Matrix metalloproteinase
Encyclopedia
Metalloproteinase
Metalloproteinases constitute a family of enzymes from the group of proteases, classified by the nature of the most prominent functional group in their active site. These are proteolytic enzymes whose catalytic mechanism involves a metal. Most metalloproteases are zinc-dependent, but some use...
s (MMPs) are zinc
Zinc
Zinc , or spelter , is a metallic chemical element; it has the symbol Zn and atomic number 30. It is the first element in group 12 of the periodic table. Zinc is, in some respects, chemically similar to magnesium, because its ion is of similar size and its only common oxidation state is +2...
-dependent endopeptidase
Endopeptidase
Endopeptidase or endoproteinase are proteolytic peptidases that break peptide bonds of nonterminal amino acids , in contrast to exopeptidases, which break peptide bonds from their end-pieces. For this reason, endopeptidases cannot break down peptides into monomers, while exopeptidases can break...
s; other family members are adamalysins, serralysins, and astacin
Astacin
In molecular biology, astacin is a family of metallopeptidases. These metallopeptidases belong to the MEROPS peptidase family M12, subfamily M12A...
s. The MMPs belong to a larger family of protease
Protease
A protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein....
s known as the metzincin superfamily.
Collectively, they are capable of degrading all kinds of extracellular matrix
Extracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...
proteins, but also can process a number of bioactive molecules. They are known to be involved in the cleavage of cell surface receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
s, the release of apoptotic
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
ligands (such as the FAS ligand
FAS ligand
Fas ligand is a type-II transmembrane protein that belongs to the tumor necrosis factor family. Its binding with its receptor induces apoptosis. Fas ligand/receptor interactions play an important role in the regulation of the immune system and the progression of cancer.- Structure :Fas ligand or...
), and chemokine
Chemokine
Chemokines are a family of small cytokines, or proteins secreted by cells. Their name is derived from their ability to induce directed chemotaxis in nearby responsive cells; they are chemotactic cytokines...
/cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
in/activation. MMPs are also thought to play a major role on cell behaviors such as cell proliferation, migration
Cell migration
Cell migration is a central process in the development and maintenance of multicellular organisms. Tissue formation during embryonic development, wound healing and immune responses all require the orchestrated movement of cells in particular directions to specific locations...
(adhesion
Cell adhesion
Cellular adhesion is the binding of a cell to a surface, extracellular matrix or another cell using cell adhesion molecules such as selectins, integrins, and cadherins. Correct cellular adhesion is essential in maintaining multicellular structure...
/dispersion), differentiation
Cellular differentiation
In developmental biology, cellular differentiation is the process by which a less specialized cell becomes a more specialized cell type. Differentiation occurs numerous times during the development of a multicellular organism as the organism changes from a simple zygote to a complex system of...
, angiogenesis
Angiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...
, apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
, and host defense
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
.
They were first described in vertebrates (1962), including humans, but have since been found in invertebrates and plants. They are distinguished from other endopeptidases by their dependence on metal ions as cofactors
Cofactor (biochemistry)
A cofactor is a non-protein chemical compound that is bound to a protein and is required for the protein's biological activity. These proteins are commonly enzymes, and cofactors can be considered "helper molecules" that assist in biochemical transformations....
, their ability to degrade extracellular matrix, and their specific evolutionary DNA sequence
DNA sequence
The sequence or primary structure of a nucleic acid is the composition of atoms that make up the nucleic acid and the chemical bonds that bond those atoms. Because nucleic acids, such as DNA and RNA, are unbranched polymers, this specification is equivalent to specifying the sequence of...
.
History
MMPs were described initially by Jerome Gross and Charles Lapiere (1962), who observed enzymatic activity (collagenCollagen
Collagen is a group of naturally occurring proteins found in animals, especially in the flesh and connective tissues of mammals. It is the main component of connective tissue, and is the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content...
triple helix
Triple helix
In geometry, a triple helix is a set of three congruent geometrical helices with the same axis, differing by a translation along the axis. Structures in the form of a triple helix include:* collagen helix...
degradation) during tadpole tail metamorphosis (by placing a tadpole tail in a collagen matrix plate). Therefore, the enzyme was named interstitial collagenase (MMP-1
MMP1
Interstitial collagenase also known as matrix metalloproteinase-1 and fibroblast collagenase is an enzyme that in humans is encoded by the MMP1 gene.- Function :...
