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Matrix metalloproteinases (MMPs), also known as matrix metallopeptidases or matrixins, are
metalloproteinase A metalloproteinase, or metalloprotease, is any protease enzyme whose catalytic mechanism involves a metal. An example is ADAM12 which plays a significant role in the fusion of muscle cells during embryo development, in a process known as myogen ...
s that are
calcium Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to ...
-dependent
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 ...
-containing
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 re ...
s; other family members are adamalysins,
serralysin Serralysin (, ''Pseudomonas aeruginosa alkaline proteinase'', ''Escherichia freundii proteinase'', ''Serratia marcescens extracellular proteinase'', ''Serratia marcescens metalloproteinase'', ''Pseudomonas aeruginosa alk. protease'', ''Serratia mar ...
s, and
astacin Astacins are a family of multidomain metalloendopeptidases which are either secreted or membrane-anchored. These metallopeptidases belong to the MEROPS peptidase family M12, subfamily M12A (astacin family, clan MA(M)). The protein fold of the pep ...
s. The MMPs belong to a larger family of
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 ...
s known as the metzincin superfamily.Matrix Metalloproteinases: Its implications in cardiovascular disorders
/ref> Collectively, these enzymes are capable of degrading all kinds of
extracellular matrix In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide stru ...
proteins, but also can process a number of bioactive molecules. They are known to be involved in the cleavage of cell surface
receptor Receptor may refer to: * Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...
s, the release of
apoptotic Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes includ ...
ligands (such as the FAS ligand), and
chemokine Chemokines (), or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In additio ...
/
cytokine Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
inactivation. MMPs are also thought to play a major role in cell behaviors such as
cell proliferation Cell proliferation is the process by which ''a cell grows and divides to produce two daughter cells''. Cell proliferation leads to an exponential increase in cell number and is therefore a rapid mechanism of tissue growth. Cell proliferation re ...
,
migration Migration, migratory, or migrate may refer to: Human migration * Human migration, physical movement by humans from one region to another ** International migration, when peoples cross state boundaries and stay in the host state for some minimum le ...
(
adhesion Adhesion is the tendency of dissimilar particles or surfaces to cling to one another ( cohesion refers to the tendency of similar or identical particles/surfaces to cling to one another). The forces that cause adhesion and cohesion can be ...
/dispersion), differentiation,
angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...
,
apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
, and
host defense The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinters, ...
. They were first described in
vertebrates Vertebrates () comprise all animal taxa within the subphylum Vertebrata () ( chordates with backbones), including all mammals, birds, reptiles, amphibians, and fish. Vertebrates represent the overwhelming majority of the phylum Chordata, ...
(1962), including humans, but have since been found in
invertebrates Invertebrates are a paraphyletic group of animals that neither possess nor develop a vertebral column (commonly known as a ''backbone'' or ''spine''), derived from the notochord. This is a grouping including all animals apart from the chordate ...
and plants. They are distinguished from other endopeptidases by their dependence on
metal ion A metal (from ancient Greek, Greek μέταλλον ''métallon'', "mine, quarry, metal") is a material that, when freshly prepared, polished, or fractured, shows a lustrous appearance, and conducts electrical resistivity and conductivity, e ...
s as
cofactors Cofactor may also refer to: * Cofactor (biochemistry), a substance that needs to be present in addition to an enzyme for a certain reaction to be catalysed * A domain parameter in elliptic curve cryptography, defined as the ratio between the order ...
, their ability to degrade extracellular matrix, and their specific evolutionary
DNA sequence DNA sequencing is the process of determining the nucleic acid sequence – the order of nucleotides in DNA. It includes any method or technology that is used to determine the order of the four bases: adenine, guanine, cytosine, and thymine. Th ...
.


