• Matrix metalloproteinases (MMPs), also known as matrix metallopeptidases or matrixins, are metalloproteinases that are calcium-dependent zinc-containing endopeptidases;^{[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.]}
  • 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.^{[ “endopeptidase”. Merriam-Webster. Archived from the original on 18 January 2017. Retrieved 18 January 2017.]} 
  • For this reason, endopeptidases cannot break down peptides into monomers, while exopeptidases can break down proteins into monomers. A particular case of endopeptidase is the oligopeptidase, whose substrates are oligopeptides instead of proteins.
  • They are usually very specific for certain amino acids. Examples of endopeptidases include:
    • Trypsin – cuts after Arg or Lys, unless followed by Pro. Very strict. Works best at pH 8.
    • Chymotrypsin – cuts after Phe, Trp, or Tyr, unless followed by Pro. Cuts more slowly after His, Met or Leu. Works best at pH 8.
    • Elastase – cuts after Ala, Gly, Ser, or Val, unless followed by Pro.
    • Thermolysin – cuts before Ile, Met, Phe, Trp, Tyr, or Val, unless preceded by Pro. Sometimes cuts after Ala, Asp, His or Thr. Heat stable.
    • Pepsin – cuts before Leu, Phe, Trp or Tyr, unless preceded by Pro. Also others, quite nonspecific; works best at pH 2.
    • Glutamyl endopeptidase – cuts after Glu. Works best at pH 8.
    • Neprilysin
• other family members are adamalysins, serralysins, and astacins.
  • Adamalysin (EC3.4.24.46, Crotalus adamanteus metalloendopeptidase, proteinase I and II, Crotalus adamanteus venom proteinase II, adamalysin II) is an enzyme.^{[Kurecki T, Laskowski M, Kress LF (November 1978). “Purification and some properties of two proteinases from Crotalus adamanteus venom that inactivate human alpha 1-proteinase inhibitor”. The Journal of Biological Chemistry. 253 (22): 8340–5. PMID 309470]}
    • This enzyme catalyses the following chemical reaction
      • Cleavage of Phe¹-Val, His⁵-Leu, His¹⁰-Leu, Ala¹⁴-Leu, Leu¹⁵-Tyr, and Tyr¹⁶-Leu of insulin B chain
    • This enzyme is present in the venom of the eastern diamondback rattlesnake (Crotalus adamanteus).
    • See also: A disintegrin and metalloproteinase
  • Serralysin (EC3.4.24.40, Pseudomonas aeruginosa alkaline proteinase, Escherichia freundii proteinase, Serratia marcescens extracellular proteinase, Serratia marcescens metalloproteinase, Pseudomonas aeruginosa alk. protease, Serratia marcescens metalloprotease) is an enzyme.^{[Morihara K, Tsuzuki H, Oka T (March 1968). “Comparison of the specificities of various neutral proteinases from microorganisms”. Archives of Biochemistry and Biophysics. 123 (3): 572–88. doi:10.1016/0003-9861(68)90179-3. PMID 4967801][Morihara K, Tsuzuki H, Oka T (June 1973). “On the specificity of Pseudomonas aeruginosa alkaline proteinase with synthetic peptides”. Biochimica et Biophysica Acta (BBA) – Enzymology. 309 (2): 414–29. doi:10.1016/0005-2744(73)90040-5. PMID 4199986][Nakajima M, Mizusawa K, Yoshida F (May 1974). “Purification and properties of an extracellular proteinase of psychrophilic Escherichia freundii”. European Journal of Biochemistry. 44 (1): 87–96. doi:10.1111/j.1432-1033.1974.tb03460.x. PMID 4212288][Decedue CJ, Broussard EA, Larson AD, Braymer HD (August 1979). “Purification and characterization of the extracellular proteinase of Serratia marcescens”. Biochimica et Biophysica Acta (BBA) – Enzymology. 569 (2): 293–301. doi:10.1016/0005-2744(79)90065-2. PMID 383155][Doerr M, Traub WH (May 1984). “Purification and characterization of two Serratia marcescens proteases”. Zentralblatt für Bakteriologie, Mikrobiologie, und Hygiene. Series A, Medical Microbiology, Infectious Diseases, Virology, Parasitology. 257 (1): 6–19. PMID 6380155][Nakahama K, Yoshimura K, Marumoto R, Kikuchi M, Lee IS, Hase T, Matsubara H (July 1986). “Cloning and sequencing of Serratia protease gene”. Nucleic Acids Research. 14 (14): 5843–55. doi:10.1093/nar/14.14.5843. PMC 311595. PMID 3016665.][Dahler GS, Barras F, Keen NT (October 1990). “Cloning of genes encoding extracellular metalloproteases from Erwinia chrysanthemi EC16”. Journal of Bacteriology. 172 (10): 5803–15. doi:10.1128/jb.172.10.5803-5815.1990. PMC 526898. PMID 2211513][Okuda K, Morihara K, Atsumi Y, Takeuchi H, Kawamoto S, Kawasaki H, Suzuki K, Fukushima J (December 1990). “Complete nucleotide sequence of the structural gene for alkaline proteinase from Pseudomonas aeruginosa IFO 3455”. Infection and Immunity. 58 (12): 4083–8. doi:10.1128/IAI.58.12.4083-4088.1990. PMC 313780. PMID 2123832]}
