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A metalloproteinase, or metalloprotease, is any protease enzyme whose catalytic mechanism involves a metal. An example of this would be meltrin which plays a significant role in the fusion of muscle cells during embryo development, in a process known as myogenesis.

Most metalloproteases require zinc, but some use cobalt. The metal ion is coordinated to the protein via three ligands. The ligands co-ordinating the metal ion can vary with histidine, glutamate, aspartate, lysine, and arginine.^{[clarification needed]} The fourth coordination position is taken up by a labile water molecule.

Treatment with chelating agents such as EDTA leads to complete inactivation. EDTA is a metal chelator that removes zinc, which is essential for activity. They are also inhibited by the chelator orthophenanthroline.

Classification

There are two subgroups of metalloproteinases:

Exopeptidases, metalloexopeptidases (EC number: 3.4.17).
Endopeptidases, metalloendopeptidases (3.4.24). Well known metalloendopeptidases include ADAM proteins and matrix metalloproteinases.

In the MEROPS database peptidase families are grouped by their catalytic type, the first character representing the catalytic type: A, aspartic; C, cysteine; G, glutamic acid; M, metallo; S, serine; T, threonine; and U, unknown. The serine, threonine and cysteine peptidases utilise the amino acid as a nucleophile and form an acyl intermediate - these peptidases can also readily act as transferases. In the case of aspartic, glutamic and metallopeptidases, the nucleophile is an activated water molecule. In many instances the structural protein fold that characterises the clan or family may have lost its catalytic activity, yet retain its function in protein recognition and binding.

Metalloproteases are the most diverse of the four main protease types, with more than 50 families classified to date. In these enzymes, a divalent cation, usually zinc, activates the water molecule. The metal ion is held in place by amino acid ligands, usually three in number. The known metal ligands are His, Glu, Asp or Lys and at least one other residue is required for catalysis, which may play an electrophillic role. Of the known metalloproteases, around half contain an HEXXH motif, which has been shown in crystallographic studies to form part of the metal-binding site.^[1] The HEXXH motif is relatively common, but can be more stringently defined for metalloproteases as 'abXHEbbHbc', where 'a' is most often valine or threonine and forms part of the S1' subsite in thermolysin and neprilysin, 'b' is an uncharged residue, and 'c' a hydrophobic residue.^[2] Proline is never found in this site, possibly because it would break the helical structure adopted by this motif in metalloproteases.^[1]

Metallopeptidases from family M48 are integral membrane proteins associated with the endoplasmic reticulum and Golgi, binding one zinc ion per subunit. These endopeptidases include CAAX prenyl protease 1, which proteolytically removes the C-terminal three residues of farnesylated proteins.^{[citation needed]}

Metalloproteinase inhibitors are found in numerous marine organisms, including fish, cephalopods, mollusks, algea and bacteria.^[3]

Members of the M50 metallopeptidase family include: mammalian sterol-regulatory element binding protein (SREBP) site 2 protease and Escherichia coli protease EcfE, stage IV sporulation protein FB.

References

^ ^a ^b Rawlings ND, Barrett AJ (1995). "Evolutionary families of metallopeptidases". Methods in Enzymology. Methods in Enzymology. 248: 183–228. doi:10.1016/0076-6879(95)48015-3. ISBN 978-0-12-182149-4. PMID 7674922.
^ Minde DP, Maurice MM, Rüdiger SG (2012). "Determining biophysical protein stability in lysates by a fast proteolysis assay, FASTpp". PLOS ONE. 7 (10): e46147. Bibcode:2012PLoSO...746147M. doi:10.1371/journal.pone.0046147. PMC 3463568. PMID 23056252.
^ Thomas NV, Kim SK (2010). "Metalloproteinase inhibitors: status and scope from marine organisms". Biochemistry Research International. 2010: 845975. doi:10.1155/2010/845975. PMC 3004377. PMID 21197102.

External links

The MEROPS online database for peptidases and their inhibitors: Metallo Peptidases
Metalloproteases at the US National Library of Medicine Medical Subject Headings (MeSH)
Proteopedia: Metalloproteases

This article incorporates text from the public domain Pfam and InterPro IPR008915

UpToDate Contents

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English Journal

Neutrophil elastase and matrix metalloproteinase 12 in cystic fibrosis lung disease.

Wagner CJ1,2,3, Schultz C2,3,4, Mall MA5,6,7,8.
Molecular and cellular pediatrics.Mol Cell Pediatr.2016 Dec;3(1):25. doi: 10.1186/s40348-016-0053-7. Epub 2016 Jul 25.
Chronic lung disease remains the major cause of morbidity and mortality in patients with cystic fibrosis (CF). Recent studies in young children with CF diagnosed by newborn screening identified neutrophil elastase (NE), a major product released from neutrophils in inflamed airways, as a key risk fac
PMID 27456476

Impact of 5A/6A polymorphism of matrix metalloproteinase-3 on recurrent atherosclerotic ischemic stroke in Chinese.

Huang XY1, Han LY1, Huang XD1, Guan CH1, Mao XL1, Ye ZS2.
The International journal of neuroscience.Int J Neurosci.2016 Oct;126(10):936-41. doi: 10.3109/00207454.2015.1088013. Epub 2015 Sep 22.
Little is known about the impact of the 5A/6A polymorphism of matrix metalloproteinase-3 (MMP-3) on recurrence of atherosclerotic ischemic stroke in Chinese. The aim of this study was to investigate the association of MMP-3 serum level and 5A/6A genetic polymorphism with the recurrence of atheroscle
PMID 26314579

Rap2b promotes proliferation, migration, and invasion of lung cancer cells.

