Information on EC 3.4.24.65 - macrophage elastase

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The expected taxonomic range for this enzyme is: Euarchontoglires

EC NUMBER
COMMENTARY
3.4.24.65
-
RECOMMENDED NAME
GeneOntology No.
macrophage elastase
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
Hydrolysis of soluble and insoluble elastin. Specific cleavages are also produced at -Ala14-/-Leu- and -Tyr16-/-Leu- in the B chain of insulin
show the reaction diagram
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
hydrolysis of peptide bond
-
-
-
-
SYNONYMS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
HME
-
-
-
-
Macrophage elastase
-
-
-
-
Matrix metalloproteinase-12
-
-
-
-
Metalloelastase
-
-
-
-
MME
-
-
-
-
MMP-12
-
-
-
-
CAS REGISTRY NUMBER
COMMENTARY
146888-86-0
-
150680-47-0
-
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
human
SwissProt
Manually annotated by BRENDA team
MMP-12 expressed in Oryctolagus cuniculus
-
-
Manually annotated by BRENDA team
recombinant
-
-
Manually annotated by BRENDA team
Balb/c and C57BL/6 mice
-
-
Manually annotated by BRENDA team
C57BL/6 mice
-
-
Manually annotated by BRENDA team
ICGN strain as a model for renal fibrosis
-
-
Manually annotated by BRENDA team
mouse
-
-
Manually annotated by BRENDA team
Mus musculus C57BL/6
C57BL/6 mice
-
-
Manually annotated by BRENDA team
male Wistar rats
-
-
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
-
degradation of elastin is central to the pathogenesis of emphysema
malfunction
-
MMP12 is implicated in inflammatory respiratory disorders such as asthma, pulmonary fibrosis and chronic obstructive pulmonary disease, with a critical role of MMP12 in the development of emphysema. MMP inhibitors applied in animal models of emphysema are successful in reducing lung inflammation
physiological function
-
HME is able to degrade extracellular matrix components such as elastin and is involved in tissue remodeling processes. Overexpression of HME is strongly correlated with the reduced angiogenesis and vascular invasion of gastric carcinoma
physiological function
-
macrophage elastase is able to degrade extracellular matrix components such as elastin and is involved in tissue remodeling in inflammatory respiratory diseases such as chronic obstructive pulmonary diseases, including emphysema. MMP-12 is also involved in asthma and fibrosis. Inhibitors demonstrate a reduction in both the inflammatory process and airspace enlargement in lung tissue. MMP-12 plays a predominant role in the inflammatory process induced by cigarette smoke
physiological function
-
macrophage elastase is able to degrade extracellular matrix components such as elastin and is involved in tissue remodeling in inflammatory respiratory diseases such as chronic obstructive pulmonary diseases, including emphysema. MMP-12 is involved in fibrosis, mechanism, overview. Balb/c mice are resistant to the development of pulmonary fibrosis, while C57BL/6 mice are not, overview
physiological function
-
macrophage-derived MMP-12 may activate angiostatin and function in host response. MMP-12 expression in cancer cells correlates with tumor aggressiveness
physiological function
-
MMP12 is a lead player in the direct killing of bacteria sequestered in the phagolysosomes. MMP12 aggregates onto the bacteria that are trapped inside the phagolysosomes and disrupts the cell wall constituents, resulting in bacterial death, overview
physiological function
-
MMP12 is involved in bacterial clearance. Intracellular stores of MMP12 are mobilized to macrophage phagolysosomes after the ingestion of bacterial pathogens. Once inside phagolysosomes, MMP12 adheres to bacterial cell walls where it disrupts cellular membranes resulting in bacterial death. The bacterial killing requires the SR20 sequence, 344-SRNQLFLFKDEKYWLINNLV-363, which alone is also active, but shorter four-amino-acid peptides, Ser-Gly-Arg-Gln, Lys-Asp-Asp-Lys and Lys-Asp-Glu-Lys, do not show antimicrobial activity, suggesting that the loop structure of the protein is required for bacterial killing. MMP12 is implicated in several disease processes, including emphysema
physiological function
-
MMP-12 leads to elastin degradation in BALB/c mice with eosinophilic meningitis caused by Angiostrongylus cantonensis
SUBSTRATE
PRODUCT                      
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
2,4-dinitrophenyl-Arg-Pro-Leu-Ala-Ala-Trp-Arg-Ser-NH2 + H2O
?
show the reaction diagram
-
-
-
?
2,4-dinitrophenyl-Arg-Pro-Leu-Ala-Arg-Trp-Arg-Ser-NH2 + H2O
?
show the reaction diagram
-
-
-
?