    • This enzyme catalyses the following chemical reaction
      • Preferential cleavage of bonds with hydrophobic residues in P1′
    • This extracellular endopeptidase is present in Pseudomonas aeruginosa, Escherichia freundii, Serratia marcescens and Erwinia chrysanthemi.
  • Astacins are a family of multidomain metalloendopeptidases which are either secreted or membrane-anchored.^{[Gomis-Rüth FX, Trillo-Muyo S, Stöcker W (October 2012). “Functional and structural insights into astacin metallopeptidases”. Biological Chemistry. 393 (10): 1027–41. doi:10.1515/hsz-2012-0149. hdl:10261/87872. PMID 23092796. S2CID 11098025]}
    • These metallopeptidases belong to the MEROPS peptidase family M12, subfamily M12A (astacin family, clan MA(M)). The protein fold of the peptidase domain for members of this family resembles that of thermolysin, the type example for clan MA and the predicted active site residues for members of this family and thermolysin occur in the motif HEXXH.^{[Rawlings ND, Barrett AJ (1995). “Evolutionary families of metallopeptidases”. Methods in Enzymology. 248: 183–228. doi:10.1016/0076-6879(95)48015-3. PMID 7674922]}
    • The astacin family of metalloendopeptidases (EC 3.4.24.21) encompasses a range of proteins found in hydra to humans, in mature and developmental systems. Their functions include activation of growth factors, degradation of polypeptides, and processing of extracellular proteins.^{[Bond JS, Beynon RJ (July 1995). “The astacin family of metalloendopeptidases”. Protein Science. 4 (7): 1247–61. doi:10.1002/pro.5560040701. PMC 2143163. PMID 7670368.]} 
    • The proteins are synthesised with N-terminal signal and pro-enzyme sequences, and many contain multiple domains C-terminal to the protease domain. They are either secreted from cells, or are associated with the plasma membrane.
    • The astacin molecule adopts a kidney shape, with a deep active-site cleft between its N- and C-terminal domains.^{[Gomis-Rüth FX, Stöcker W, Huber R, Zwilling R, Bode W (February 1993). “Refined 1.8 A X-ray crystal structure of astacin, a zinc-endopeptidase from the crayfish Astacus astacus L. Structure determination, refinement, molecular structure and comparison with thermolysin”. Journal of Molecular Biology. 229 (4): 945–68. doi:10.1006/jmbi.1993.1098. PMID 8445658]} 
    • The zinc ion, which lies at the bottom of the cleft, exhibits a unique penta-coordinated mode of binding, involving 3 histidine residues, a tyrosine and a water molecule (which is also bound to the carboxylate side chain of Glu93).^{[Gomis-Rüth FX, Stöcker W, Huber R, Zwilling R, Bode W (February 1993). “Refined 1.8 A X-ray crystal structure of astacin, a zinc-endopeptidase from the crayfish Astacus astacus L. Structure determination, refinement, molecular structure and comparison with thermolysin”. Journal of Molecular Biology. 229 (4): 945–68. doi:10.1006/jmbi.1993.1098. PMID 8445658]} 
    • The N-terminal domain comprises 2 alpha-helices and a 5-stranded beta-sheet. The overall topology of this domain is shared by the archetypal zinc-endopeptidase thermolysin.
    • Astacin protease domains also share common features with serralysins, matrix metalloendopeptidases, and snake venom proteases; they cleave peptide bonds in polypeptides such as insulin B chain and bradykinin, and in proteins such as casein and gelatin; and they have arylamidase activity.^{[Bond JS, Beynon RJ (July 1995). “The astacin family of metalloendopeptidases”. Protein Science. 4 (7): 1247–61. doi:10.1002/pro.5560040701. PMC 2143163. PMID 7670368.]}