).
Later, it was purified from human skin (1968), and was recognized to be synthesized as a zymogen
Zymogen
A zymogen is an inactive enzyme precursor. A zymogen requires a biochemical change for it to become an active enzyme. The biochemical change usually occurs in a lysosome where a specific part of the precursor enzyme is cleaved in order to activate it...
.
The "cysteine switch" was described in 1990.
Structure
The MMPs have a common domain structureProtein structure
Proteins are an important class of biological macromolecules present in all organisms. Proteins are polymers of amino acids. Classified by their physical size, proteins are nanoparticles . Each protein polymer – also known as a polypeptide – consists of a sequence formed from 20 possible L-α-amino...
. The three common domains are the pro-peptide, the catalytic domain, and the haemopexin
Haemopexin
Hemopexin , also known as beta-1B-glycoprotein is a protein that in humans is encoded by the HPX gene and belongs to hemopexin family of proteins.- Function :...
-like C-terminal domain, which is linked to the catalytic domain by a flexible hinge region.
The pro-peptide
The MMPs are initially synthesized as inactive zymogens with a pro-peptide domain that must be removed before the enzymeEnzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
is active. The pro-peptide domain is part of the “cysteine switch.” This contains a conserved cysteine
Cysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...
residue that interacts with the zinc
Zinc
Zinc , or spelter , is a metallic chemical element; it has the symbol Zn and atomic number 30. It is the first element in group 12 of the periodic table. Zinc is, in some respects, chemically similar to magnesium, because its ion is of similar size and its only common oxidation state is +2...
in the active site
Active site
In biology the active site is part of an enzyme where substrates bind and undergo a chemical reaction. The majority of enzymes are proteins but RNA enzymes called ribozymes also exist. The active site of an enzyme is usually found in a cleft or pocket that is lined by amino acid residues that...
and prevents binding and cleavage of the substrate
Substrate (biochemistry)
In biochemistry, a substrate is a molecule upon which an enzyme acts. Enzymes catalyze chemical reactions involving the substrate. In the case of a single substrate, the substrate binds with the enzyme active site, and an enzyme-substrate complex is formed. The substrate is transformed into one or...
, keeping the enzyme in an inactive form. In the majority of the MMPs, the cysteine
Cysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...
residue is in the conserved sequence
Conserved sequence
In biology, conserved sequences are similar or identical sequences that occur within nucleic acid sequences , protein sequences, protein structures or polymeric carbohydrates across species or within different molecules produced by the same organism...
PRCGxPD. Some MMPs have a prohormone convertase cleavage site (Furin-like) as part of this domain, which, when cleaved, activates the enzyme. MMP-23A and MMP-23B include a transmembrane
Transmembrane protein
A transmembrane protein is a protein that goes from one side of a membrane through to the other side of the membrane. Many TPs function as gateways or "loading docks" to deny or permit the transport of specific substances across the biological membrane, to get into the cell, or out of the cell as...
segment in this domain.
The catalytic domain
X-ray crystallographicX-ray crystallography
X-ray crystallography is a method of determining the arrangement of atoms within a crystal, in which a beam of X-rays strikes a crystal and causes the beam of light to spread into many specific directions. From the angles and intensities of these diffracted beams, a crystallographer can produce a...
structures of several MMP catalytic domains have shown that this domain is an oblate sphere measuring 35 x 30 x 30 Å
Ångström
The angstrom or ångström, is a unit of length equal to 1/10,000,000,000 of a meter . Its symbol is the Swedish letter Å....
(3.5 x 3 x 3 nm). The active site
Active site
In biology the active site is part of an enzyme where substrates bind and undergo a chemical reaction. The majority of enzymes are proteins but RNA enzymes called ribozymes also exist. The active site of an enzyme is usually found in a cleft or pocket that is lined by amino acid residues that...
is a 20 Å (2 nm) groove that runs across the catalytic domain. In the part of the catalytic domain forming the active site
Active site
In biology the active site is part of an enzyme where substrates bind and undergo a chemical reaction. The majority of enzymes are proteins but RNA enzymes called ribozymes also exist. The active site of an enzyme is usually found in a cleft or pocket that is lined by amino acid residues that...
there is a catalytically important Zn
Zinc
Zinc , or spelter , is a metallic chemical element; it has the symbol Zn and atomic number 30. It is the first element in group 12 of the periodic table. Zinc is, in some respects, chemically similar to magnesium, because its ion is of similar size and its only common oxidation state is +2...
