέταλλον ''métallon'', "mine, quarry, metal") is a material that, when freshly prepared, polished, or fractured, shows a lustrous appearance, and conducts electricity and heat relatively well. Metals are typicall ...
. An example is
ADAM12
Disintegrin and metalloproteinase domain-containing protein 12 (previously Meltrin) is an enzyme that in humans is encoded by the ''ADAM12'' gene. ADAM12 has two splice variants: ADAM12-L, the long form, has a transmembrane region and ADAM12-S, a ...
which plays a significant role in the fusion of muscle cells during embryo development, in a process known as
myogenesis
Myogenesis is the formation of skeletal muscular tissue, particularly during embryonic development.
Muscle fibers generally form through the fusion of precursor myoblasts into multinucleated fibers called ''myotubes''. In the early development o ...
.
Most metalloproteases require
zinc
Zinc is a chemical element with the symbol Zn and atomic number 30. Zinc is a slightly brittle metal at room temperature and has a shiny-greyish appearance when oxidation is removed. It is the first element in group 12 (IIB) of the periodi ...
, but some use
cobalt
Cobalt is a chemical element with the symbol Co and atomic number 27. As with nickel, cobalt is found in the Earth's crust only in a chemically combined form, save for small deposits found in alloys of natural meteoric iron. The free element, p ...
. The metal
ion
An ion () is an atom or molecule with a net electrical charge.
The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conve ...
is coordinated to the
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
via three
ligand
In coordination chemistry, a ligand is an ion or molecule ( functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's elec ...
s. The ligands coordinating the metal ion can vary with
histidine
Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated –NH3+ form under biological conditions), a carboxylic acid group (which is in the d ...
,
glutamate,
aspartate,
lysine, and
arginine. The fourth coordination position is taken up by a
labile
Lability refers to something that is constantly undergoing change or is likely to undergo change.
Biochemistry
In reference to biochemistry, this is an important concept as far as kinetics is concerned in metalloproteins. This can allow for th ...
water molecule.
Treatment with
chelating agent
Chelation is a type of bonding of ions and molecules to metal ions. It involves the formation or presence of two or more separate coordinate bonds between a polydentate (multiple bonded) ligand and a single central metal atom. These ligands ar ...
s such as
EDTA
Ethylenediaminetetraacetic acid (EDTA) is an aminopolycarboxylic acid with the formula H2N(CH2CO2H)2sub>2. This white, water-soluble solid is widely used to bind to iron (Fe2+/Fe3+) and calcium ions (Ca2+), forming water-soluble complexes ev ...
leads to complete inactivation. EDTA is a metal chelator that removes zinc, which is essential for activity. They are also inhibited by the chelator
orthophenanthroline
1,10-Phenanthroline (phen) is a heterocyclic organic compound. It is a white solid that is soluble in organic solvents. The 1,10 refer to the location of the nitrogen atoms that replace CH's in the hydrocarbon called phenanthrene.
Abbreviated ...
.
Classification
There are two subgroups of metalloproteinases:
*
Exopeptidase
An exopeptidase is any peptidase that catalyzes the cleavage of the terminal (or the penultimate) peptide bond; the process releases a single amino acid, dipeptide or a tripeptide from the peptide chain. Depending on whether the amino acid is rel ...
s,
metalloexopeptidases (
EC number: 3.4.17).
*
Endopeptidase
Endopeptidase or endoproteinase are proteolytic peptidases that break peptide bonds of nonterminal amino acids (i.e. within the molecule), in contrast to exopeptidases, which break peptide bonds from end-pieces of terminal amino acids. For this ...
s,
metalloendopeptidase A metalloendopeptidase is an enzyme that functions as a metalloproteinase endopeptidase
Endopeptidase or endoproteinase are proteolytic peptidases that break peptide bonds of nonterminal amino acids (i.e. within the molecule), in contrast to exop ...
s (3.4.24). Well known metalloendopeptidases include
ADAM protein
ADAMs (short for a disintegrin and metalloproteinase) are a family of single-pass transmembrane and secreted metalloendopeptidases. All ADAMs are characterized by a particular domain organization featuring a pro-domain, a metalloprotease, a disi ...
s and
matrix metalloproteinase
Matrix metalloproteinases (MMPs), also known as matrix metallopeptidases or matrixins, are metalloproteinases that are calcium-dependent zinc-containing endopeptidases; other family members are adamalysins, serralysins, and astacins. The MMPs be ...
s, and M16 metalloproteinases such as Insulin Degrading Enzyme and Presequence Protease
In the
MEROPS database
MEROPS is an online database for peptidases (also known as proteases, proteinases and proteolytic enzymes) and their inhibitors. The classification scheme for peptidases was published by Rawlings & Barrett in 1993, and that for protein inhibito ...
peptidase families are grouped by their catalytic type, the first character representing the catalytic type: A, aspartic; C,
cysteine; G, glutamic acid; M, metallo; S,
serine; T,
threonine; and U, unknown. The serine, threonine and cysteine peptidases utilise the
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha a ...
as a
nucleophile and form an acyl
intermediate - these peptidases can also readily act as
transferase
A transferase is any one of a class of enzymes that catalyse the transfer of specific functional groups (e.g. a methyl or glycosyl group) from one molecule (called the donor) to another (called the acceptor). They are involved in hundreds of ...
s. In the case of aspartic, glutamic and metallopeptidases, the nucleophile is an activated
water
Water (chemical formula ) is an Inorganic compound, inorganic, transparent, tasteless, odorless, and Color of water, nearly colorless chemical substance, which is the main constituent of Earth's hydrosphere and the fluids of all known living ...
molecule
A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and bioche ...