2,4-dinitrophenyl-Arg-Pro-Leu-Ala-Glu-Trp-Arg-Ser-NH2 + H2O
?
show the reaction diagram
-
-
-
?
2,4-dinitrophenyl-Arg-Pro-Leu-Ala-Leu-Trp-Arg-Ser-NH2 + H2O
?
show the reaction diagram
-
-
-
?
2,4-dinitrophenyl-Arg-Pro-Leu-Ala-Lys-Trp-Arg-Ser-NH2 + H2O
?
show the reaction diagram
-
-
-
?
2,4-dinitrophenyl-Arg-Pro-Leu-Ala-Phe-Trp-Arg-Ser-NH2 + H2O
?
show the reaction diagram
-
-
-
?
2,4-dinitrophenyl-Arg-Pro-Leu-Ala-Ser-Trp-Arg-Ser-NH2 + H2O
?
show the reaction diagram
-
-
-
?
2,4-dinitrophenyl-Arg-Pro-Leu-Ala-Trp-Trp-Arg-Ser-NH2 + H2O
?
show the reaction diagram
-
-
-
?
2,4-dinitrophenyl-Arg-Pro-Leu-Ala-Tyr-Trp-Arg-Ser-NH2 + H2O
?
show the reaction diagram
-
-
-
?
alpha-1-antitrypsin + H2O
?
show the reaction diagram
-
recombinant enzyme rHME
-
?
alpha-casein + H2O
?
show the reaction diagram
-
-
-
-
?
alpha1-antitrypsin + H2O
?
show the reaction diagram
-
-
-
-
?
beta-casein + H2O
?
show the reaction diagram
-
-
-
-
?
casein + H2O
?
show the reaction diagram
-
-
-
-
?
casein + H2O
?
show the reaction diagram
-
degradation
-
-
?
casein + H2O
?
show the reaction diagram
Mus musculus C57BL/6
-
-
-
-
?
chondroitan sulfate + H2O
?
show the reaction diagram
-
recombinant enzyme rHME
-
?
Collagen type I + H2O
?
show the reaction diagram
-
the potential of MMP-12 in recognizing sites in human skin collagen types I and III has been investigated. The catalytic domain of MMP-12 binds to the triple helix and cleaves the typical sites -Gly775-Leu776- in alpha-2 type I collagen and -Gly775-Ile776- in alpha-1 type I and type III collagens and at multiple other sites in both collagen types. The region around these typical sites contains comparatively less prolines, of which some have been proven to be only partially hydroxylated
-
-
?
Collagen type III + H2O
?
show the reaction diagram
-
the potential of MMP-12 in recognizing sites in human skin collagen types I and III has been investigated. The catalytic domain of MMP-12 binds to the triple helix and cleaves the typical sites -Gly775-Leu776- in alpha-2 type I collagen and -Gly775-Ile776- in alpha-1 type I and type III collagens and at multiple other sites in both collagen types. The region around these typical sites contains comparatively less prolines, of which some have been proven to be only partially hydroxylated
-
-
?
DQ-collagen I + H2O
?
show the reaction diagram
-
-
-
-
?
DQ-collagen IV + H2O
?
show the reaction diagram
-
-
-
-
?
Elastin + H2O
?
show the reaction diagram
-
-
-
-
?
Elastin + H2O
?
show the reaction diagram
-
-
-
?
Elastin + H2O
?
show the reaction diagram
-
-
-
?
Elastin + H2O
?
show the reaction diagram
-
-
-
-
?
Elastin + H2O
?
show the reaction diagram
-
degradation
-
-
?
Elastin + H2O
?
show the reaction diagram
-
MMP-12 is active against multiple extracellular protein substrates such as elastin, its effect on elastin is central to emphysema in the lung and photoaging of skin, its expression in the skin increases on photodamaged skin and upon aging, cleavage site determination and peptide mapping by mass spectrometry, based on the human tropoelastin isoform 9 sequence, SwissProt accession number P15502-9, preference of amino acids Ala and Gly at subsites, overview
-
-
?
elastin fELN-125 + H2O
?
show the reaction diagram
-
-
-
-
?
enactin + H2O
?
show the reaction diagram
-
recombinant enzyme rHME
-
?
extracellular matrix protein + H2O
?
show the reaction diagram
-
may be required for macrophages to penetrate basement membranes and remodel injured tissue during inflammation
-
?
fEln-100 + H2O
?
show the reaction diagram
-
alpha-elastin
-
-
?
Fibronectin + H2O
?
show the reaction diagram
-
-
-
-
?
Fibronectin + H2O
?
show the reaction diagram
-
-
-
-
?
