Matrix metalloproteinase

Matrix metalloproteinase
Matrix metalloproteinase
Identifiers
Symbol	MMP
Pfam clan	CL0126
InterPro	IPR021190
Membranome	317

Last updated April 27, 2024

Matrix metalloproteinases (MMPs), also known as matrix metallopeptidases or matrixins, are metalloproteinases that are calcium-dependent zinc-containing endopeptidases;^[1] other family members are adamalysins, serralysins, and astacins. The MMPs belong to a larger family of proteases known as the metzincin superfamily.^[2]

Collectively, these enzymes are capable of degrading all kinds of extracellular matrix proteins, but also can process a number of bioactive molecules. They are known to be involved in the cleavage of cell surface receptors, the release of apoptotic ligands (such as the FAS ligand), and chemokine/cytokine inactivation.^[3] MMPs are also thought to play a major role in cell behaviors such as cell proliferation, migration (adhesion/dispersion), differentiation, angiogenesis, apoptosis, and host defense.

They were first described in vertebrates in 1962,^[4] 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, their ability to degrade extracellular matrix, and their specific evolutionary DNA sequence.

History

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

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

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

Structure

The MMPs have a common domain structure. The three common domains are the pro-peptide, the catalytic domain, and the haemopexin-like C-terminal domain, which is linked to the catalytic domain by a flexible hinge region.^[2]

The pro-peptide

The MMPs are initially synthesized as inactive zymogens with a pro-peptide domain that must be removed before the enzyme is active. The pro-peptide domain is part of the "cysteine switch." This contains a conserved cysteine residue that interacts with the zinc in the active site and prevents binding and cleavage of the substrate, keeping the enzyme in an inactive form. In the majority of the MMPs, the cysteine residue is in the conserved 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 and MMP-23B include a transmembrane segment in this domain.^[9]

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 is a 20 Å (2 nm) groove that runs across the catalytic domain. In the part of the catalytic domain forming the active site there is a catalytically important Zn ²⁺ ion, which is bound by three histidine residues found in the conserved sequence HExxHxxGxxH. Hence, this sequence is a zinc-binding motif.

The gelatinases, such as MMP-2, incorporate Fibronectin type II modules inserted immediately before in the zinc-binding motif in the catalytic domain.^[10]

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 acids long, and has no determinable structure.

The hemopexin-like C-terminal domain

The C-terminal domain has structural similarities to the serum protein hemopexin. 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). The hemopexin-like domain is absent in MMP-7, MMP-23, MMP-26, and the plant and nematode. The membrane-bound MMPs (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^[11] 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^[12] suggested an interaction between a water molecule and the Zn²⁺ ion during the acid-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 in catalysis 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, 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 methods to compare the primary sequences of the MMPs suggest the following evolutionary groupings of the MMPs:

MMP-19
MMPs 11, 14, 15, 16, and 17
MMP-2 and MMP-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 the substrate specificities of the enzymes.

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 collagens into distinctive 3/4 and 1/4 fragments. These collagens are the major components of bone, cartilage and dentin, and MMPs are the only known mammalian enzymes 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, and there is evidence that No. 2 is capable of collagenolysis. In MeSH, 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 gelatinases are type IV collagen and gelatin, 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 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 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