2+ ion, which is bound by three histidine
Histidine
Histidine Histidine, an essential amino acid, has a positively charged imidazole functional group. It is one of the 22 proteinogenic amino acids. Its codons are CAU and CAC. Histidine was first isolated by German physician Albrecht Kossel in 1896. Histidine is an essential amino acid in humans...
residues found in the conserved sequence HExxHxxGxxH. Hence, this sequence is a zinc-binding motif.
The gelatinases, such as MMP-2
MMP2
72 kDa type IV collagenase also known as matrix metalloproteinase-2 and gelatinase A is an enzyme that in humans is encoded by the MMP2 gene....
, incorporate Fibronectin
Fibronectin
Fibronectin is a high-molecular weight glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. In addition to integrins, fibronectin also binds extracellular matrix components such as collagen, fibrin and heparan sulfate proteoglycans...
type II modules inserted immediately before in the zinc
Zinc
Zinc , or spelter , is a metallic chemical element; it has the symbol Zn and atomic number 30. It is the first element in group 12 of the periodic table. Zinc is, in some respects, chemically similar to magnesium, because its ion is of similar size and its only common oxidation state is +2...
-binding motif in the catalytic domain.
The hinge region
The catalytic domain is connected to the C-terminal domain by a flexible hinge or linker region. This is up to 75 amino acidAmino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s long, and has no determinable structure.
The haemopexin-like C-terminal domain
The C-terminal domain has structural similarities to the serumBlood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
haemopexin
Haemopexin
Hemopexin , also known as beta-1B-glycoprotein is a protein that in humans is encoded by the HPX gene and belongs to hemopexin family of proteins.- Function :...
. It has a four-bladed β-propeller structure. β-Propeller structures provide a large flat surface that is thought to be involved in protein-protein interactions. This determines substrate specificity and is the site for interaction with TIMP’s (tissue inhibitor of metalloproteinases
Tissue inhibitor of metalloproteinases
The matrix metalloproteinases are inhibited by specific endogenous tissue inhibitors of metalloproteinases , which comprise a family of four protease inhibitors: TIMP1, TIMP2, TIMP3 and TIMP4....
). The haemopexin-like domain is absent in MMP-7, MMP-23, MMP-26, and the plant
Plant
Plants are living organisms belonging to the kingdom Plantae. Precise definitions of the kingdom vary, but as the term is used here, plants include familiar organisms such as trees, flowers, herbs, bushes, grasses, vines, ferns, mosses, and green algae. The group is also called green plants or...
and nematode
Nematode
The nematodes or roundworms are the most diverse phylum of pseudocoelomates, and one of the most diverse of all animals. Nematode species are very difficult to distinguish; over 28,000 have been described, of which over 16,000 are parasitic. It has been estimated that the total number of nematode...
. MT-MMPs are anchored to the plasma membrane via a transmembrane or a GPI-anchoring domain.
Catalytic mechanism
There are three catalytic mechanisms published.- In the first mechanism, Browner M.F. and colleagues proposed the base-catalysis mechanism, carried out by the conserved glutamate residue and the Zn2+ZincZinc , or spelter , is a metallic chemical element; it has the symbol Zn and atomic number 30. It is the first element in group 12 of the periodic table. Zinc is, in some respects, chemically similar to magnesium, because its ion is of similar size and its only common oxidation state is +2...
ion.
- In the second mechanism, the Matthews-mechanism, Kester and Matthews suggested an interaction between a water molecule and the Zn2+ZincZinc , or spelter , is a metallic chemical element; it has the symbol Zn and atomic number 30. It is the first element in group 12 of the periodic table. Zinc is, in some respects, chemically similar to magnesium, because its ion is of similar size and its only common oxidation state is +2...
ion during the acid-base catalysisAcid catalysisIn acid catalysis and base catalysis a chemical reaction is catalyzed by an acid or a base. The acid is often the proton and the base is often a hydroxyl ion. Typical reactions catalyzed by proton transfer are esterfications and aldol reactions. In these reactions the conjugate acid of the carbonyl...
.