    • HISTORY: In 1965 R. Zwilling observed during his doctorate work that the oncosphaere of the mouse tapeworm Hymenolepis diminuta easily hatched in vitro in the presence of the digestive fluid of its intermediate host Tenebrio molitor (Meal beetle). After the digestion of its protein shell the oncosphaere started its typical hook movements. The same effect could not be achieved with bovine trypsin which raised the question, by what different proteases invertebrate animals might digest their protein diet. This was unknown at that time.^{[Zwilling R (1968). “Das Schlüpfen der Oncosphaere von Hymenolepis dimunuta (Cestoda) unter dem Einfluß einer native Proteine hydrolysierenden Endopeptidase”. Zeitschrift für Naturforschung. 23b: 287–288. doi:10.1515/znb-1968-0237. S2CID 84596011]}
      • WHO: Zwilling R, Stöcker W, eds. (1997). The Astacins. Structure and Function of a New Protein Family. Hamburg: Verlag Kovacs. p. 370. ISBN 3-86064-624-9.
    • From the small Tenebrio beetles sufficient digestive fluid for extended studies could not be obtained. But from large crayfish cultures (Astacus astacus) it was possible to gather up to 100-200 ml gestric juice from the living animals by introducing a glass capillary through the proboscis into the cardia (stomach). From the resulting darkbrown fluid the proteolytic fractions were purified by gelfiltration, anion exchange chromatography and affinity chromatography to a high degree. The freeze-dried material obtained in this way has remained the basis for all further studies on crayfish astacin, includig the elucidation of the amino acid sequence, genomic organization and spatial configuration. On the basis of its primary structure one proteolytic fraction from Astacus obviously represented an unknown protein and was named Astacin. In addition to astacin the crayfish possesses an invertebrate trypsin, but no pepsin.^{[Zwilling R, Dörsam H, Torff HJ, Rödl J (May 1981). “Low molecular mass protease: evidence for a new family of proteolytic enzymes”. FEBS Letters. 127 (1): 75–8. doi:10.1016/0014-5793(81)80344-4. PMID 6788602. S2CID 31926929][Titani K, Torff HJ, Hormel S, Kumar S, Walsh KA, Rödl J, et al. (January 1987). “Amino acid sequence of a unique protease from the crayfish Astacus fluviatilis”. Biochemistry. 26 (1): 222–6. doi:10.1021/bi00375a029. PMID 3548817]} 
    • Soon afterwards Wozney et al.^{[Wozney JM, Rosen V, Celeste AJ, Mitsock LM, Whitters MJ, Kriz RW, et al. (December 1988). “Novel regulators of bone formation: molecular clones and activities”. Science. 242 (4885): 1528–34. Bibcode:1988Sci…242.1528W. doi:10.1126/science.3201241. PMID 3201241]} have shown that the astacin sequence is inserted into the human bone morphogenetic protein (BMP) with significant homology.
      • WHO:
    • Proteins containing the astacin domain include:
      • Astacin-like metallo-endopeptidase (ASTL)
      • Bone morphogenetic protein 1 (BMP1)
      • Meprin A subunit alpha (MEP1A)
      • Meprin A subunit beta (MEP1B)
      • Tolloid-like protein 1 (TLL1)
      • Tolloid-like protein 2 (TLL2)

The MMPs belong to a larger family of proteases known as the metzincin superfamily.^{[ Matrix Metalloproteinases: Its implications in cardiovascular disorders]}

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.^{[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]} 

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 (1962),^{[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]} 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 (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 Zn²⁺ 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	glycosylphosphatidylinositol-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	glycosylphosphatidylinositol-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.

See also

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

References

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.
2. ^ Jump up to:^a b c Matrix Metalloproteinases: Its implications in cardiovascular disorders
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.
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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
• Currently identified substrates for mammalian MMPs at clip.ubc.ca
• Matrix+metalloproteinases at the US National Library of Medicine Medical Subject Headings (MeSH)

Proteases: metalloendopeptidases (EC 3.4.24)

Enzymes

Categories: 

• Matrix metalloproteinases
• EC 3.4.24
• Metalloproteins
• Zinc enzymes

From Wikipedia where the main page was last updated December 10, 2021