Gene	Name	Aliases	Location	Description
MMP1	Interstitial collagenase	CLG, CLGN	secreted	Substrates include Col I, II, III, VII, VIII, X, gelatin
MMP2	Gelatinase-A, 72 kDa gelatinase		secreted	Substrates include Gelatin, Col I, II, III, IV, Vii, X
MMP3	Stromelysin 1	CHDS6, MMP-3, SL-1, STMY, STMY1, STR1	secreted	Substrates include Col II, IV, IX, X, XI, gelatin
MMP7	Matrilysin, PUMP 1	MMP-7, MPSL1, PUMP-1	secreted	membrane associated through binding to cholesterol sulfate in cell membranes, substrates include: fibronectin, laminin, Col IV, gelatin
MMP8	Neutrophil collagenase	CLG1, HNC, MMP-8, PMNL-CL	secreted	Substrates include Col I, II, III, VII, VIII, X, aggrecan, gelatin
MMP9	Gelatinase-B, 92 kDa gelatinase	CLG4B, GELB, MANDP2, MMP-9	secreted	Substrates include Gelatin, Col IV, V
MMP10	Stromelysin 2	SL-2, STMY2	secreted	Substrates include Col IV, laminin, fibronectin, elastin
MMP11	Stromelysin 3	SL-3, ST3, STMY3	secreted	MMP-11 shows more similarity to the MT-MMPs, is convertase-activatable and is secreted therefore usually associated to convertase-activatable MMPs. Substrates include Col IV, fibronectin, laminin, aggrecan
MMP12	Macrophage metalloelastase	HME, ME, MME, MMP-12	secreted	Substrates include elastin, fibronectin, Col IV
MMP13	Collagenase 3	CLG3, MANDP1, MMP-13	secreted	Substrates include Col I, II, III, IV, IX, X, XIV, gelatin
MMP14	MT1-MMP	MMP-14, MMP-X1, MT-MMP, MT-MMP 1, MT1-MMP, MT1MMP, MTMMP1, WNCHRS	membrane-associated	type-I transmembrane MMP; substrates include gelatin, fibronectin, laminin
MMP15	MT2-MMP	MT2-MMP, MTMMP2, SMCP-2, MMP-15, MT2MMP	membrane-associated	type-I transmembrane MMP; substrates include gelatin, fibronectin, laminin
MMP16	MT3-MMP	C8orf57, MMP-X2, MT-MMP2, MT-MMP3, MT3-MMP	membrane-associated	type-I transmembrane MMP; substrates include gelatin, fibronectin, laminin
MMP17	MT4-MMP	MT4-MMP, MMP-17, MT4MMP, MTMMP4	membrane-associated	glycosyl phosphatidylinositol-attached; substrates include fibrinogen, fibrin
MMP18	Collagenase 4, xcol4, xenopus collagenase		–	No known human orthologue
MMP19	RASI-1, occasionally referred to as stromelysin-4	MMP18, RASI-1, CODA	–
MMP20	Enamelysin	AI2A2, MMP-20	secreted
MMP21	X-MMP	MMP-21, HTX7	secreted
MMP23A	CA-MMP		membrane-associated	type-II transmembrane cysteine array
MMP23B	–	MIFR, MIFR-1, MMP22, MMP23A	membrane-associated	type-II transmembrane cysteine array
MMP24	MT5-MMP	MMP-24, MMP25, MT-MMP 5, MT-MMP5, MT5-MMP, MT5MMP, MTMMP5	membrane-associated	type-I transmembrane MMP
MMP25	MT6-MMP	MMP-25, MMP20, MMP20A, MMPL1, MT-MMP 6, MT-MMP6, MT6-MMP, MT6MMP, MTMMP6	membrane-associated	glycosyl phosphatidylinositol-attached
MMP26	Matrilysin-2, endometase		–
MMP27	MMP-22, C-MMP	MMP-27	–
MMP28	Epilysin	EPILYSIN, MM28, MMP-25, MMP-28, MMP25	secreted	Discovered in 2001 and given its name due to have been discovered in human keratinocytes. Unlike other MMPs this enzyme is constitutivley expressed in many tissues (Highly expressed in testis and at lower levels in lung, heart, brain, colon, intestine, placenta, salivary glands, uterus, skin). A threonine replaces proline in its cysteine switch (PRCGVTD).^[14]

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 or pathological processes such as morphogenesis, angiogenesis, tissue repair, cirrhosis, arthritis, and metastasis. MMP-2 and MMP-9 are thought to be important in metastasis. MMP-1 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.^[15]

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 (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 atom at the MMP active site tightly. Common chelating groups include hydroxamates, carboxylates, thiols, and phosphinyls. Hydroxymates are particularly potent inhibitors of MMPs and other zinc-dependent enzymes, due to their bidentate chelation 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]

Pharmacology

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 of periodontal disease 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 (BB-2516), a broad-spectrum MMP inhibitor, and cipemastat (Ro 32-3555), an MMP-1 selective inhibitor, have performed poorly in clinical trials. The failure of Marimastat was partially responsible for the folding of British 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 in animal models.

Related Research Articles

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 myogenesis.