Fibronectin + H2O
?
show the reaction diagram
-
degradation
-
-
?
Fibronectin + H2O
?
show the reaction diagram
-
recombinant enzyme rHME
-
?
Gelatin + H2O
?
show the reaction diagram
-
-
-
-
?
Gelatin + H2O
?
show the reaction diagram
-
-
-
-
?
heparan sulfate + H2O
?
show the reaction diagram
-
recombinant enzyme rHME
-
?
human apolipoprotein (alpha) + H2O
?
show the reaction diagram
-
cleaves in the linker region between kringles IV-4 and IV-5
-
?
Insulin B-chain + H2O
?
show the reaction diagram
-
hydrolyzes Ala-Leu and Tyr-Leu, not His10-Leu11, on amino side of Leu-residue, not Val-residue
-
-
-
Laminin + H2O
?
show the reaction diagram
-
-
-
-
?
Laminin + H2O
?
show the reaction diagram
-
degradation
-
-
?
Laminin + H2O
?
show the reaction diagram
-
recombinant enzyme rHME
-
?
Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2 + H2O
?
show the reaction diagram
-
-
-
-
?
Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2 + H2O
?
show the reaction diagram
-
soluble Knight's peptide substrate MCA-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2
-
-
?
Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2 + H2O
Mca-Pro-Leu-Gly + Leu-Dpa-Ala-Arg-NH2
show the reaction diagram
-
-
-
-
?
TNF-alpha + H2O
?
show the reaction diagram
-
-
-
-
?
triple helical peptide alpha1(V) + H2O
?
show the reaction diagram
-
collagen V fibrils
-
-
?
Type IV collagen + H2O
?
show the reaction diagram
-
-
-
-
?
Type IV collagen + H2O
?
show the reaction diagram
-
-
-
-
?
Type IV collagen + H2O
?
show the reaction diagram
-
recombinant enzyme rHME
-
?
type-IV collagen + H2O
?
show the reaction diagram
-
degradation
-
-
?
Elastin + H2O
?
show the reaction diagram
-
a key structural component of the lung extracellular matrix
-
-
?
Elastin + H2O
additional information
-
-
-
-
-
-
Elastin + H2O
additional information
-
-
preferentially cleaves on amino-side of Leus, not Val
products of elastin hydrolysis are predominantly high MW peptides, MW 90000-100000
-
Elastin + H2O
additional information
-
-
bovine ligament elastin
-
-
-
Mca-Pro-Leu-Gly-Leu-Glu-Glu-Ala-Dpa-NH2 + H2O
Mca-Pro-Leu-Gly + Leu-Glu-Glu-Ala-Dpa-NH2
show the reaction diagram
-
selective cleavage, the Glu-Glu motif interacts with the S'2 and S'3 subsites of MMP-12
-
-
?
additional information
?
-
-
acetyl-Ala-Ala-Ala 4-nitroanilide or benzyloxycarbonyl-Ala 2-naphthyl esters
-
-
-
additional information
?
-
-
no substrates are Glu-Ala-Leu-Tyr-Leu-Val (i.e. residues 13-18 of insulin B-chain)
-
-
-
additional information
?
-
P45452
able to degrade all components of extracellular matrix
-
?
additional information
?
-
-
important role in inflammatory processes contributing to tissue remodelling
-
?
additional information
?
-
-
macrophage-derived overexpression of MMP-12 causes accelerated atherosclerosis. Overexpression of human MMP-12 in macrophages of rabbits results in enhanced atherosclerosis
-
-
-
additional information
?
-
-
MMP-12 does not appear to be involved in the fibrogenic pathway of bleomycin-induced lung injury. MMP-12 deficiency does not influence the bleomycin-induced raise of neither TGF-beta-1 nor TIMP-1 in lung, which are described as important pro-fibrogenic effectors
-
-
-
additional information
?
-
-
MMP-12 exacerbates atherosclerosis, emphysema, aortic aneurysm, rheumatoid arthritis, and inflammatory bowel disease
-
-
-
additional information
?
-
-
protease-activated receptor 1, PAR-1, controls MMP-12 release
-
-
-
additional information
?
-
-
the enzyme induces inflammation in murine airways after direct instillation eliciting the inflammatory response by neutrophil influx, cytokine release, and gelatinase activation, and delayed response by macrophage recruitment, overview
-
-
-
additional information
?
-
-
the enzyme induces inflammation in murine airways after direct instillation eliciting the inflammatory response by neutrophil influx, cytokine release, and gelatinase activation, and delayed response by macrophage recruitment, resident alveolar macrophages and recruited neutrophils do not play a role in the delayed macrophage recruitment induced by MMP-12, overview
-
-
-
additional information
?