- In the third mechanism, the Manzetti-mechanism, Manzetti Sergio and colleagues provided evidence that a coordination between water and zinc during catalysis was unlikely, and suggested a third mechanism wherein a histidine from the HExxHxxGxxH-motif participates in catalysis by allowing the Zn2+ZincZinc , or spelter , is a metallic chemical element; it has the symbol Zn and atomic number 30. It is the first element in group 12 of the periodic table. Zinc is, in some respects, chemically similar to magnesium, because its ion is of similar size and its only common oxidation state is +2...
ion to assume a quasi-penta coordinated state, via its dissociation from it. In this state, the Zn2+ZincZinc , or spelter , is a metallic chemical element; it has the symbol Zn and atomic number 30. It is the first element in group 12 of the periodic table. Zinc is, in some respects, chemically similar to magnesium, because its ion is of similar size and its only common oxidation state is +2...
ion is coordinated with the two oxygen atoms from the catalytic glutamic acid, the substrate's carbonyl oxygen atom, and the two histidine residues, and can polarize the glutamic acid's oxygen atom, proximate the scissile bond, and induce it to act as reversible electron donor. This forms an oxyanion transition state. At this stage, a water molecule acts on the dissociated scissile bond and completes the hydrolyzation of the substrate.
Classification
Evolutionary
Use of bioinformaticBioinformatics
Bioinformatics is the application of computer science and information technology to the field of biology and medicine. Bioinformatics deals with algorithms, databases and information systems, web technologies, artificial intelligence and soft computing, information and computation theory, software...
methods to compare the primary sequences of the MMPs suggest the following evolution
Evolution
Evolution is any change across successive generations in the heritable characteristics of biological populations. Evolutionary processes give rise to diversity at every level of biological organisation, including species, individual organisms and molecules such as DNA and proteins.Life on Earth...
ary groupings of the MMPs:
- MMP-19
- MMPs 11, 14MMP14Matrix metalloproteinase-14 is an enzyme that in humans is encoded by the MMP14 gene.Proteins of the matrix metalloproteinase family are involved in the breakdown of extracellular matrix in normal physiological processes, such as embryonic development, reproduction, and tissue remodeling, as well...
, 15, 16, and 17 - MMP-2MMP272 kDa type IV collagenase also known as matrix metalloproteinase-2 and gelatinase A is an enzyme that in humans is encoded by the MMP2 gene....
and MMP-9MMP9Matrix metallopeptidase 9 , also known as 92 kDa type IV collagenase, 92 kDa gelatinase or gelatinase B , is an enzyme that in humans is encoded by the MMP9 gene.- Function :... - All the other MMPs
Analysis of the catalytic domains in isolation suggests that the catalytic domains evolved further once the major groups had differentiated, as is also indicated by the substrate specificities of the enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s.
Functional
The most commonly used groupings (by researchers in MMP biology) are based partly on historical assessment of the substrate specificity of the MMP and partly on the cellular localization of the MMP. These groups are the collagenases, the gelatinases, the stromelysins, and the membrane-type MMPs (MT-MMPs).- The collagenases are capable of degrading triple-helical fibrillar collagenCollagenCollagen is a group of naturally occurring proteins found in animals, especially in the flesh and connective tissues of mammals. It is the main component of connective tissue, and is the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content...
s into distinctive 3/4 and 1/4 fragments. These collagenCollagenCollagen is a group of naturally occurring proteins found in animals, especially in the flesh and connective tissues of mammals. It is the main component of connective tissue, and is the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content...
s are the major components of boneBoneBones are rigid organs that constitute part of the endoskeleton of vertebrates. They support, and protect the various organs of the body, produce red and white blood cells and store minerals. Bone tissue is a type of dense connective tissue...
, cartilageCartilageCartilage is a flexible connective tissue found in many areas in the bodies of humans and other animals, including the joints between bones, the rib cage, the ear, the nose, the elbow, the knee, the ankle, the bronchial tubes and the intervertebral discs...
and dentinDentinDentine is a calcified tissue of the body, and along with enamel, cementum, and pulp is one of the four major components of teeth. Usually, it is covered by enamel on the crown and cementum on the root and surrounds the entire pulp...