Gelatinases are enzymes capable of degrading gelatin through hydrolysis, playing a major role in degradation of extracellular matrix and tissue remodeling. Gelatinases are a type of matrix metalloproteinase (MMP), a family of enzymes that depend on zinc as a cofactor and can break down parts of the extracellular matrix. MMPs have multiple subgroups, including gelatinase A and gelatinase B. Gelatinases are assigned a variety of Enzyme Commission numbers: gelatinase A uses 3.4.24.24, and gelatinase B uses 3.4.24.35, in which the first three numbers are same. The first digit, 3, is the class. Class 3 enzymes are hydrolases, enzymes that catalyze hydrolysis reactions, that is, they cleave bonds in presence of water. The next digit represents sub-class 4, or proteases, which are enzymes who hydrolyze peptide bonds in proteins. The next number is the sub-subclass of 24, which consists of metalloendopeptidases which contain metal ions in their active sites, in this case zinc, which help in cleaving peptide bonds. The last part of the EC number is the serial number, identifying specific enzymes within a sub-subclass. 24 represents gelatinase A, which is a metalloproteinase that breaks down gelatin and collagen, while 35 represents gelatinase B, which hydrolyzes peptide bonds.

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 gas gangrene. They normally target the connective tissue in muscle cells and other body organs.

Carboxypeptidase A usually refers to the pancreatic exopeptidase that hydrolyzes peptide bonds of C-terminal residues with aromatic or aliphatic side-chains. Most scientists in the field now refer to this enzyme as CPA1, and to a related pancreatic carboxypeptidase as CPA2.

Matrix metalloproteinase-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 extracellular matrix. In humans the MMP9 gene encodes for a signal peptide, a propeptide, a catalytic domain with inserted three repeats of fibronectin type II domain followed by a C-terminal hemopexin-like domain.

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.

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. MMP-1 was the first vertebrate collagenase both purified to homogeneity as a protein, and cloned as a cDNA. MMP-1 has an estimated molecular mass of 54 kDa.

Stromelysin-1 also known as matrix metalloproteinase-3 (MMP-3) is an enzyme that in humans is encoded by the MMP3 gene. The MMP3 gene is part of a cluster of MMP genes which localize to chromosome 11q22.3. MMP-3 has an estimated molecular weight of 54 kDa.

Tissue inhibitor of metalloproteinases 2 (TIMP2) is a gene and a corresponding protein. The gene is a member of the TIMP gene family. The protein is thought to be a metastasis suppressor.

Matrilysin also known as matrix metalloproteinase-7 (MMP-7), pump-1 protease (PUMP-1), or uterine metalloproteinase is an enzyme in humans that is encoded by the MMP7 gene. The enzyme has also been known as matrin, putative metalloproteinase-1, matrix metalloproteinase pump 1, PUMP-1 proteinase, PUMP, metalloproteinase pump-1, putative metalloproteinase, MMP). Human MMP-7 has a molecular weight around 30 kDa.

Collagenase 3 is an enzyme that in humans is encoded by the MMP13 gene. It is a member of the matrix metalloproteinase (MMP) family. Like most MMPs, it is secreted as an inactive pro-form. MMP-13 has a predicted molecular weight around 54 kDa. It is activated once the pro-domain is cleaved, leaving an active enzyme composed of the catalytic domain and the hemopexin-like domain PDB: 1PEX. Although the actual mechanism has not been described, the hemopexin domain participates in collagen degradation, the catalytic domain alone being particularly inefficient in collagen degradation. During embryonic development, MMP-13 is expressed in the skeleton as required for restructuring the collagen matrix for bone mineralization. In pathological situations it is highly overexpressed; this occurs in human carcinomas, rheumatoid arthritis and osteoarthritis.

Matrix metalloproteinase-12 (MMP-12) also known as macrophage metalloelastase (MME) or macrophage elastase (ME) is an enzyme that in humans is encoded by the MMP12 gene.

Matrix metalloproteinase-26 also known as matrilysin-2 and endometase is an enzyme that in humans is encoded by the MMP26 gene.

Metalloproteinase inhibitor 4 is an enzyme that in humans is encoded by the TIMP4 gene.

Neutrophil collagenase, also known as matrix metalloproteinase-8 (MMP-8) or PMNL collagenase (MNL-CL), is a collagen cleaving enzyme which is present in the connective tissue of most mammals. In humans, the MMP-8 protein is encoded by the MMP8 gene. The gene is part of a cluster of MMP genes which localize to chromosome 11q22.3. Most MMP's are secreted as inactive proproteins which are activated when cleaved by extracellular proteinases. However, the enzyme encoded by this gene is stored in secondary granules within neutrophils and is activated by autolytic cleavage.