-
-
the enzyme is important for allowing macrophage migration through extracellular matrix, and probably plays an important role in the causation of inflammatory bowel disease, IBD, MMP-12 expression is increased in ulcerative colitis and in Crohns disease
-
-
-
additional information
?
-
-
the enzyme is involved in the development of chronic obstructive pulmonary disease and airway inflammation and is associated with allergic bronchial asthma, phenotype, overview
-
-
-
additional information
?
-
-
the enzyme plays an important role in inflammatory processes and is involved in a number of physiological or pathological situations, such as conversion of plasminogen into angiostatin, allergic airway inflammation, vascular remodeling or alteration, as well as emphysema
-
-
-
additional information
?
-
-
active site structure, surfaces and internal pocket between helix B and beta-strand IV in the active-site cleft, overview
-
-
-
additional information
?
-
-
no activity with interstitial collagens or gelatin
-
-
-
additional information
?
-
-
HME has the ability to convert plasminogen into angiostatin, an essential and potent inhibitor of endothelial cell proliferation and tumor angiogenesis
-
-
-
additional information
?
-
-
MMP12 has a direct bactericidal activity but is unable to kill certain bacteria such as those that have the ability to escape the phagosome, which is exerted by the C-terminal domain, that also alone shows bacterial killing activity
-
-
-
additional information
?
-
-
MMP12 is involved in bacterial clearance. Intracellular stores of MMP12 are mobilized to macrophage phagolysosomes after the ingestion of bacterial pathogens. Once inside phagolysosomes, MMP12 adheres to bacterial cell walls where it disrupts cellular membranes resulting in bacterial death. The bacterial killing requires the SR20 sequence, 344-SRNQLFLFKDEKYWLINNLV-363, which alone is also active, but shorter four-amino-acid peptides, Ser-Gly-Arg-Gln, Lys-Asp-Asp-Lys and Lys-Asp-Glu-Lys, do not show antimicrobial activity, suggesting that the loop structure of the protein is required for bacterial killing
-
-
-
additional information
?
-
-
MMP-12 has in vitro, a wide variety of potential substrates, including type IV collagen, fibronectin, laminin, and gelatin, as well as non-matrix proteins such as alpha1-antitrypsin and latent TNF-alpha
-
-
-
additional information
?
-
-
MMP12, through the catalytic domain, can cleave a variety of substrates in addition to elastin such as type IV collagen, fibronectin, and gelatin in in vitro assays
-
-
-
additional information
?
-
Mus musculus C57BL/6
-
protease-activated receptor 1, PAR-1, controls MMP-12 release
-
-
-
NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
casein + H2O
?
show the reaction diagram
-
degradation
-
-
?
Elastin + H2O
?
show the reaction diagram
-
-
-
-
?
Elastin + H2O
?
show the reaction diagram
-
-
-
-
?
Elastin + H2O
?
show the reaction diagram
-
degradation
-
-
?
Elastin + H2O
?
show the reaction diagram
-
MMP-12 is active against multiple extracellular protein substrates such as elastin, its effect on elastin is central to emphysema in the lung and photoaging of skin, its expression in the skin increases on photodamaged skin and upon aging
-
-
?
Elastin + H2O
?
show the reaction diagram
-
a key structural component of the lung extracellular matrix
-
-
?
extracellular matrix protein + H2O
?
show the reaction diagram
-
may be required for macrophages to penetrate basement membranes and remodel injured tissue during inflammation
-
?
Fibronectin + H2O
?
show the reaction diagram
-
degradation
-
-
?
Gelatin + H2O
?
show the reaction diagram
-
-
-
-
?
type-IV collagen + H2O
?
show the reaction diagram
-
degradation
-
-
?
Laminin + H2O
?
show the reaction diagram
-
degradation
-
-
?
additional information
?
-
P45452
able to degrade all components of extracellular matrix
-
?
additional information
?
-
-
important role in inflammatory processes contributing to tissue remodelling
-
?
additional information
?
-
-
macrophage-derived overexpression of MMP-12 causes accelerated atherosclerosis. Overexpression of human MMP-12 in macrophages of rabbits results in enhanced atherosclerosis
-
-
-
additional information
?
-
-
MMP-12 does not appear to be involved in the fibrogenic pathway of bleomycin-induced lung injury. MMP-12 deficiency does not influence the bleomycin-induced raise of neither TGF-beta-1 nor TIMP-1 in lung, which are described as important pro-fibrogenic effectors
-
-
-
additional information
?
-
-
MMP-12 exacerbates atherosclerosis, emphysema, aortic aneurysm, rheumatoid arthritis, and inflammatory bowel disease
-
-
-
additional information
?
