Overview: Matrix metalloproteinases (MMP) are calcium- and zinc-dependent proteinases regulating the extracellular matrix and are often divided (e.g. Verma and Hansch, 2007) on functional and structural bases into gelatinases, collagenases, stromyelinases and matrilysins, as well as membrane-type MMP.
| Nomenclature | EC number | Other names | Ensembl ID | Selective inhibitors |
|---|---|---|---|---|
| MMP1 | 3.4.24.7 | Collagenase-1, interstitial collagenase, fibroblast collagenase | ENSG00000196611 | |
| MMP2 | 3.4.24.24 | Gelatinase-A, 72 kDa type IV collagenase precursor, TBE- 1 | ENSG00000087245 | ARP100 (Tuccinardi et al., 2006) |
| MMP3 | 3.4.24.17 | Stromelysin-1, transin-1 | ENSG00000149968 | |
| MMP7 | 3.4.24.23 | Matrilysin, PUMP-1 protease, uterine metalloproteinase, matrin | ENSG00000137673 | |
| MMP8 | 3.4.24.34 | Neutrophil collagenase, PMNL collagenase | ENSG00000118113 | |
| MMP9 | 3.4.24.35 | Gelatinases-B, 92 kDa type IV collagenase, GELB | ENSG00000100985 | |
| MMP10 | 3.4.24.22 | Stromelysin-2, transin-2 | ENSG00000166670 | |
| MMP11 | Stromelysin-3 | ENSG00000099953 | ||
| MMP12 | 3.4.24.65 | Macrophage metalloelastase, macrophage elastase, HME | ENSG00000110347 | |
| MMP13 | Collagenase-3 | ENSG00000137745 | CL82198, WAY170523 (Chen et al., 2000) | |
| MMP14 | 3.4.24.80 | MT1-MMP, MMP- X1 | ENSG00000157227 | |
| MMP15 | MT2-MMP, SMCP- 2 | ENSG00000102996 | ||
| MMP16 | MT3-MMP, MMP- X2 | ENSG00000156103 | ||
| MMP17 | MT4-MMP | ENSG00000198598 | ||
| MMP19 | Matrix metalloproteinase RASI, MMP18 | ENSG00000123342 | ||
| MMP20 | Enamelysin, enamel metalloproteinase | ENSG00000137674 | ||
| MMP21 | – | ENSG00000154485 | ||
| MMP23 | Matrix metallopeptidase 21, MMP-21, matrix metalloprotease 22, MMP-22, Femalysin, MIFR-1 | ENSG00000189409 | ||
| MMP24 | MT5-MMP | ENSG00000125966 | ||
| MMP25 | MT6-MMP, leukolysin | ENSG00000008516 | ||
| MMP26 | Matrilysin-2, endometase | ENSG00000167346 | ||
| MMP27 | – | ENSG00000137675 | ||
| MMP28 | Epilysin | ENSG00000129270 |
A number of small molecule ‘broad spectrum’ inhibitors of MMP have been described, including marimastat and batimastat.
Tissue inhibitors of metalloproteinase (TIMP) proteins are endogenous inhibitors acting to chelate MMP proteins.
| Nomenclature | Other names | Ensembl ID |
|---|---|---|
| TIMP1 | Tissue inhibitor of metalloproteinases 1, metalloproteinase inhibitor 1, erythroid-potentiating activity, EPA, fibroblast collagenase inhibitor, collagenase inhibitor | ENSG00000102265 |
| TIMP2 | CSC-21K | ENSG00000035862 |
| TIMP3 | Tissue inhibitor of metalloproteinases 3, metalloproteinase inhibitor 3 Precursor, MIG-5 | ENSG00000100234 |
| TIMP4 | Tissue inhibitor of metalloproteinases 4, metalloproteinase inhibitor 4 | ENSG00000157150 |
ADAM (A Disintegrin And Metalloproteinase domain containing proteins) and ADAMTS (with thrombospondin motifs) metalloproteinases cleave cell-surface or transmembrane proteins to generate soluble and membrane-limited products.