History

MMPs were described initially by
Jerome Gross Jerome Gross (February 25, 1917 - January 27, 2014) was an American biologist and member of the National Academy of Sciences. His research at Harvard Medical School and the Massachusetts General Hospital in the 1950s helped launch the fields of co ...
and
Charles Lapiere Charles is a masculine given name predominantly found in English and French speaking countries. It is from the French form ''Charles'' of the Proto-Germanic name (in runic alphabet) or ''*karilaz'' (in Latin alphabet), whose meaning was " ...
(1962), who observed enzymatic activity (
collagen Collagen () is the main structural protein in the extracellular matrix found in the body's various connective tissues. As the main component of connective tissue, it is the most abundant protein in mammals, making up from 25% to 35% of the whole ...
triple helix In the fields of geometry and biochemistry, a triple helix (plural triple helices) is a set of three congruent geometrical helices with the same axis, differing by a translation along the axis. This means that each of the helices keeps the same d ...
degradation) during tadpole tail metamorphosis (by placing a tadpole tail in a collagen matrix plate). Therefore, the enzyme was named interstitial
collagenase Collagenases are enzymes that break the peptide bonds in collagen. They assist in destroying extracellular structures in the pathogenesis of bacteria such as ''Clostridium''. They are considered a virulence factor, facilitating the spread of ...
(
MMP-1 Interstitial collagenase, also known as fibroblast collagenase, and matrix metalloproteinase-1 (MMP-1) is an enzyme that in humans is encoded by the ''MMP1'' gene. The gene is part of a cluster of MMP genes which localize to chromosome 11q22.3. ...
). Later, it was purified from human skin (1968), and was recognized to be synthesized as a
zymogen In biochemistry, a zymogen (), also called a proenzyme (), is an inactive precursor of an enzyme. A zymogen requires a biochemical change (such as a hydrolysis reaction revealing the active site, or changing the configuration to reveal the active ...
. The "cysteine switch" was described in 1990.


Structure

The MMPs have a common domain
structure A structure is an arrangement and organization of interrelated elements in a material object or system, or the object or system so organized. Material structures include man-made objects such as buildings and machines and natural objects such as ...
. The three common domains are the pro-peptide, the
catalytic domain In biology and biochemistry, the active site is the region of an enzyme where substrate molecules bind and undergo a chemical reaction. The active site consists of amino acid residues that form temporary bonds with the substrate (binding site) a ...
, and the haemopexin-like
C-terminal The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
domain, which is linked to the catalytic domain by a flexible hinge region.


The pro-peptide

The MMPs are initially synthesized as inactive
zymogens In biochemistry, a zymogen (), also called a proenzyme (), is an inactive precursor of an enzyme. A zymogen requires a biochemical change (such as a hydrolysis reaction revealing the active site, or changing the configuration to reveal the active ...
with a pro-peptide domain that must be removed before 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. A ...
is active. The pro-peptide domain is part of the "cysteine switch." This contains a conserved
cysteine Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile. When present as a deprotonated catalytic residue, sometime ...
residue that interacts with the
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 ...
in the
active site In biology and biochemistry, the active site is the region of an enzyme where substrate molecules bind and undergo a chemical reaction. The active site consists of amino acid residues that form temporary bonds with the substrate (binding site) a ...
and prevents binding and cleavage of the substrate, keeping the enzyme in an inactive form. In the majority of the MMPs, the
cysteine Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile. When present as a deprotonated catalytic residue, sometime ...
residue is in the
conserved sequence In evolutionary biology, conserved sequences are identical or similar sequences in nucleic acids ( DNA and RNA) or proteins across species ( orthologous sequences), or within a genome ( paralogous sequences), or between donor and receptor taxa ...
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 A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequentl ...
segment in this domain.