Peng YG1,2, Zhang ZQ2, Chen YB1, Huang JA1.
Journal of receptor and signal transduction research.J Recept Signal Transduct Res.2016 Oct;36(5):459-64. doi: 10.3109/10799893.2015.1122044. Epub 2015 Dec 16.
Rap2b, a member of the guanosine triphosphate-binding proteins, is widely up-regulated in many types of tumors. However, the functional role of Rap2b in tumorigenesis of lung cancer remains to be fully elucidated. In this study, we investigated the effect of Rap2b on the lung cancer malignant phenot
PMID 26671640

Japanese Journal

Shedding of kidney injury molecule-1 by membrane-type 1 matrix metalloproteinase

Luyang Guo,Takahisa Takino,Yoshio Endo [他]
The journal of biochemistry 152(5), 425-432, 2012-11
NAID 40019507331

HIF-1α Contributes to Hypoxia-induced Invasion and Metastasis of Esophageal Carcinoma via Inhibiting E-cadherin and Promoting MMP-2 Expression

Jing Shao-Wu,Wang Ya-Di,Kuroda Masahiro,Su Jing-Wei,Sun Guo-Gui,Liu Qing,Cheng Yun-Jie,Yang Cong-Rong
Acta Medica Okayama 66(5), 399-407, 2012-10
… mRNA and protein expression of HIF-1α, E-cadherin and matrix metalloproteinase-2 (MMP-2) under hypoxia were detected by RT-PCR and Western blotting. …
NAID 120004873436

Effects of site-directed mutagenesis of Asn116 in the β-hairpin of the N-terminal domain of thermolysin on its activity and stability

Menach Evans,Yasukawa Kiyoshi,Inouye Kuniyo
Journal of Biochemistry 152(3), 231-239, 2012-09
NAID 40019415197

Related Pictures

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★リンクテーブル★

リンク元	「メタロプロテアーゼ」「metalloprotease」「metallopeptidase」
拡張検索	「membrane-associated matrix metalloproteinase」「matrix metalloproteinase 10」「matrix metalloproteinase 12」「matrix metalloproteinase 17」「matrix metalloproteinase」
関連記事	「metalloproteinases」

「メタロプロテアーゼ」

Peptidase_M50
Identifiers
Symbol	Peptidase_M50
Pfam	PF02163
Pfam clan	CL0126
InterPro	IPR008915
MEROPS	M50
OPM superfamily	205
OPM protein	3b4r
Available protein structures:
Pfam	structures
PDB	RCSB PDB; PDBe; PDBj
PDBsum	structure summary

Available protein structures:
Pfam	structures
PDB	RCSB PDB; PDBe; PDBj
PDBsum	structure summary

Peptidase_M48
Identifiers
Symbol	Peptidase_M48
Pfam	PF01435
Pfam clan	CL0126
InterPro	IPR001915
MEROPS	M48
OPM superfamily	460
OPM protein	4aw6
Available protein structures:
Pfam	structures
PDB	RCSB PDB; PDBe; PDBj
PDBsum	structure summary

　　[★]

英: metalloprotease, metalloproteinase
同: 金属プロテアーゼ、メタロプロテイナーゼ

「metalloprotease」

　　[★]

メタロプロテアーゼ、金属プロテアーゼ

関: metallopeptidase、metalloproteinase

「metallopeptidase」

　　[★]

メタロペプチダーゼ

関: metalloprotease、metalloproteinase

「membrane-associated matrix metalloproteinase」

　　[★]

膜結合型マトリックスメタロプロテアーゼ、膜型マトリックスメタロプロテアーゼ

「matrix metalloproteinase 10」

　　[★]

マトリックスメタロプロテアーゼ10

関: MMP-10

「matrix metalloproteinase 12」

　　[★]

マトリックスメタロプロテアーゼ12

関: MMP-12

「matrix metalloproteinase 17」

　　[★]

マトリックスメタロプロテアーゼ17

関: MMP-17

「matrix metalloproteinase」

　　[★] マトリックスメタロプロテアーゼ MMP

「metalloproteinases」

　　[★] メタロプロテアーゼ

[pmid7674922-1] Rawlings ND, Barrett AJ (1995). "Evolutionary families of metallopeptidases". Methods in Enzymology. Methods in Enzymology. 248: 183–228. doi:10.1016/0076-6879(95)48015-3. ISBN 978-0-12-182149-4. PMID 7674922.

[2] Minde DP, Maurice MM, Rüdiger SG (2012). "Determining biophysical protein stability in lysates by a fast proteolysis assay, FASTpp". PLOS ONE. 7 (10): e46147. Bibcode:2012PLoSO...746147M. doi:10.1371/journal.pone.0046147. PMC 3463568. PMID 23056252.

[3] Thomas NV, Kim SK (2010). "Metalloproteinase inhibitors: status and scope from marine organisms". Biochemistry Research International. 2010: 845975. doi:10.1155/2010/845975. PMC 3004377. PMID 21197102.

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 Catalytically perfect enzyme Coenzyme Cofactor Enzyme catalysis Enzyme kinetics Lineweaver–Burk plot Michaelis–Menten kinetics

Regulation	Allosteric regulation Cooperativity Enzyme inhibitor

Classification	EC number Enzyme superfamily Enzyme family List of enzymes

Types	EC1 Oxidoreductases (list) EC2 Transferases (list) EC3 Hydrolases (list) EC4 Lyases (list) EC5 Isomerases (list) EC6 Ligases (list)

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案内

metalloproteinase