, and MMPs are the only known mammalMammalMammals are members of a class of air-breathing vertebrate animals characterised by the possession of endothermy, hair, three middle ear bones, and mammary glands functional in mothers with young...
ian enzymeEnzymeEnzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s capable of degrading them. The collagenases are #1, #8, #13, and #18. In addition, #14 has also been shown to cleave fibrillar collagenCollagenCollagen is a group of naturally occurring proteins found in animals, especially in the flesh and connective tissues of mammals. It is the main component of connective tissue, and is the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content...
, and there is evidence that #2 is capable of collagenolysis. In MeSHMedical Subject HeadingsMedical Subject Headings is a comprehensive controlled vocabulary for the purpose of indexing journal articles and books in the life sciences; it can also serve as a thesaurus that facilitates searching...
, the current list of collegenases includes #1, #2, #8, #9, and #13. Collegenase #14 is present in MeSH but not listed as a collegenase, while #18 is absent from MeSH.
- The main substrates of the gelatinaseGelatinaseIn biology and chemistry, gelatinase is a proteolytic enzyme that allows a living organism to hydrolyse gelatin into its sub-compounds that can cross the cell membrane and be used by the organism...
s are type IV collagenCollagenCollagen is a group of naturally occurring proteins found in animals, especially in the flesh and connective tissues of mammals. It is the main component of connective tissue, and is the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content...
and gelatinGelatinGelatin is a translucent, colorless, brittle , flavorless solid substance, derived from the collagen inside animals' skin and bones. It is commonly used as a gelling agent in food, pharmaceuticals, photography, and cosmetic manufacturing. Substances containing gelatin or functioning in a similar...
, and these enzymes are distinguished by the presence of an additional domain inserted into the catalytic domain. This gelatin-binding region is positioned immediately before the zinc-binding motif, and forms a separate folding unit that does not disrupt the structure of the catalytic domain. The gelatinases are #2 and #9.
- The stromelysins display a broad ability to cleave extracellular matrixExtracellular matrixIn biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...
proteinProteinProteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s but are unable to cleave the triple-helical fibrillar collagenCollagenCollagen is a group of naturally occurring proteins found in animals, especially in the flesh and connective tissues of mammals. It is the main component of connective tissue, and is the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content...
s. The three canonical members of this group are #3, #10, and #11.
- All six membrane-type MMPs (#14MMP14Matrix metalloproteinase-14 is an enzyme that in humans is encoded by the MMP14 gene.Proteins of the matrix metalloproteinase family are involved in the breakdown of extracellular matrix in normal physiological processes, such as embryonic development, reproduction, and tissue remodeling, as well...
, #15, #16, #17, #24, and #25) have a furinFurinFurin is a protein that in humans is encoded by the FURIN gene. It was named furin because it was in the upstream region of an oncogene known as FES. The gene was known as FUR and therefore the protein was named furin...
cleavage site in the pro-peptide, which is a feature also shared by #11.
However, it is becoming increasingly clear that these divisions are somewhat artificial as there are a number of MMPs that do not fit into any of the traditional groups.
Genes
| Gene | Name | Location | Description >- | MMP1 MMP1 Interstitial collagenase also known as matrix metalloproteinase-1 and fibroblast collagenase is an enzyme that in humans is encoded by the MMP1 gene.- Function :... |
Interstitial collagenase | secreted | >- | Gelatinase-A, 72 kDa gelatinase | secreted | >- | Stromelysin 1 | secreted | >- | Matrilysin, PUMP 1 | secreted | >- | Neutrophil collagenase | secreted | >- | Gelatinase-B, 92 kDa gelatinase | secreted | >- | Stromelysin 2 | secreted | >- | Stromelysin 3 | secreted | >- | Macrophage metalloelastase | secreted | >- | Collagenase 3 | secreted | >- | MT1-MMP | membrane-associated | >- | MT2-MMP | membrane-associated | >- | MT3-MMP | membrane-associated | >- | MT4-MMP | membrane-associated | >- | Collagenase 4, xcol4, xenopus Xenopus Xenopus is a genus of highly aquatic frogs native to Sub-Saharan Africa. There are 19 species in the Xenopus genus... collagenase |