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 is increased in various pathological conditions like inflammatory conditions, metabolic bone disease, to cancer invasion, metastasis and angiogenesis. Examples of diseases are periodontitis, hepatitis, glomerulonephritis, atherosclerosis, emphysema, asthma, autoimmune disorders of skin and dermal photoaging, rheumatoid arthritis, osteoarthritis, multiple sclerosis, Alzheimer's disease, chronic ulcerations, uterine involution, corneal epithelial defects, bone resorption and tumor progression and metastasis. Due to the role of MMPs in pathological conditions, inhibitors of MMPs may have therapeutic potential. Several other proteins have similar inhibitory effects, however none as effective. They might have other biological activities which have yet been fully characterised.

Angiogenesis is the process of forming new blood vessels from existing blood vessels, formed in vasculogenesis. It is a highly complex process involving extensive interplay between cells, soluble factors, and the extracellular matrix (ECM). Angiogenesis is critical during normal physiological development, but it also occurs in adults during inflammation, wound healing, ischemia, and in pathological conditions such as rheumatoid arthritis, hemangioma, and tumor growth. Proteolysis has been indicated as one of the first and most sustained activities involved in the formation of new blood vessels. Numerous proteases including matrix metalloproteinases (MMPs), a disintegrin and metalloproteinase domain (ADAM), a disintegrin and metalloproteinase domain with throbospondin motifs (ADAMTS), and cysteine and serine proteases are involved in angiogenesis. This article focuses on the important and diverse roles that these proteases play in the regulation of angiogenesis.

Peptidoglycan binding domains have a general peptidoglycan binding function and a common core structure consisting of a closed, three-helical bundle with a left-handed twist. It is found at the N or C terminus of a variety of enzymes involved in bacterial cell wall degradation. Examples are:

The hemopexin family is a family of evolutionarily related proteins. Hemopexin-like repeats occur in vitronectin and some matrix metalloproteinases family (matrixins). The HX repeats of some matrixins bind tissue inhibitor of metallopeptidases (TIMPs).

Plant matrix metalloproteinases are metalloproteins and zinc enzymes found in plants.

