Matrix metalloproteinases (MMPs), also known asmatrix metallopeptidases ormatrixins, aremetalloproteinases that arecalcium-dependentzinc-containingendopeptidases;^[1] other family members areadamalysins,serralysins, andastacins. The MMPs belong to a larger family ofproteases known as themetzincin superfamily.^[2]

Collectively, these enzymes are capable of degrading all kinds ofextracellular matrix proteins, but also can process a number ofbioactive molecules. They are known to be involved in the cleavage of cell surfacereceptors, the release ofapoptotic ligands (such as theFAS ligand), andchemokine/cytokine inactivation.^[3] MMPs are also thought to play a major role in cell behaviors such ascell proliferation,migration (adhesion/dispersion),differentiation,angiogenesis,apoptosis, andhost defense.

They were first described invertebrates in 1962,^[4] including humans, but have since been found ininvertebrates and plants. They are distinguished from other endopeptidases by their dependence onmetal ions ascofactors, their ability to degrade extracellular matrix, and their specific evolutionaryDNA sequence.

MMPs were described initially byJerome Gross andCharles Lapiere in 1962, who observed enzymatic activity (collagentriple helix degradation) during tadpole tail metamorphosis (by placing a tadpole tail in a collagen matrix plate).^[5] Therefore, the enzyme was named interstitialcollagenase (MMP-1).

Later, it was purified from human skin (1968),^[6] and was recognized to be synthesized as azymogen.^[7]

The "cysteine switch" was described in 1990.^[8]

The MMPs have a common domainstructure. The three common domains are the pro-peptide, thecatalytic domain, and thehaemopexin-likeC-terminal domain, which is linked to the catalytic domain by a flexible hinge region.^[2]

The MMPs are initially synthesized as inactivezymogens with a pro-peptide domain that must be removed before theenzyme is active. The pro-peptide domain is part of the "cysteine switch." This contains a conservedcysteine residue that interacts with thezinc in theactive site and prevents binding and cleavage of thesubstrate, keeping the enzyme in an inactive form. In the majority of the MMPs, thecysteine residue is in theconserved sequence PRCGxPD. Some MMPs have a prohormone convertase cleavage site (Furin-like) as part of this domain, which, when cleaved, activates the enzyme. MMP-23A andMMP-23B include atransmembrane segment in this domain.^[9]

X-ray crystallographic structures of several MMP catalytic domains have shown that this domain is an oblate sphere measuring 35 x 30 x 30Å (3.5 × 3 x 3nm). Theactive site is a 20 Å (2 nm) groove that runs across the catalytic domain. In the part of the catalytic domain forming theactive site there is a catalytically importantZn²⁺ ion, which is bound by threehistidine residues found in the conserved sequence HExxHxxGxxH. Hence, this sequence is a zinc-binding motif.

Thegelatinases, such asMMP-2, incorporateFibronectin type II modules inserted immediately before in thezinc-binding motif in the catalytic domain.^[10]

The catalytic domain is connected to the C-terminal domain by a flexible hinge or linker region. This is up to 75amino acids long, and has no determinable structure.

The C-terminal domain has structural similarities to theserumproteinhemopexin. It has a four-bladed β-propeller structure. β-Propeller structures provide a large flat surface that is thought to be involved inprotein-protein interactions. This determines substrate specificity and is the site for interaction with TIMP's (tissue inhibitor of metalloproteinases). The hemopexin-like domain is absent inMMP-7, MMP-23, MMP-26, and the plant andnematode. The membrane-bound MMPs (MT-MMPs) are anchored to theplasma membrane via a transmembrane or a GPI-anchoring domain.

There are three catalytic mechanisms published.

• In the first mechanism, Browner M.F. and colleagues^[11] proposed the base-catalysis mechanism, carried out by the conserved glutamate residue and theZn²⁺ ion.
• In the second mechanism, the Matthews-mechanism, Kester and Matthews^[12] suggested an interaction between a water molecule and theZn²⁺ ion during theacid-base catalysis.
• In the third mechanism, the Manzetti-mechanism, Manzetti Sergio and colleagues^[13] 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 incatalysis by allowing theZn²⁺ ion to assume a quasi-penta coordinated state, via its dissociation from it. In this state, theZn²⁺ 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 thescissile bond, and induce it to act as reversible electron donor. This forms an oxyaniontransition state. At this stage, a water molecule acts on the dissociated scissile bond and completes the hydrolyzation of the substrate.

The MMPs can be subdivided in different ways.

Use ofbioinformatic methods to compare the primary sequences of the MMPs suggest the followingevolutionary groupings of the MMPs:

• MMP-19
• MMPs 11,14, 15, 16, and 17
• MMP-2 andMMP-9
• 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 thesubstrate specificities of theenzymes.

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 thecellular localization of the MMP. These groups are the collagenases, the gelatinases, the stromelysins, and the membrane-type MMPs (MT-MMPs).

• Thecollagenases are capable of degrading triple-helical fibrillarcollagens into distinctive 3/4 and 1/4 fragments. These collagens are the major components ofbone,cartilage anddentin, and MMPs are the only knownmammalianenzymes 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 fibrillarcollagen, and there is evidence that No. 2 is capable of collagenolysis. InMeSH, 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 thegelatinases aretype IV collagen andgelatin, 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 cleaveextracellular matrix 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 afurin 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.

Matrix metalloproteinases combines with the metal binding protein, metallothionine; thus helping in metal binding mechanism.