The catalytic domain

X-ray crystallographic structures of several MMP catalytic domains have shown that this domain is an oblate sphere measuring 35 x 30 x 30 Å (3.5 × 3 x 3 nm). The
active site In biology and biochemistry, the active site is the region of an enzyme where substrate molecules bind and undergo a chemical reaction. The active site consists of amino acid residues that form temporary bonds with the substrate (binding site) a ...
is a 20 Å (2 nm) groove that runs across the catalytic domain. In the part of the catalytic domain forming the
active site In biology and biochemistry, the active site is the region of an enzyme where substrate molecules bind and undergo a chemical reaction. The active site consists of amino acid residues that form temporary bonds with the substrate (binding site) a ...
there is a catalytically important Zn2+ ion, which is bound by three
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 de ...
residues found in the conserved sequence HExxHxxGxxH. Hence, this sequence is a zinc-binding motif. The
gelatinase Gelatinases are enzymes capable of degrading gelatin. Gelatinases are expressed in several bacteria including ''Pseudomonas aeruginosa'' and ''Serratia marcescens''. In humans, the gelatinases are matrix metalloproteinases MMP2 and MMP9 Matrix ...
s, such as
MMP-2 72 kDa type IV collagenase also known as matrix metalloproteinase-2 (MMP-2) and gelatinase A is an enzyme that in humans is encoded by the ''MMP2'' gene. The ''MMP2'' gene is located on chromosome 16 at position 12.2. Function Proteins of the ...
, incorporate
Fibronectin Fibronectin is a high- molecular weight (~500-~600 kDa) glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. Fibronectin also binds to other extracellular matrix proteins such as collage ...
type II modules inserted immediately before in the
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 ...
-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 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 am ...
s long, and has no determinable structure.


The hemopexin-like C-terminal domain

The C-terminal domain has structural similarities to the serum
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, respo ...
hemopexin Hemopexin (or haemopexin; Hpx; Hx), also known as beta-1B-glycoprotein, is a glycoprotein that in humans is encoded by the ''HPX'' gene and belongs to the hemopexin family of proteins. Hemopexin is the plasma protein with the highest binding affi ...
. 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 inhibitors of metalloproteinases (TIMPs) are specific endogenous protease inhibitors to the matrix metalloproteinases. There are four TIMPs; '' TIMP1'', ''TIMP2'', ''TIMP3'' and '' TIMP4''. TIMP3 has been observed progressively downregulated ...
). The hemopexin-like domain is absent in MMP-7, MMP-23, MMP-26, and the plant and
nematode The nematodes ( or grc-gre, Νηματώδη; la, Nematoda) or roundworms constitute the phylum Nematoda (also called Nemathelminthes), with plant-Parasitism, parasitic nematodes also known as eelworms. They are a diverse animal phylum inhab ...
. The membrane-bound MMPs (MT-MMPs) are anchored to the
plasma membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (t ...
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+ ion. * In the second mechanism, the Matthews-mechanism, Kester and Matthews suggested an interaction between a water molecule and the Zn2+ ion during the
acid-base catalysis In acid catalysis and base catalysis, a chemical reaction is catalyzed by an acid or a base. By Brønsted–Lowry acid–base theory, the acid is the proton (hydrogen ion, H+) donor and the base is the proton acceptor. Typical reactions catalyze ...
. *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 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 ...
by allowing the Zn2+ ion to assume a quasi-penta coordinated state, via its dissociation from it. In this state, the Zn2+ 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 In molecular biology, a scissile bond is a covalent chemical bond that can be broken by an enzyme. Examples would be the cleaved bond in the self-cleaving hammerhead ribozyme or the peptide bond In organic chemistry, a peptide bond is an amide ...
, 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

The MMPs can be subdivided in different ways.