| Nomenclature | EC number | Other names | Ensembl ID |
|---|---|---|---|
| ADAM2 | Fertilin subunit β, PH30β, cancer/testis antigen 15, CT15 | ENSG00000104755 | |
| ADAM3 | ADAM3A, cyritestin 1, CYRN1, tMDCI | ENSG00000197475 | |
| ADAM5 | Transmembrane metalloproteinase-like, disintegrin-like, and cysteine-rich protein II, tMDC II | ENSG00000196115 | |
| ADAM6 | C14orf96, tMDCIV | ENSG00000233988 | |
| ADAM7 | Sperm maturation-related glycoprotein GP-83 | ENSG00000069206 | |
| ADAM8 | Cell surface antigen MS2, CD156a antigen | ENSG00000151651 | |
| ADAM9 | Metalloprotease/disintegrin/cysteine-rich protein 9, myeloma cell metalloproteinase, meltrin γ, cellular disintegrin-related protein | ENSG00000168615 | |
| ADAM10 | 3.4.24.81 | Mammalian disintegrin-metalloprotease, Kuzbanian protein homolog, CDw156, CD156c antigen | ENSG00000137845 |
| ADAM11 | Metalloproteinase-like, disintegrin-like, and cysteine-rich protein, MDC | ENSG00000073670 | |
| ADAM12 | Meltrin α | ENSG00000148848 | |
| ADAM15 | Metalloproteinase-like, disintegrin-like, and cysteine-rich protein 15, MDC-15, Metalloprotease RGD disintegrin protein, metargidin | ENSG00000143537 | |
| ADAM17 | 3.4.24.86 | TNF α-converting enzyme, TNF α convertase, snake venom-like protease, CD156b antigen | ENSG00000151694 |
| ADAM18 | Transmembrane metalloproteinase-like, disintegrin-like, and cysteine-rich protein III, tMDC III, ADAM27 | ENSG00000168619 | |
| ADAM19 | Meltrin β, metalloprotease and disintegrin dendritic antigen marker, MADDAM | ENSG00000135074 | |
| ADAM20 | – | ENSG00000134007 | |
| ADAM21 | ADAM21P, ADAM31 | ENSG00000139985 | |
| ADAM22 | Metalloproteinase-like, disintegrin-like, and cysteine-rich protein 2, metalloproteinase-disintegrin ADAM22-3 | ENSG00000008277 | |
| ADAM23 | Metalloproteinase-like, disintegrin-like, and cysteine-rich protein 3, MDC-3 | ENSG00000114948 | |
| ADAM28 | Metalloproteinase-like, disintegrin-like, and cysteine-rich protein L, MDC-L, epididymial metalloproteinase-like, disintegrin-like, and cysteine-rich protein II, eMDC II | ENSG00000042980 | |
| ADAM29 | Cancer/testis antigen 73, CT73 | ENSG00000168594 | |
| ADAM30 | – | ENSG00000134249 | |
| ADAM32 | – | ENSG00000197140 | |
| ADAM33 | – | ENSG00000149451 |
Additional family members include AC123767.2 (cDNA FLJ58962, moderately similar to mouse ADAM3, ENSG00000231168), AL160191.3 (ADAM21-like protein, ENSG00000235812), AC136428.3-2 (ENSG00000185520) and ADAMDEC1 (decysin 1, ENSG00000134028).