. In many instances, the structural
protein fold
A protein superfamily is the largest grouping (clade) of proteins for which common ancestry can be inferred (see homology). Usually this common ancestry is inferred from structural alignment and mechanistic similarity, even if no sequence similari ...
that characterises the clan or family may have lost its catalytic activity, yet retained its function in
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
recognition and
binding.
Metalloproteases are the most diverse of the four main protease types, with more than 50 families classified to date. In these enzymes, a
divalent
In chemistry, the valence (US spelling) or valency (British spelling) of an chemical element, element is the measure of its combining capacity with other atoms when it forms chemical compounds or molecules.
Description
The combining capacity, ...
cation, usually zinc, activates the water molecule. The metal
ion
An ion () is an atom or molecule with a net electrical charge.
The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conve ...
is held in place by
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha a ...
ligands, usually three in number. The known metal
ligands are histidine, glutamate, aspartate or lysine and at least one other residue is required for catalysis, which may play an electrophilic role. Of the known metalloproteases, around half contain an HEXXH motif, which has been shown in crystallographic studies to form part of the metal-binding site.
The HEXXH
motif is relatively common, but can be more stringently defined for metalloproteases as 'abXHEbbHbc', where 'a' is most often
valine
Valine (symbol Val or V) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated −NH3+ form under biological conditions), an α- carboxylic acid group (which is in the deprotona ...
or threonine and forms part of the S1' subsite in
thermolysin
Thermolysin (, ''Bacillus thermoproteolyticus neutral proteinase'', ''thermoase'', ''thermoase Y10'', ''TLN'') is a thermostable neutral metalloproteinase enzyme produced by the Gram-positive bacteria ''Bacillus thermoproteolyticus''. It requires ...
and
neprilysin
Neprilysin (), also known as membrane metallo-endopeptidase (MME), neutral endopeptidase (NEP), cluster of differentiation 10 (CD10), and common acute lymphoblastic leukemia antigen (CALLA) is an enzyme that in humans is encoded by the ''MME'' ge ...
, 'b' is an uncharged residue, and 'c' a
hydrophobic
In chemistry, hydrophobicity is the physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water.
Hydrophobic molecules tend to be nonpolar and, t ...
residue
Residue may refer to:
Chemistry and biology
* An amino acid, within a peptide chain
* Crop residue, materials left after agricultural processes
* Pesticide residue, refers to the pesticides that may remain on or in food after they are applied ...
.
Proline is never found in this site, possibly because it would break the
helical
Helical may refer to:
* Helix, the mathematical concept for the shape
* Helical engine, a proposed spacecraft propulsion drive
* Helical spring, a coilspring
* Helical plc, a British property company, once a maker of steel bar stock
* Helicoil
A t ...
structure adopted by this
motif in metalloproteases.
Metallopeptidases from family M48 are
integral membrane protein
An integral, or intrinsic, membrane protein (IMP) is a type of membrane protein that is permanently attached to the biological membrane. All ''transmembrane proteins'' are IMPs, but not all IMPs are transmembrane proteins. IMPs comprise a sign ...
s associated with the
endoplasmic reticulum and Golgi, binding one
zinc
Zinc is a chemical element with the symbol Zn and atomic number 30. Zinc is a slightly brittle metal at room temperature and has a shiny-greyish appearance when oxidation is removed. It is the first element in group 12 (IIB) of the periodi ...
ion per subunit. These
endopeptidase
Endopeptidase or endoproteinase are proteolytic peptidases that break peptide bonds of nonterminal amino acids (i.e. within the molecule), in contrast to exopeptidases, which break peptide bonds from end-pieces of terminal amino acids. For this ...
s include CAAX prenyl
protease
A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the ...
1, which proteolytically removes the C-terminal
three residues of
farnesylated proteins.
Metalloproteinase inhibitors are found in numerous marine organisms, including fish, cephalopods, mollusks, algae and bacteria.
Members of the M50 metallopeptidase family include:
mammalia
Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fur o ...
n sterol-regulatory element binding protein (SREBP) site 2 protease and ''Escherichia coli'' protease EcfE, stage IV
sporulation
In biology, a spore is a unit of sexual or asexual reproduction that may be adapted for dispersal and for survival, often for extended periods of time, in unfavourable conditions. Spores form part of the life cycles of many plants, algae, ...
protein FB.
See also
*
Matrix metalloproteinase
Matrix metalloproteinases (MMPs), also known as matrix metallopeptidases or matrixins, are metalloproteinases that are calcium-dependent zinc-containing endopeptidases; other family members are adamalysins, serralysins, and astacins. The MMPs be ...
*
The Proteolysis Map
The Proteolysis MAP (PMAP) is an integrated web resource focused on proteases.
Rationale
PMAP is to aid the protease researchers in reasoning about proteolytic networks and metabolic pathways.
History and funding
PMAP was originally created ...
References
External links
* The
MEROPS
MEROPS is an online database for peptidases (also known as proteases, proteinases and proteolytic enzymes) and their inhibitors. The classification scheme for peptidases was published by Rawlings & Barrett in 1993, and that for protein inhibit ...
online database for peptidases and their inhibitors
Metallo Peptidases*
* Proteopedia:
Metalloproteases'
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*
*
Protein families
Proteases