Evolutionary

Use of
bioinformatic Bioinformatics () is an interdisciplinary field that develops methods and software tools for understanding biological data, in particular when the data sets are large and complex. As an interdisciplinary field of science, bioinformatics combine ...
methods to compare the primary sequences of the MMPs suggest the following
evolution Evolution is change in the heritable characteristics of biological populations over successive generations. These characteristics are the expressions of genes, which are passed on from parent to offspring during reproduction. Variation ...
ary groupings of the MMPs: * MMP-19 * MMPs 11, 14, 15, 16, and 17 *
MMP-2 72 kDa type IV collagenase also known as matrix metalloproteinase-2 (MMP-2) and gelatinase A is an enzyme that in humans is encoded by the ''MMP2'' gene. The ''MMP2'' gene is located on chromosome 16 at position 12.2. Function Proteins of the ...
and
MMP-9 Matrix metallopeptidase 9 (MMP-9), also known as 92 kDa type IV collagenase, 92 kDa gelatinase or gelatinase B (GELB), is a matrixin, a class of enzymes that belong to the zinc-metalloproteinases family involved in the degradation of the extracel ...
* 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 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. A ...
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
collagenase Collagenases are enzymes that break the peptide bonds in collagen. They assist in destroying extracellular structures in the pathogenesis of bacteria such as ''Clostridium''. They are considered a virulence factor, facilitating the spread of ...
s are capable of degrading triple-helical fibrillar
collagen Collagen () is the main structural protein in the extracellular matrix found in the body's various connective tissues. As the main component of connective tissue, it is the most abundant protein in mammals, making up from 25% to 35% of the whole ...
s into distinctive 3/4 and 1/4 fragments. These collagens are the major components of
bone A bone is a Stiffness, rigid Organ (biology), organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red blood cell, red and white blood cells, store minerals, provid ...
,
cartilage Cartilage is a resilient and smooth type of connective tissue. In tetrapods, it covers and protects the ends of long bones at the joints as articular cartilage, and is a structural component of many body parts including the rib cage, the neck an ...
and
dentin Dentin () (American English) or dentine ( or ) (British English) ( la, substantia eburnea) is a calcified tissue of the body and, along with enamel, cementum, and pulp, is one of the four major components of teeth. It is usually covered by ena ...
, and MMPs are the only known
mammal 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 or ...
ian
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. A ...
s capable of degrading them. The collagenases are No. 1, No. 8, No. 13, and No. 18. In addition, No. 14 has also been shown to cleave fibrillar
collagen Collagen () is the main structural protein in the extracellular matrix found in the body's various connective tissues. As the main component of connective tissue, it is the most abundant protein in mammals, making up from 25% to 35% of the whole ...
, and there is evidence that No. 2 is capable of collagenolysis. In
MeSH A mesh is a barrier made of connected strands of metal, fiber, or other flexible or ductile materials. A mesh is similar to a web or a net in that it has many attached or woven strands. Types * A plastic mesh may be extruded, oriented, ex ...
, the current list of collagenases includes No. 1, No. 2, No. 8, No. 9, and No. 13. Collagenase No. 14 is present in MeSH but not listed as a collagenase, while No. 18 is absent from MeSH. * The main substrates of the
gelatinase Gelatinases are enzymes capable of degrading gelatin. Gelatinases are expressed in several bacteria including ''Pseudomonas aeruginosa'' and ''Serratia marcescens''. In humans, the gelatinases are matrix metalloproteinases MMP2 and MMP9 Matrix ...
s are
type IV collagen Collagen IV (ColIV or Col4) is a type of collagen found primarily in the basal lamina. The collagen IV C4 domain at the C-terminus is not removed in post-translational processing, and the fibers link head-to-head, rather than in parallel. Also, ...
and
gelatin Gelatin or gelatine (from la, gelatus meaning "stiff" or "frozen") is a translucent, colorless, flavorless food ingredient, commonly derived from collagen taken from animal body parts. It is brittle when dry and rubbery when moist. It may also ...
, 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 No. 2 and No. 9. * The stromelysins display a broad ability to cleave
extracellular matrix In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide stru ...
proteins but are unable to cleave the triple-helical fibrillar collagens. The three canonical members of this group are No. 3, No. 10, and No. 11. * All six membrane-type MMPs ( No. 14, No. 15, No. 16, No. 17, No. 24, and No. 25) have a
furin Furin is a protease, a proteolytic enzyme that in humans and other animals is encoded by the ''FURIN'' gene. Some proteins are inactive when they are first synthesized, and must have sections removed in order to become active. Furin cleaves these s ...
cleavage site in the pro-peptide, which is a feature also shared by No. 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