- | >- | RASI-1, occasionally referred to as stromelysin-4 | - | >- | Enamelysin | secreted | >- | X-MMP | secreted | >- | CA-MMP | membrane-associated | >- | - | membrane-associated | >- | MT5-MMP | membrane-associated | >- | MT6-MMP | membrane-associated | >- | Matrilysin-2, endometase | - | >- | MMP-22, C-MMP | - | >- | Epilysin | secreted | Discovered in 2001 and given its name due to have been discovered in human keratinocyte Keratinocyte Keratinocytes are the predominant cell type in the epidermis, the outermost layer of the human skin, constituting 95% of the cells found there. Those keratinocytes found in the basal layer of the skin are sometimes referred to as "basal cells" or "basal keratinocytes"... s. Unlike other MMPs this enzyme is constitutivley expressed in many tissues (Highly expressed in testis and at lower levels in lung Lung The lung is the essential respiration organ in many air-breathing animals, including most tetrapods, a few fish and a few snails. In mammals and the more complex life forms, the two lungs are located near the backbone on either side of the heart... , heart Heart The heart is a myogenic muscular organ found in all animals with a circulatory system , that is responsible for pumping blood throughout the blood vessels by repeated, rhythmic contractions... , brain Brain The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,... , colon Colon (anatomy) The colon is the last part of the digestive system in most vertebrates; it extracts water and salt from solid wastes before they are eliminated from the body, and is the site in which flora-aided fermentation of unabsorbed material occurs. Unlike the small intestine, the colon does not play a... , intestine Intestine In human anatomy, the intestine is the segment of the alimentary canal extending from the pyloric sphincter of the stomach to the anus and, in humans and other mammals, consists of two segments, the small intestine and the large intestine... , placenta Placenta The placenta is an organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. "True" placentas are a defining characteristic of eutherian or "placental" mammals, but are also found in some snakes and... , salivary gland Salivary gland The salivary glands in mammals are exocrine glands, glands with ducts, that produce saliva. They also secrete amylase, an enzyme that breaks down starch into maltose... s, uterus Uterus The uterus or womb is a major female hormone-responsive reproductive sex organ of most mammals including humans. One end, the cervix, opens into the vagina, while the other is connected to one or both fallopian tubes, depending on the species... , skin Skin -Dermis:The dermis is the layer of skin beneath the epidermis that consists of connective tissue and cushions the body from stress and strain. The dermis is tightly connected to the epidermis by a basement membrane. It also harbors many Mechanoreceptors that provide the sense of touch and heat... ). A threonine replaces proline in its cysteine switch (PRCGVTD). |
Matrix metalloproteinases combines with the metal binding protein, metallothionine; thus helping in metal binding mechanism.
Function
The MMPs play an important role in tissue remodeling associated with various physiological and pathological processes such as morphogenesisMorphogenesis
Morphogenesis , is the biological process that causes an organism to develop its shape...
, angiogenesis
Angiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...
, tissue repair, cirrhosis
Cirrhosis
Cirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrosis, scar tissue and regenerative nodules , leading to loss of liver function...
, arthritis
Arthritis
Arthritis is a form of joint disorder that involves inflammation of one or more joints....
, and metastasis
Metastasis
Metastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...
. MMP-2
MMP2
72 kDa type IV collagenase also known as matrix metalloproteinase-2 and gelatinase A is an enzyme that in humans is encoded by the MMP2 gene....
and MMP-9
MMP9
Matrix metallopeptidase 9 , also known as 92 kDa type IV collagenase, 92 kDa gelatinase or gelatinase B , is an enzyme that in humans is encoded by the MMP9 gene.- Function :...
are thought to be important in metastasis. MMP-1
MMP1
Interstitial collagenase also known as matrix metalloproteinase-1 and fibroblast collagenase is an enzyme that in humans is encoded by the MMP1 gene.- Function :...
is thought to be important in rheumatoid and osteo-arthritis. Recent data suggests active role of MMPs in the pathogenesis of Aortic Aneurysm. Excess MMPs degrade the structural proteins of the aortic wall.
Activation
Inhibitors
The MMPs are inhibited by specific endogenous tissue inhibitor of metalloproteinasesTissue inhibitor of metalloproteinases
The matrix metalloproteinases are inhibited by specific endogenous tissue inhibitors of metalloproteinases , which comprise a family of four protease inhibitors: TIMP1, TIMP2, TIMP3 and TIMP4....
(TIMPs), which comprise a family of four protease inhibitor
Protease inhibitor
Protease inhibitor can refer to:* Protease inhibitor : a class of medication that inhibits viral protease* Protease inhibitor : molecules that inhibit proteases...
s: TIMP-1, TIMP-2, TIMP-3, and TIMP-4.
