Matrix metalloproteinase
Matrix metalloproteinase | |
---|---|
Identifiers | |
Symbol | MMP |
Pfam clan | CL0126 |
InterPro | IPR021190 |
Membranome | 317 |
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
They were first described in
History
MMPs were described initially by
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
The pro-peptide
The MMPs are initially synthesized as inactive
The catalytic domain
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
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:
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
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 intestine, placenta, salivary glands, uterus, skin). A threonine replaces proline in its cysteine switch (PRCGVTD).[14]
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Matrix metalloproteinases combines with the metal binding protein, metallothionine; thus helping in metal binding mechanism.
Function
The MMPs play an important role in
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
Synthetic inhibitors generally contain a
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
See also
- Collagen hybridizing peptide, a peptide that can bind and stain MMP cleaved collagen
- Drug discovery and development of MMP inhibitors
- Proteases in angiogenesis
References
- PMID 17275314. Archived from the original(PDF) on 13 May 2015. Retrieved 21 October 2015.
- ^ a b c Matrix Metalloproteinases: Its implications in cardiovascular disorders
- PMID 17709402.
- PMID 13902219.
- PMID 13902219.
- PMID 4967132.
- PMID 4331330.
- PMID 2164689.
- PMID 10945999.
- PMID 12486137.
- PMID 7756291.
- PMID 861218.
- S2CID 17453639.
- PMID 11121398.
- 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)