The MMPs play an important role intissue remodeling associated with various physiological or pathological processes such asmorphogenesis,angiogenesis,tissue repair,cirrhosis,arthritis, andmetastasis.MMP-2 andMMP-9 are thought to be important in metastasis.MMP-1 is thought to be important in rheumatoid arthritis and osteoarthritis. Recent data suggests an active role of MMPs in the pathogenesis of aortic aneurysms; excess MMPs degrade the structural proteins of the aortic wall. Dysregulation of the balance between MMPs and TIMPs is also a characteristic of acute and chronic cardiovascular diseases.^[15]

During wound healing, matrix metalloproteinases serve as a cleanup team, breaking down old tissues to make room for new ones. MMP-8 from neutrophils jumps in early to clear debris and accelerate skin healing overall, while MMP-1 from collagenases enhances keratinocyte movement across collagen fibers, helping to begin the repair after injury. MMP-13 then takes over to reduce the size of the wound and initiate re-epithelialization. Faster closure is achieved by drawing the wound edges together. Meanwhile, by activating MMP-9 and directing keratinocytes to migrate into the gap, the gelatinases MMP-2 speed up the healing process, while MMP-9 itself promotes cell migration everywhere within the wound.^[16][17][18]

Based on that, the stromelysins and other MMPs fine-tune the final stages. MMP-3 activates MMP-9 further and helps in the contraction of the wound, preventing scarring or tissue deformation, while MMP-10 secreted by keratinocytes at the wound edges to support the remodeling. MMP-7 ‘s main role is re-epithelialization, going through barriers like elastin and laminin allowing new skin cells to spread out, and MMP-12 manages the angiogenesis by making angiostatin, which controls new blood vessel growth preventing their overgrowth. These MMPs work together to balance the breakdown and rebuild, transforming the damaged tissue into healthy tissue.^[19][20][21]

When MMPs are dysregulated, they can make diseases become more aggressive and worsen them instead of curing them. For instance, elevated levels of MMP-1 releases growth factors that enhance cancer metastasis, and in diabetic foot ulcers it slows healing by over-degrading tissues. MMP-8 levels rise in asthma, and in diabetes, it increases the chronic inflammation. MMP-13 drives joint damage in osteoarthritis, while MMP-2 and MMP-9 levels soar in colorectal cancer and heart diseases, carrying out abnormal changes in vessel walls and causing fibrosis. MMP-3 aids rheumatoid arthritis and spine issues, MMP-10 affects bone growth, MMP-7 increases in artery-clogging atherosclerosis, and MMP-12 cause immune cells to overreact, causing severe inflammation. Basically, unchecked MMP activity turns helpful tools into troublemakers.^{[22][23][24][25]}

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.

The MMPs are inhibited by specific endogenoustissue inhibitor of metalloproteinases (TIMPs), which comprise a family of fourprotease inhibitors: TIMP-1, TIMP-2, TIMP-3, and TIMP-4.

TIMPs are small proteins made of two parts that has N-terminal domain (this is the main inhibitory part) and a C-terminal domain. Besides stopping MMPs, TIMPs can also do other jobs, like binding directly to receptors on the cell surface for signalling.^[26]

There are four main TIMPs:

• TIMP-1 is produced by almost every cell in the body. it has higher affinity towards MMP-9 and pro-MMP-9, but it does not inhibit some of the membrane-type MMPs (like MMP-14, MMP-16, MMP-18, MMP-19, MT1-MMP, MT2-MMP, MT3-MMP, and MT5-MMP).
• TIMP-2 is always present in most tissues; cells produce it all the time and growth factors don’t change its levels much.
• TIMP-3 stays in the extracellular matrix and is found especially in the basal membranes of the eyes and kidneys.
• TIMP-4 is mostly made in the heart, ovaries, kidneys, pancreas, colon, testes, brain, and fat tissue.^[27][28]

Synthetic inhibitors generally contain achelating group that binds the catalyticzinc atom at the MMPactive site tightly. Common chelating groups includehydroxamates,carboxylates,thiols, andphosphinyls. Hydroxymates are particularly potent inhibitors of MMPs and other zinc-dependent enzymes, due to theirbidentatechelation 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.^[2]

Under physiological conditions, MMPs are regulated at five levels: transcription; activation of zymogen precursors; interaction with ECM components; inhibition by TIMPs; and regulated absorption/elimination of active proteases from the extracellular environment. The majority of the literature is based on an investigation of transcriptional level (level 1) modifications, which lacks information on the physiologically relevant actions and control of secreted and post-translationally activated proteases. Future study could focus on the post-transcriptional regulation of MMP activity, especially in vivo.^[29]

Doxycycline, 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 ofperiodontal disease and is the only MMP inhibitor that is widely available clinically. It is sold under the trade name Periostat by the companyCollaGenex. 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 asmarimastat (BB-2516), a broad-spectrum MMP inhibitor, andcipemastat (Ro 32-3555), anMMP-1 selective inhibitor, have performed poorly inclinical trials. The failure of Marimastat was partially responsible for the folding ofBritish Biotech, 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 inanimal models.

• Collagen hybridizing peptide, a peptide that can bind and stain MMP cleaved collagen
• Drug discovery and development of MMP inhibitors
• Proteases in angiogenesis

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.

• MBInfo – Matrix metalloproteinases (MMPs) facilitate extracellular matrix disassembly
• The Matrix Metalloproteinase Protein
• Extracellular proteolysis at fibrinolysis.org
• Currently identified substrates for mammalian MMPs at clip.ubc.ca
• Matrix+metalloproteinases at the U.S. National Library of MedicineMedical Subject Headings (MeSH)

• Matrix metalloproteinases
• EC 3.4.24
• Metalloproteins
• Zinc enzymes

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