References

↑ Verma RP, Hansch C (March 2007). "Matrix metalloproteinases (MMPs): chemical-biological functions and (Q)SARs" (PDF). Bioorg. Med. Chem. 15 (6): 2223–68. doi:10.1016/j.bmc.2007.01.011. PMID 17275314. Archived from the original (PDF) on 13 May 2015. Retrieved 21 October 2015.
1 2 3 Matrix Metalloproteinases: Its implications in cardiovascular disorders
↑ Van Lint P, Libert C (December 2007). "Chemokine and cytokine processing by matrix metalloproteinases and its effect on leukocyte migration and inflammation". J. Leukoc. Biol. 82 (6): 1375–81. doi: 10.1189/jlb.0607338 . PMID 17709402.
↑ Gross, J.; Lapiere, C. M. (June 1962). "Collagenolytic activity in amphibian tissues: a tissue culture assay". Proceedings of the National Academy of Sciences. 48 (6): 1014–22. Bibcode:1962PNAS...48.1014G. doi: 10.1073/pnas.48.6.1014 . PMC 220898 . PMID 13902219.
↑ Gross J, Lapiere C (1962). "Collagenolytic Activity in Amphibian Tissues: A Tissue Culture Assay". Proc Natl Acad Sci USA. 48 (6): 1014–22. Bibcode:1962PNAS...48.1014G. doi: 10.1073/pnas.48.6.1014 . PMC 220898 . PMID 13902219.
↑ Eisen A, Jeffrey J, Gross J (1968). "Human skin collagenase. Isolation and mechanism of attack on the collagen molecule". Biochim Biophys Acta. 151 (3): 637–45. doi:10.1016/0005-2744(68)90010-7. PMID 4967132.
↑ Harper E, Bloch K, Gross J (1971). "The zymogen of tadpole collagenase". Biochemistry. 10 (16): 3035–41. doi:10.1021/bi00792a008. PMID 4331330.
↑ Van Wart H, Birkedal-Hansen H (1990). "The cysteine switch: a principle of regulation of metalloproteinase activity with potential applicability to the entire matrix metalloproteinase gene family". Proc Natl Acad Sci USA. 87 (14): 5578–82. Bibcode:1990PNAS...87.5578V. doi: 10.1073/pnas.87.14.5578 . PMC 54368 . PMID 2164689.
↑ Pei D, Kang T, Qi H (2000). "Cysteine array matrix metalloproteinase (CA-MMP)/MMP-23 is a type II transmembrane matrix metalloproteinase regulated by a single cleavage for both secretion and activation". J Biol Chem. 275 (43): 33988–97. doi: 10.1074/jbc.M006493200 . PMID 10945999.
↑ Trexler M, Briknarová K, Gehrmann M, Llinás M, Patthy L (2003). "Peptide ligands for the fibronectin type II modules of matrix metalloproteinase 2 (MMP-2)". J Biol Chem. 278 (14): 12241–6. doi: 10.1074/jbc.M210116200 . PMID 12486137.
↑ Browner MF, Smith WW, Castelhano AL (1995). "Matrilysin-inhibitor complexes: common themes among metalloproteases". Biochemistry. 34 (20): 6602–10. doi:10.1021/bi00020a004. PMID 7756291.
↑ Kester WR, Matthews BW (1977). "Crystallographic study of the binding of dipeptide inhibitors to thermolysin: implications for the mechanism of catalysis". Biochemistry. 16 (11): 2506–16. doi:10.1021/bi00630a030. PMID 861218.
↑ Manzetti S, McCulloch DR, Herington AC, van der Spoel D (2003). "Modeling of enzyme-substrate complexes for the metalloproteases MMP-3, ADAM-9 and ADAM-10". J. Comput.-Aided Mol. Des. 17 (9): 551–65. Bibcode:2003JCAMD..17..551M. doi:10.1023/B:JCAM.0000005765.13637.38. PMID 14713188. S2CID 17453639.
↑ Lohi J, Wilson CL, Roby JD, Parks WC (2001). "Epilysin, a novel human matrix metalloproteinase (MMP-28) expressed in testis and keratinocytes and in response to injury". J Biol Chem. 276 (13): 10134–10144. doi: 10.1074/jbc.M001599200 . PMID 11121398.
↑ Snoek-van Beurden PAM; Von den Hoff JW (2005). "Zymographic techniques for the analysis of matrix metalloproteinases and their inhibitors". BioTechniques. 38 (1): 73–83. doi: 10.2144/05381RV01 . hdl: 2066/47379 . PMID 15679089.

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
Extracellular proteolysis at fibrinolysis.org
peptide shop
Currently identified substrates for mammalian MMPs at clip.ubc.ca
Matrix+metalloproteinases at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

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[pmid17275314-1] Verma RP, Hansch C (March 2007). "Matrix metalloproteinases (MMPs): chemical-biological functions and (Q)SARs" (PDF). Bioorg. Med. Chem. 15 (6): 2223–68. doi:10.1016/j.bmc.2007.01.011. PMID 17275314. Archived from the original (PDF) on 13 May 2015. Retrieved 21 October 2015.

[MMP-2] 1 2 3 Matrix Metalloproteinases: Its implications in cardiovascular disorders

[pmid17709402-3] Van Lint P, Libert C (December 2007). "Chemokine and cytokine processing by matrix metalloproteinases and its effect on leukocyte migration and inflammation". J. Leukoc. Biol. 82 (6): 1375–81. doi: 10.1189/jlb.0607338 . PMID 17709402.

[4] Gross, J.; Lapiere, C. M. (June 1962). "Collagenolytic activity in amphibian tissues: a tissue culture assay". Proceedings of the National Academy of Sciences. 48 (6): 1014–22. Bibcode:1962PNAS...48.1014G. doi: 10.1073/pnas.48.6.1014 . PMC 220898 . PMID 13902219.

[5] Gross J, Lapiere C (1962). "Collagenolytic Activity in Amphibian Tissues: A Tissue Culture Assay". Proc Natl Acad Sci USA. 48 (6): 1014–22. Bibcode:1962PNAS...48.1014G. doi: 10.1073/pnas.48.6.1014 . PMC 220898 . PMID 13902219.