ADAMTS family
| Nomenclature | EC number | Other names | Ensembl ID | |
|---|---|---|---|---|
| ADAMTS1 | METH-1 | ENSG00000154734 | ||
| ADAMTS2 | 3.4.24.14 | Procollagen I/II amino propeptide-processing enzyme, procollagen I N-proteinase, PC I-NP, procollagen N-endopeptidase, pNPI | ENSG00000087116 | |
| ADAMTS3 | Procollagen II amino propeptide-processing enzyme, procollagen II N-proteinase, PC II-NP | ENSG00000156140 | ||
| ADAMTS4 | 3.4.24.82 | Aggrecanase-1, ADMP-1 | ENSG00000158859 | |
| ADAMTS5 | Aggrecanase-2, ADMP-2, ADAMTS11 | ENSG00000154736 | ||
| ADAMTS6 | – | ENSG00000049192 | ||
| ADAMTS7 | COMPase | ENSG00000136378 | ||
| ADAMTS8 | METH-2, METH-8 | ENSG00000134917 | ||
| ADAMTS9 | – | ENSG00000163638 | ||
| ADAMTS10 | – | ENSG00000142303 | ||
| ADAMTS12 | – | ENSG00000151388 | ||
| ADAMTS13 | von Willebrand factor-cleaving protease, vWF-CP | ENSG00000160323 | Loss-of-function mutations of autoimmune antibodies are associated with thrombotic thrombocytopenic purpura | |
| ADAMTS14 | – | ENSG00000138316 | ||
| ADAMTS15 | – | ENSG00000166106 | ||
| ADAMTS16 | – | ENSG00000145536 | ||
| ADAMTS17 | – | ENSG00000140470 | ||
| ADAMTS18 | ADAMTS21 | ENSG00000140873 | ||
| ADAMTS19 | – | ENSG00000145808 | ||
| ADAMTS20 | – | ENSG00000173157 | ||
| PAPLN | Papilin | ENSG00000100767 |
Other family members include AC104758.12-5 (FLJ00317 protein Fragment ENSG00000231463), AC139425.3-1 (ENSG00000225577), and AC126339.6-1 (ENSG00000225734).
Glossary
Abbreviations:
- ARP100
2-([{1,1′-biphenyl}-4-ylsulfonyl]-[1-methylethoxy]amino)-N-hydroxyacetamide
- CL82189
N-(4-[4-morpholinyl]butyl)-2-benzofurancarboxamide hydrochloride
- WAY170523
N-(2-[4-{([2-{(hydroxyamino)carbonyl}-4,6-dimethylphenyl) (phenylmethyl) amino]sulfonyl} phenoxy]ethyl)-2-benzofurancarboxamide
Further Reading
Catania JM, Chen G, Parrish AR (2007). Role of matrix metalloproteinases in renal pathophysiologies. Am J Physiol -Renal Physiol292: F905–F911.
Charrier-Hisamuddin L, Laboisse CL, Merlin D (2008). ADAM-15: a metalloprotease that mediates inflammation. FASEB J22: 641–653.
Christiaens V, Lijnen HR (2006). Role of the fibrinolytic and matrix metalloproteinase systems in development of adipose tissue. Arch Physiol Biochem112: 254–259.
Clark IM, Swingler TE, Sampieri CL, Edwards DR (2008). The regulation of matrix metalloproteinases and their inhibitors. Int J Biochem Cell Biol40: 1362–1378.
DasGupta S, Murumkar PR, Giridhar R, Yadav MR (2009). Current perspective of TACE inhibitors: a review. Bioorg Med Chem17: 444–459.
Greenlee KJ, Werb Z, Kheradmand F (2007). Matrix metalloproteinases in lung: multiple, multifarious, and multifaceted. Physiol Rev87: 69–98.
Gueders MM, Foidart JM, Noel A, Cataldo DD (2006). Matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs in the respiratory tract: potential implications in asthma and other lung diseases. Eur J Pharmacol533: 133–144.
Gupta SP (2007). Quantitative structure-activity relationship studies on zinc-containing metalloproteinase inhibitors. Chem Rev107: 3042–3087.
Hu J, Van den Steen PE, Sang QX, Opdenakker G (2007). Matrix metalloproteinase inhibitors as therapy for inflammatory and vascular diseases. Nat Rev Drug Discov6: 480–498.
Hynes NE & Schlange T (2006). Targeting ADAMS and ERBBs in lung cancer. Cancer Cell10: 7–11.
Itoh Y, Seiki M (2006). MT1-MMP: a potent modifier of pericellular microenvironment. J Cell Physiol206: 1–8.
MacFadyen RJ (2007). Can matrix metalloproteinase inhibitors provide a realistic therapy in cardiovascular medicine? Curr Opin Pharmacol7: 171–178.
Mastroianni CM, Liuzzi GM (2007). Matrix metalloproteinase dysregulation in HIV infection: implications for therapeutic strategies. Trends Mol Med13: 449–459.