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 Tissue remodeling is the reorganization or renovation of existing tissues. Tissue remodeling can be either physiological or pathological. The process can either change the characteristics of a tissue such as in blood vessel remodeling, or result in ...
associated with various physiological or pathological processes such as
morphogenesis Morphogenesis (from the Greek ''morphê'' shape and ''genesis'' creation, literally "the generation of form") is the biological process that causes a cell, tissue or organism to develop its shape. It is one of three fundamental aspects of devel ...
,
angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...
,
tissue repair Tissue engineering is a biomedical engineering discipline that uses a combination of cells, engineering, materials methods, and suitable biochemical and physicochemical factors to restore, maintain, improve, or replace different types of biologi ...
,
cirrhosis Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, and end-stage liver disease, is the impaired liver function caused by the formation of scar tissue known as fibrosis due to damage caused by liver disease. Damage causes tissue repai ...
,
arthritis Arthritis is a term often used to mean any disorder that affects joints. Symptoms generally include joint pain and stiffness. Other symptoms may include redness, warmth, swelling, and decreased range of motion of the affected joints. In som ...
, and
metastasis Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, ...
.
MMP-2 72 kDa type IV collagenase also known as matrix metalloproteinase-2 (MMP-2) and gelatinase A is an enzyme that in humans is encoded by the ''MMP2'' gene. The ''MMP2'' gene is located on chromosome 16 at position 12.2. Function Proteins of the ...
and
MMP-9 Matrix metallopeptidase 9 (MMP-9), also known as 92 kDa type IV collagenase, 92 kDa gelatinase or gelatinase B (GELB), is a matrixin, a class of enzymes that belong to the zinc-metalloproteinases family involved in the degradation of the extracel ...
are thought to be important in metastasis.
MMP-1 Interstitial collagenase, also known as fibroblast collagenase, and matrix metalloproteinase-1 (MMP-1) is an enzyme that in humans is encoded by the ''MMP1'' gene. The gene is part of a cluster of MMP genes which localize to chromosome 11q22.3. ...
is thought to be important in rheumatoid arthritis and osteoarthritis. Recent data suggests active role of MMPs in the pathogenesis of Aortic Aneurysm. Excess MMPs degrade the structural proteins of the aortic wall. Disregulation of the balance between MMPs and TIMPs is also a characteristic of acute and chronic cardiovascular diseases.


Activation

All MMPs are synthesized in the latent form (Zymogen). They are secreted as proenzymes and require extracellular activation. They can be activated in vitro by many mechanisms including organomercurials, chaotropic agents, and other proteases.


Inhibitors

The MMPs are inhibited by specific endogenous
tissue inhibitor of metalloproteinases Tissue inhibitors of metalloproteinases (TIMPs) are specific endogenous protease inhibitors to the matrix metalloproteinases. There are four TIMPs; '' TIMP1'', ''TIMP2'', ''TIMP3'' and '' TIMP4''. TIMP3 has been observed progressively downregulated ...
(TIMPs), which comprise a family of four protease inhibitors: TIMP-1, TIMP-2, TIMP-3, and TIMP-4. Synthetic inhibitors generally contain a chelating group that binds the catalytic
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 ...
atom at the MMP
active site In biology and biochemistry, the active site is the region of an enzyme where substrate molecules bind and undergo a chemical reaction. The active site consists of amino acid residues that form temporary bonds with the substrate (binding site) a ...
tightly. Common chelating groups include
hydroxamate A hydroxamic acid is a class of organic compounds bearing the functional group RC(O)N(OH)R', with R and R' as organic residues and CO as a carbonyl group. They are amides (RC(O)NHR') wherein the NH center has an OH substitution. They are often us ...
s,
carboxylates In organic chemistry, a carboxylate is the conjugate base of a carboxylic acid, (or ). It is an ion with negative charge. Carboxylate salts are salts that have the general formula , where M is a metal and ''n'' is 1, 2,...; ''carboxylat ...
,
thiol In organic chemistry, a thiol (; ), or thiol derivative, is any organosulfur compound of the form , where R represents an alkyl or other organic substituent. The functional group itself is referred to as either a thiol group or a sulfhydryl gro ...
s, and phosphinyls. Hydroxymates are particularly potent inhibitors of MMPs and other zinc-dependent enzymes, due to their bidentate
chelation 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 Denticity, polydentate (multiple bonded) ligand and a single central metal atom. These l ...
of the zinc atom. Other substituents 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

