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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

Molecular and Cellular Biology portal

UpToDate Contents

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English Journal

Activity-Dependent Photoaffinity Labeling of Metalloproteases.

Prely L1, Klein T1, Geurink PP2, Paal K1, Overkleeft HS3, Bischoff R4.
Methods in molecular biology (Clifton, N.J.).Methods Mol Biol.2017;1491:103-111.
Metalloproteases, notably members of the matrix metalloprotease (MMP) and A Disintegrin And Metalloprotease (ADAM) families play crucial roles in tissue remodeling, the liberation of growth factors and cytokines from cell membranes (shedding) and cell-cell or cell-matrix interactions. Activity of MM
PMID 27778284

2-Deoxy glucose regulate MMP-9 in a SIRT-1 dependent and NFkB independent mechanism.

Edatt L1, Haritha K1, Sruthi TV1, Aswini P1, Sameer Kumar VB2.
Molecular and cellular biochemistry.Mol Cell Biochem.2016 Dec;423(1-2):197-206. Epub 2016 Oct 4.
MMP9 is a member of the family of zinc-containing endopeptidases which degrade various components of the extracellular matrix, thereby regulating matrix remodeling. Since matrix remodeling plays an important role during growth and progression of cancer and considering the fact that, tumor cells swit
PMID 27704463

Recent discovery of non-nucleobase thymidine phosphorylase inhibitors targeting cancer.

Bera H1, Chigurupati S2.
European journal of medicinal chemistry.Eur J Med Chem.2016 Nov 29;124:992-1003. doi: 10.1016/j.ejmech.2016.10.032. Epub 2016 Oct 17.
Thymidine phosphorylase (TP, EC 2.4.2.4), an enzyme involved in pyrimidine salvage pathway, is identical to platelet-derived endothelial cell growth factor (PD-ECGF) and gliostatin. It is extremely upregulated in a variety of solid tumours. The TP amplification is associated with concomitant overexp
PMID 27783978

Japanese Journal

新規疼痛制御分子としてのマクロファージ由来マトリックスメタロプロテアーゼ12 の可能性

小林悠佳,岸岡史郎
PAIN RESEARCH 30(1), 37-45, 2015
… Increasing evidence suggests that matrix metalloproteases (MMPs), which are proteases for degradation of extracellular matrix, may involve in neuroinflammation through induction of cytokines and chemokines. …
NAID 130005061789

Celecoxib down-regulates mechanically induced ADAMTS-4 gene expression in 3D cultured tissue of human synovium-derived cells at lower concentration than indomethacin

Kondo Mayo,Nakata Ken,Kakudo Kenji
Journal of Osaka Dental University 48(1), 55-59, 2014-04
… We developed the cyclic loading bioreactor, in which matrix metalloproteases (MMPs) and a disintegrin, and metalloproteinase with thrombospondin motifs (ADAMTSs) are induced by mechanical stimulation to three-dimensional (3D) cultured tissue. …
NAID 110009810299

Related Pictures

Matrix metalloproteinase 15; Membrane-type Biochemistry/Enzyme/Metalloproteases Serine protease mechanism by snellios.png Google Images Metalloproteases; Metalloproteinases Metalloproteases - Chemwiki

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関連記事	「metalloprotease」

「metalloprotease」

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

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メタロプロテアーゼ、金属プロテアーゼ

関: metallopeptidase、metalloproteinase

[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.

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metalloproteases