-
-
protease-activated receptor 1, PAR-1, controls MMP-12 release
-
-
-
additional information
?
-
-
the enzyme induces inflammation in murine airways after direct instillation eliciting the inflammatory response by neutrophil influx, cytokine release, and gelatinase activation, and delayed response by macrophage recruitment, overview
-
-
-
additional information
?
-
-
the enzyme induces inflammation in murine airways after direct instillation eliciting the inflammatory response by neutrophil influx, cytokine release, and gelatinase activation, and delayed response by macrophage recruitment, resident alveolar macrophages and recruited neutrophils do not play a role in the delayed macrophage recruitment induced by MMP-12, overview
-
-
-
additional information
?
-
-
the enzyme is important for allowing macrophage migration through extracellular matrix, and probably plays an important role in the causation of inflammatory bowel disease, IBD, MMP-12 expression is increased in ulcerative colitis and in Crohns disease
-
-
-
additional information
?
-
-
the enzyme is involved in the development of chronic obstructive pulmonary disease and airway inflammation and is associated with allergic bronchial asthma, phenotype, overview
-
-
-
additional information
?
-
-
the enzyme plays an important role in inflammatory processes and is involved in a number of physiological or pathological situations, such as conversion of plasminogen into angiostatin, allergic airway inflammation, vascular remodeling or alteration, as well as emphysema
-
-
-
additional information
?
-
-
HME has the ability to convert plasminogen into angiostatin, an essential and potent inhibitor of endothelial cell proliferation and tumor angiogenesis
-
-
-
additional information
?
-
-
MMP12 has a direct bactericidal activity but is unable to kill certain bacteria such as those that have the ability to escape the phagosome, which is exerted by the C-terminal domain, that also alone shows bacterial killing activity
-
-
-
additional information
?
-
-
MMP12 is involved in bacterial clearance. Intracellular stores of MMP12 are mobilized to macrophage phagolysosomes after the ingestion of bacterial pathogens. Once inside phagolysosomes, MMP12 adheres to bacterial cell walls where it disrupts cellular membranes resulting in bacterial death. The bacterial killing requires the SR20 sequence, 344-SRNQLFLFKDEKYWLINNLV-363, which alone is also active, but shorter four-amino-acid peptides, Ser-Gly-Arg-Gln, Lys-Asp-Asp-Lys and Lys-Asp-Glu-Lys, do not show antimicrobial activity, suggesting that the loop structure of the protein is required for bacterial killing
-
-
-
additional information
?
-
Mus musculus C57BL/6
-
protease-activated receptor 1, PAR-1, controls MMP-12 release
-
-
-
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Ca2+
-
requirement
Zn2+
-
requirement
Zn2+
-
metalloendopeptidase, contains zinc-binding motif, the catalytic domain that coordiantes the active-site zinc
Zn2+
-
catalytic zinc ion
Zn2+
-
zinc metalloprotease
Zn2+
-
-
Zn2+
-
dependent on
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
(1S,5S,7R)-3-aza-6,8-dioxa-bicyclo[3.2.1]octane-3,7-dicarboxylic acid 7-[(biphenyl-4-ylmethyl)-amide] 3-hydroxyamide
-
-
(1S,5S,7R)-3-biphenyl-4-ylmethyl-2-oxo-3-aza-6,8-dioxa-bicyclo[3.2.1]octane-7-carboxylic acid
-
-
(1S,5S,7R)-3-biphenyl-4-ylmethyl-2-oxo-3-aza-6,8-dioxa-bicyclo[3.2.1]octane-7-carboxylic acid hydroxyamide
-
-
(1S,5S,7R)-3-biphenyl-4-ylmethyl-3-aza-6,8-dioxabicyclo[3.2.1]octane-7-carboxylic acid
-
-
(1S,5S,7R)-3-biphenyl-4-ylmethyl-3-aza-6,8-dioxabicyclo[3.2.1]octane-7-carboxylic acid hydroxyamide
-
-
(3R)-3-([[4-(4'-acetylbiphenyl-4-yl)-5-fluorothiophen-2-yl]carbonyl]amino)-3-phenylpropanoic acid
-
-
(3R)-3-[([5-fluoro-4-[4-(pyridin-4-yl)phenyl]thiophen-2-yl]carbonyl)amino]-3-phenylpropanoic acid
-
-