Doxycycline Doxycycline is a broad-spectrum tetracycline class antibiotic used in the treatment of infections caused by bacteria and certain parasites. It is used to treat bacterial pneumonia, acne, chlamydia infections, Lyme disease, cholera, typhus, an ...
, 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, also known as gum disease, is a set of inflammatory conditions affecting the tissues surrounding the teeth. In its early stage, called gingivitis, the gums become swollen and red and may bleed. It is considered the main caus ...
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 was a proposed antineoplastic drug developed by British Biotech. It acted as a broad-spectrum matrix metalloproteinase inhibitor A matrix metalloproteinase inhibitor (MMPI) inhibits matrix metalloproteinases. As they inhibit cell mi ...
(BB-2516), a broad-spectrum MMP inhibitor, and
cipemastat Cipemastat (rINN, also known as Ro 32-3555 and by the tentative trade name Trocade) is a selective inhibitor of matrix metalloproteinase-1 that has been investigated as an anti- arthritis agent. It is being developed by Roche F. Hoffmann-L ...
(Ro 32-3555), an
MMP-1 Interstitial collagenase, also known as fibroblast collagenase, and matrix metalloproteinase-1 (MMP-1) is an enzyme that in humans is encoded by the ''MMP1'' gene. The gene is part of a cluster of MMP genes which localize to chromosome 11q22.3. ...
selective inhibitor, have performed poorly in
clinical trial Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietar ...
s. The failure of Marimastat was partially responsible for the folding of
British Biotech British Biotech was a British-based biotechnology company founded as British Biotechnology Limited in 1986 by former G D Searle managers Keith McCullagh and Brian Richards. It was the first British biotech company to be publicly listed when it ...
, 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 An animal model (short for animal disease model) is a living, non-human, often genetic-engineered animal used during the research and investigation of human disease, for the purpose of better understanding the disease process without the risk of ha ...
s.


See also

* Proteases in angiogenesis *
Drug discovery and development of MMP inhibitors Metalloprotease inhibitors are cellular inhibitors of the Matrix metalloproteinases (MMPs). MMPs belong to a family of zinc-dependent neutral endopeptidases. These enzymes have the ability to break down connective tissue. The expression of MMPs i ...
* Collagen Hybridizing Peptide, a peptide that can bind and stain MMP cleaved collagen


References

Synergistic effect of stromelysin-1 (matrix metalloproteinase-3) promoter (-1171 5A->6A) polymorphism in oral submucous fibrosis and head and neck lesions.Chaudhary AK, Singh M, Bharti AC, Singh M, Shukla S, Singh AK, Mehrotra R. BMC Cancer. 2010 Jul 14;10:369.


External links


MBInfo – Matrix metalloproteinases (MMPs) facilitate extracellular matrix disassembly

The Matrix Metalloproteinase Protein



Currently identified substrates for mammalian MMPs at clip.ubc.ca
* {{DEFAULTSORT:Matrix Metalloproteinase * Metalloproteins Zinc enzymes