Synthetic inhibitors generally contain a chelating group
Chelation
Chelation is the formation or presence of two or more separate coordinate bonds between apolydentate ligand and a single central atom....
that binds the catalytic zinc
Zinc
Zinc , or spelter , is a metallic chemical element; it has the symbol Zn and atomic number 30. It is the first element in group 12 of the periodic table. Zinc is, in some respects, chemically similar to magnesium, because its ion is of similar size and its only common oxidation state is +2...
atom at the MMP active site
Active site
In biology the active site is part of an enzyme where substrates bind and undergo a chemical reaction. The majority of enzymes are proteins but RNA enzymes called ribozymes also exist. The active site of an enzyme is usually found in a cleft or pocket that is lined by amino acid residues that...
tightly. Common chelating groups include hydroxamates, carboxylates
Carboxylic acid
Carboxylic acids are organic acids characterized by the presence of at least one carboxyl group. The general formula of a carboxylic acid is R-COOH, where R is some monovalent functional group...
, thiol
Thiol
In organic chemistry, a thiol is an organosulfur compound that contains a carbon-bonded sulfhydryl group...
s, and phosphinyls. Hydroxymates are particularly potent inhibitors of MMPs and other zinc-dependent enzymes, due to their bidentate chelation
Chelation
Chelation is the formation or presence of two or more separate coordinate bonds between apolydentate ligand and a single central atom....
of the zinc atom. Other substitutents of these inhibitors are usually designed to interact with various binding pockets on the MMP of interest, making the inhibitor more or less specific for given MMPs.
Pharmacology
DoxycyclineDoxycycline
Doxycycline INN is a member of the tetracycline antibiotics group, and is commonly used to treat a variety of infections. Doxycycline is a semisynthetic tetracycline invented and clinically developed in the early 1960s by Pfizer Inc. and marketed under the brand name Vibramycin. Vibramycin...
, at subantimicrobial doses, inhibits MMP activity, and has been used in various experimental systems for this purpose, such as for recalcitrant recurrent corneal erosions. It is used clinically for the treatment of periodontal disease
Periodontal disease
Periodontitis is a set of inflammatory diseases affecting the periodontium, i.e., the tissues that surround and support the teeth. Periodontitis involves progressive loss of the alveolar bone around the teeth, and if left untreated, can lead to the loosening and subsequent loss of teeth...
and is the only MMP inhibitor that is widely available clinically. It is sold under the trade name Periostat by the company CollaGenex. Minocycline, another tetracycline antibiotic, has also been shown to inhibit MMP activity.
A number of rationally designed MMP inhibitors have shown some promise in the treatment of pathologies that MMPs are suspected to be involved in (see above). However, most of these, such as marimastat
Marimastat
Marimastat was a proposed antineoplastic drug developed by British Biotech. It acted as a broad-spectrum matrix metalloproteinase inhibitor.Marimastat performed poorly in clinical trials, and development was terminated....
(BB-2516), a broad-spectrum MMP inhibitor, and cipemastat
Cipemastat
Cipemastat is a selective inhibitor of matrix metalloproteinase-1 that has been investigated as an anti-arthritis agent. It is being developed by Roche....
(Ro 32-3555), an MMP-1
MMP1
Interstitial collagenase also known as matrix metalloproteinase-1 and fibroblast collagenase is an enzyme that in humans is encoded by the MMP1 gene.- Function :...
selective inhibitor, have performed poorly in clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s. The failure of Marimastat was partially responsible for the folding of British Biotech
British Biotech
British Biotech was a British based biotech company.British Biotechnology Limited was founded in 1986 by former G D Searle managers Keith McCullagh and Brian Richards,...
, which developed it. The failure of these drugs has been due largely to toxicity (in particular, musculo-skeletal toxicity in the case of broad spectrum inhibitors) and failure to show expected results (in the case of trocade, promising results in rabbit arthritis models were not replicated in human trials). The reasons behind the largely disappointing clinical results of MMP inhibitors is unclear, especially in light of their activity in animal model
Animal model
An animal model is a living, non-human animal used during the research and investigation of human disease, for the purpose of better understanding the disease without the added risk of causing harm to an actual human being during the process...
s.