(3R)-3-[([5-fluoro-4-[4-(trifluoromethoxy)phenyl]thiophen-2-yl]carbonyl)amino]-3-phenylpropanoic acid
-
-
alpha2-Macroglobulin
-
SDS abolishes inhibition
-
alpha2-Macroglobulin
-
SDS abolishes inhibition
-
batimastat
P45452
BB-94
CGS-27023A
-
a hydroxamate inhibitor
CGS27023A
-
-
dexamethasone
-
in vivo inhibition of the human enzyme in mice leading to inhibited cytokine release and neutrophil influx, overview
dithiothreitol
-
-
EDTA
-
Zn2+ at a 1:10 ratio of Zn2+/EDTA protects and reverses, not Ca2+, no reversal by Co2+ or Mg2+
EDTA
-
-
EGTA
-
less effective than EDTA, Ca2+ at a 3:1 ratio of Ca2+/EDTA protects and reverses partially, Zn2+ at a 1:10 ratio of Zn2+/EGTA protects and reverses
N-(3-[(4-bromophenyl)(hydroxy)phosphoryl]-2-[3-[4-(dimethylamino)phenyl]isoxazol-5-yl]propanoyl)-L-alpha-glutamyl-L-alpha-glutamine
-
-
N-isobutyl-N-[4-methoxyphenylsulfonyl] glycyl hydroxamic acid
-
-
N-[(1R)-3-amino-3-oxo-1-phenylpropyl]-5-fluoro-4-[4-(trifluoromethoxy)phenyl]thiophene-2-carboxamide
-
-
N-[3-[(4-bromophenyl)(hydroxy)phosphoryl]-2-[3-(3'-chlorobiphenyl-4-yl)isoxazol-5-yl]propanoyl]-L-alpha-glutamyl-L-alpha-glutamine
-
-
Organic solvents
-
enzyme form B, above 0.5% v/v
-
Rabbit antiserum against purified elastase form B
-
-
-
rolipram
-
in vivo inhibition of the human enzyme in mice leading to inhibited neutrophil influx, overview
TIMP-1
-
a major fibrogenic effector in lungs. Indeed, upon fibrogenic stimuli, large amounts of TIMP-1 in the remodeling tissue are believed to contribute to the creation of a non-degrading environment, leading to the alteration of protease-anti-protease balance, extracellular matrix accumulation, and tissue fibrosis. MMP-12 deficiency does not seem to be involved in TIMP-1 regulation
-
Tissue inhibitor of metalloproteinase
-
i.e. TIMP-1, recombinant enzyme
-
Tissue inhibitor of metalloproteinase
-
i.e. TIMP-1, recombinant enzyme
-
trans-4-[([[4-(4'-acetylbiphenyl-4-yl)-5-fluorothiophen-2-yl]carbonyl]amino)methyl]cyclohexanecarboxylic acid
-
-
trans-4-[[([3-[4-(trifluoromethoxy)phenyl]-1,2-thiazol-5-yl]carbonyl)amino]methyl]cyclohexanecarboxylic acid
-
-
trans-4-[[([4-[4-(trifluoromethoxy)phenyl]thiophen-2-yl]carbonyl)amino]methyl]cyclohexanecarboxylic acid
-
-
trans-4-[[([5-fluoro-4-[4-(trifluoromethoxy)phenyl]thiophen-2-yl]carbonyl)amino]methyl]cyclohexanecarboxylic acid
-
-
trans-4-[[([5-[4-(trifluoromethoxy)phenyl]-1,2-thiazol-3-yl]carbonyl)amino]methyl]cyclohexanecarboxylic acid
-
-
Zn2+
-
at a 3fold molar excess of Zn2+ over chelating agent
marimastat
-
in vivo inhibition of the human enzyme in mice leading to inhibited macrophage recruitment, neutrophil influx, and cytokine release, overview
additional information
-
diisopropylphosphorofluoridate, PCMB, NEM, mersalyl, soybean trypsin inhibitor, acetyltetraalanylchloromethane, phosphoramidon, glycoprotein tissue inhibitor, alpha1-proteinase inhibitor; no inhibition by PMSF (form B)
-
additional information
-
compound E-64, i.e. trans-epoxysuccinyl-L-leucyl-amido-(4-guanidino)butane; no inhibition by PMSF (form B)
-
additional information
-
inhibition of MMP-12 may be a potential modality for the treatment of rheumatoid arthritis
-
additional information
-
alpha1-antitrypsin, hirudin, aprotinin, and pertussis toxin, the G-protein coupled receptor inhibitor, suppress TNF-alpha and MMP-12 production by cigarette smoke-stimulated macrophage, while the PAR-1 agonist TRAP increases the release of MMP-12 and TNF-alpha, overview, TNF-alpha release in alveolar macrophages is related to MMP-12 secretion, alpha1-antitrypsin does not inhibit the activation of the MMP-12 proenzyme
-
additional information
-
inhibitor design and synthesis based on a 3-aza-6,8-dioxa-bicyclo[3.2.1]octane scaffold, library construction and screening, determination of affinity for the catalytic domain of MMP-12 by NMR, overview
-
additional information
-