[6] Eisen A, Jeffrey J, Gross J (1968). "Human skin collagenase. Isolation and mechanism of attack on the collagen molecule". Biochim Biophys Acta. 151 (3): 637–45. doi:10.1016/0005-2744(68)90010-7. PMID 4967132.

[7] Harper E, Bloch K, Gross J (1971). "The zymogen of tadpole collagenase". Biochemistry. 10 (16): 3035–41. doi:10.1021/bi00792a008. PMID 4331330.

[8] Van Wart H, Birkedal-Hansen H (1990). "The cysteine switch: a principle of regulation of metalloproteinase activity with potential applicability to the entire matrix metalloproteinase gene family". Proc Natl Acad Sci USA. 87 (14): 5578–82. Bibcode:1990PNAS...87.5578V. doi: 10.1073/pnas.87.14.5578 . PMC 54368 . PMID 2164689.

[9] Pei D, Kang T, Qi H (2000). "Cysteine array matrix metalloproteinase (CA-MMP)/MMP-23 is a type II transmembrane matrix metalloproteinase regulated by a single cleavage for both secretion and activation". J Biol Chem. 275 (43): 33988–97. doi: 10.1074/jbc.M006493200 . PMID 10945999.

[10] Trexler M, Briknarová K, Gehrmann M, Llinás M, Patthy L (2003). "Peptide ligands for the fibronectin type II modules of matrix metalloproteinase 2 (MMP-2)". J Biol Chem. 278 (14): 12241–6. doi: 10.1074/jbc.M210116200 . PMID 12486137.

[11] Browner MF, Smith WW, Castelhano AL (1995). "Matrilysin-inhibitor complexes: common themes among metalloproteases". Biochemistry. 34 (20): 6602–10. doi:10.1021/bi00020a004. PMID 7756291.

[12] Kester WR, Matthews BW (1977). "Crystallographic study of the binding of dipeptide inhibitors to thermolysin: implications for the mechanism of catalysis". Biochemistry. 16 (11): 2506–16. doi:10.1021/bi00630a030. PMID 861218.

[13] Manzetti S, McCulloch DR, Herington AC, van der Spoel D (2003). "Modeling of enzyme-substrate complexes for the metalloproteases MMP-3, ADAM-9 and ADAM-10". J. Comput.-Aided Mol. Des. 17 (9): 551–65. Bibcode:2003JCAMD..17..551M. doi:10.1023/B:JCAM.0000005765.13637.38. PMID 14713188. S2CID 17453639.

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v t e Proteases: metalloendopeptidases (EC 3.4.24)
ADAM proteins	Alpha secretases ADAM9 ADAM10 ADAM17 ADAM19 ADAM2 ADAM7 ADAM8 ADAM11 ADAM12 ADAM15 ADAM18 ADAM22 ADAM23 ADAM28 ADAM33 ADAMTS1 ADAMTS2 ADAMTS3 ADAMTS4 ADAMTS5 ADAMTS8 ADAMTS9 ADAMTS10 ADAMTS12 ADAMTS13
Matrix metalloproteinases	Collagenases MMP1 MMP8 Gelatinases MMP2 MMP9 MMP3 MMP7 MMP10 MMP11 MMP12 MMP13 MMP14 MMP15 MMP16 MMP17 MMP19 MMP20 MMP21 MMP23A MMP23B MMP24 MMP25 MMP26 MMP27 MMP28
Other	Neprilysin Procollagen peptidase Thermolysin Pregnancy-associated plasma protein A Bone morphogenetic protein 1 Lysostaphin Insulin-degrading enzyme ZMPSTE24

v t e Enzymes
Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Diffusion-limited enzyme Cofactor Enzyme catalysis
Regulation	Allosteric regulation Cooperativity Enzyme inhibitor Enzyme activator
Classification	EC number Enzyme superfamily Enzyme family List of enzymes
Kinetics	Enzyme kinetics Eadie–Hofstee diagram Hanes–Woolf plot Lineweaver–Burk plot Michaelis–Menten kinetics
Types	EC1 Oxidoreductases (list) EC2 Transferases (list) EC3 Hydrolases (list) EC4 Lyases (list) EC5 Isomerases (list) EC6 Ligases (list) EC7 Translocases (list)