Medina C, Radomski MW (2006). Role of matrix metalloproteinases in intestinal inflammation. J Pharmacol Exp Ther318: 933–938.
Murphy G (2008). The ADAMs: signalling scissors in the tumour microenvironment. Nat Rev Cancer8: 929–941.
O'Brien P & O'Connor BF (2008). Seprase: an overview of an important matrix serine protease. Biochim Biophys Acta, 1784, 1130–1145.
Overall CM, Kleifeld O (2006). Tumour microenvironment – opinion: validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy. Nat Rev Cancer6: 227–239.
Page-McCaw A, Ewald AJ, Werb Z (2007). Matrix metalloproteinases and the regulation of tissue remodelling. Nat Rev Mol Cell Biol8: 221–233.
Pirard B (2007). Insight into the structural determinants for selective inhibition of matrix metalloproteinases. Drug Discov Today12: 640–646.
Reiss K, Ludwig A, Saftig P (2006). Breaking up the tie: disintegrin-like metalloproteinases as regulators of cell migration in inflammation and invasion. Pharmacol Ther111: 985–1006.
Rengel Y, Ospelt C & Gay S (2007). Proteinases in the joint: clinical relevance of proteinases in joint destruction. Arthritis Res Ther9: 221.
Rocks N, Paulissen G, El Hour M et al. (2008). Emerging roles of ADAM and ADAMTS metalloproteinases in cancer. Biochimie90: 369–379.
Rosell A & Lo EH (2008). Multiphasic roles for matrix metalloproteinases after stroke. Curr Opin Pharmacol8: 82–89.
Rosenberg GA (2009). Matrix metalloproteinases and their multiple roles in neurodegenerative diseases. Lancet Neurol8: 205–216.
Schulz R (2007). Intracellular targets of matrix metalloproteinase-2 in cardiac disease: rationale and therapeutic approaches. Annu Rev Pharmacol Toxicol47: 211–242.
Shah BH & Catt KJ (2006). TACE-dependent EGF receptor activation in angiotensin-II-induced kidney disease. Trends Pharmacol Sci27: 235–237.
Shi YB, Fu L, Hasebe T, Ishizuya-Oka A (2007). Regulation of extracellular matrix remodeling and cell fate determination by matrix metalloproteinase stromelysin-3 during thyroid hormone-dependent post-embryonic development. Pharmacol Ther116: 391–400.
Stefanidakis M, Koivunen E (2006). Cell-surface association between matrix metalloproteinases and integrins: role of the complexes in leukocyte migration and cancer progression. Blood108: 1441–1450.
Tveita A, Rekvig OP, Zykova SN (2008). Glomerular matrix metalloproteinases and their regulators in the pathogenesis of lupus nephritis. Arthritis Res Ther10: 229.
Verma RP, Hansch C (2007). Matrix metalloproteinases (MMPs): chemical-biological functions and (Q)SARs. Bioorg Med Chem15: 2223–2268.
Vincenti MP, Brinckerhoff CE (2007). Signal transduction and cell-type specific regulation of matrix metalloproteinase gene expression: can MMPs be good for you? J Cell Physiol213: 355–364.
Webster NL, Crowe SM (2006). Matrix metalloproteinases, their production by monocytes and macrophages and their potential role in HIV-related diseases. J Leukoc Biol80: 1052–1066.
Wilson TJ, Singh RK (2008). Proteases as modulators of tumor-stromal interaction: primary tumors to bone metastases. Biochim Biophys Acta1785: 85–95.
Wolfe MS (2009). Intramembrane proteolysis. Chem Rev109: 1599–1612.
Yan C, Boyd DD (2007). Regulation of matrix metalloproteinase gene expression. J Cell Physiol211: 19–26.
Zolkiewska A (2008). ADAM proteases: ligand processing and modulation of the Notch pathway. Cell Mol Life Sci65: 2056–2068.
References
- Chen JM, et al. J Am Chem Soc. 2000;122:9648–9654. [Google Scholar]
- Tuccinardi T, et al. Bioorg Med Chem. 2006;14:4260–4276. doi: 10.1016/j.bmc.2006.01.056. [DOI] [PubMed] [Google Scholar]