role of the P'3 position in inhibitor selectivity, overview, interaction of compound 1 with the catalytic domain of MMP12, molecular modeling, overview
-
additional information
-
MMP inhibitors applied in animal models of emphysema are successful in reducing lung inflammation
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
-
MMP-12 expression is 11.9 and 7.3fold, respectively, induced by PWM- and alphaCD3+IL12, MMP-12 expression is increased 7.3fold in ulcerative colitis and 3.6fold in Crohns disease
-
additional information
-
MMP-12 is upregulated after the induction of asthmatic reaction
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.001
fEln-100
-
pH 7.5, 25C, wild-type
-
0.00109
fEln-100
-
pH 7.5, 25C, mutant D124Q/A182G
-
0.00114
fEln-100
-
pH 7.5, 25C, mutant A182G
-
0.00115
fEln-100
-
pH 7.5, 25C, mutant M103F; pH 7.5, 25C, mutant R117S
-
0.00119
fEln-100
-
pH 7.5, 25C, mutant D124Q/M156E/I180S
-
0.00127
fEln-100
-
pH 7.5, 25C, mutant D124Q/I180S
-
0.0013
fEln-100
-
pH 7.5, 25C, mutant I180S
-
0.00135
fEln-100
-
pH 7.5, 25C, mutant D124Q/M156E/F185Y
-
0.00145
fEln-100
-
pH 7.5, 25C, mutant D124Q/M156E/T205K
-
0.00171
fEln-100
-
pH 7.5, 25C, mutant D124Q/M156E/A182G
-
0.00175
fEln-100
-
pH 7.5, 25C, mutant D124Q
-
0.00239
fEln-100
-
pH 7.5, 25C, mutant M156E
-
0.0034
fEln-100
-
pH 7.5, 25C, mutant D124Q/M156E
-
0.00399
fEln-100
-
pH 7.5, 25C, mutant M156E/I180S
-
0.00466
fEln-100
-
pH 7.5, 25C, mutant M156E/A182G
-
0.113
Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2
-
pH 7.5, 25C, mutant D124Q/M156E/T205K; pH 7.5, 25C, mutant R117S
0.118
Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2
-
pH 7.5, 25C, mutant M156E/A182G
0.119
Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2
-
pH 7.5, 25C, mutant M156E/I180S
0.124
Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2
-
pH 7.5, 25C, mutant D124Q/M156E
0.125
Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2
-
pH 7.5, 25C, mutant D124Q; pH 7.5, 25C, mutant M156E
0.128
Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2
-
pH 7.5, 25C, mutant M103F
0.129
Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2
-
pH 7.5, 25C, wild-type
0.13
Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2
-
pH 7.5, 25C, mutant A182G
0.135
Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2
-
pH 7.5, 25C, mutant D124Q/M156E/F185Y
0.17
Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2
-
pH 7.5, 25C, mutant I180S
0.18
Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2
-
pH 7.5, 25C, mutant D124Q/M156E/I180S
0.194
Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2
-
pH 7.5, 25C, mutant D124Q/A182G
0.202
Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2
-
pH 7.5, 25C, mutant D124Q/M156E/A182G
0.241
Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2
-
pH 7.5, 25C, mutant D124Q/I180S
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.001
fEln-100
-
pH 7.5, 25C, mutant D124Q/M156E/A182G; pH 7.5, 25C, mutant D124Q/M156E/I180S
-
0.0018
fEln-100
-
pH 7.5, 25C, mutant D124Q/A182G
-
0.0024
fEln-100
-
pH 7.5, 25C, mutant D124Q/I180S
-
0.0037
fEln-100
-
pH 7.5, 25C, mutant I180S
-
0.0048
fEln-100
-
pH 7.5, 25C, mutant D124Q/M156E/F185Y
-
0.0052
fEln-100
-
pH 7.5, 25C, mutant M156E/I180S
-
0.0057
fEln-100
-
pH 7.5, 25C, mutant A182G
-
0.0065
fEln-100
-
pH 7.5, 25C, mutant D124Q/M156E/T205K
-
0.0072
fEln-100
-
pH 7.5, 25C, mutant R117S
-
0.0092
fEln-100
-
pH 7.5, 25C, mutant M103F
-
0.01
fEln-100
-
pH 7.5, 25C, wild-type
-
0.0117
fEln-100
-
pH 7.5, 25C, mutant M156E
-
0.0124
fEln-100
-
pH 7.5, 25C, mutant D124Q
-
0.0143
fEln-100
-
pH 7.5, 25C, mutant D124Q/M156E
-
0.021
fEln-100
-
pH 7.5, 25C, mutant M156E/A182G
-
6.8
Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2
-
pH 7.5, 25C, mutant M156E/I180S
8.4
Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2
-
pH 7.5, 25C, mutant D124Q/M156E/A182G
9.7
Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2
-
pH 7.5, 25C, mutant D124Q/M156E/I180S
10.6
Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2
-
pH 7.5, 25C, mutant D124Q/A182G
13.7
Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2
-
pH 7.5, 25C, mutant R117S
15.6
Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2
-
pH 7.5, 25C, mutant A182G
16.2
Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2
-
pH 7.5, 25C, mutant D124Q/I180S
16.7
Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2
-
pH 7.5, 25C, mutant D124Q/M156E
16.9
Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2
-
pH 7.5, 25C, mutant M156E
17.1
Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2
-
pH 7.5, 25C, mutant D124Q
17.2
Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2
-
pH 7.5, 25C, mutant M156E/A182G
17.3
Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2
-
pH 7.5, 25C, wild-type
18
Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2
-
pH 7.5, 25C, mutant D124Q/M156E/F185Y; pH 7.5, 25C, mutant D124Q/M156E/T205K
18.7
Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2
-
pH 7.5, 25C, mutant M103F
24.1
Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2
-
pH 7.5, 25C, mutant I180S
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
34.6
DQ-collagen I
-
pH 7.5, 25C
0
29.2
DQ-collagen IV
-
pH 7.5, 25C
0
9.8
elastin fELN-125
-
pH 7.5, 25C
0
0.59
fEln-100
-
pH 7.5, 25C, mutant D124Q/M156E/A182G
0
0.82
fEln-100
-
pH 7.5, 25C, mutant D124Q/M156E/I180S
0
1.31
fEln-100
-
pH 7.5, 25C, mutant M156E/I180S
0
1.66
fEln-100
-
pH 7.5, 25C, mutant D124Q/A182G
0
1.855
fEln-100
-
pH 7.5, 25C, mutant D124Q/I180S
0
2.86
fEln-100
-
pH 7.5, 25C, mutant I180S
0
3.57
fEln-100
-
pH 7.5, 25C, mutant D124Q/M156E/F185Y
0
4.21
fEln-100
-
pH 7.5, 25C, mutant D124Q/M156E
0
4.5
fEln-100
-
pH 7.5, 25C, mutant D124Q/M156E/T205K
0
4.65
fEln-100
-
pH 7.5, 25C, mutant M156E/A182G
0
4.89
fEln-100
-
pH 7.5, 25C, mutant M156E
0
4.97
fEln-100
-
pH 7.5, 25C, mutant A182G
0
7.06
fEln-100
-
pH 7.5, 25C, mutant D124Q
0
7.13
fEln-100
-
pH 7.5, 25C, mutant R117S
0
8.04
fEln-100
-
pH 7.5, 25C, mutant M103F
0
10.69
fEln-100
-
pH 7.5, 25C, wild-type
0
51.57
Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2
-
pH 7.5, 25C, mutant D124Q/M156E/A182G
2206
53.66
Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2
-
pH 7.5, 25C, mutant D124Q/M156E/I180S
2206
54.61
Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2
-
pH 7.5, 25C, mutant D124Q/A182G
2206
57.42
Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2
-
pH 7.5, 25C, mutant M156E/I180S
2206
67.23
Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2
-
pH 7.5, 25C, mutant D124Q/I180S
2206
120.1
Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2
-
pH 7.5, 25C, mutant A182G
2206
120.8
Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2
-
pH 7.5, 25C, mutant R117S
2206
133.4
Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2
-
pH 7.5, 25C, mutant D124Q/M156E/F185Y
2206
133.8
Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2
-
pH 7.5, 25C, wild-type
2206
133.8
Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2
-
pH 7.5, 25C
2206
134.7
Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2
-
pH 7.5, 25C, mutant D124Q/M156E
2206
135.2
Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2
-
pH 7.5, 25C, mutant M156E
2206
136.7
Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2
-
pH 7.5, 25C, mutant D124Q
2206
141.8
Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2
-
pH 7.5, 25C, mutant I180S
2206
145.4
Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2
-
pH 7.5, 25C, mutant M156E/A182G
2206
146.3
Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2
-
pH 7.5, 25C, mutant M103F
2206
159.7
Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2
-
pH 7.5, 25C, mutant D124Q/M156E/T205K
2206
55.4
triple helical peptide alpha1(V)
-
pH 7.5, 25C
0
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0000044
N-(3-[(4-bromophenyl)(hydroxy)phosphoryl]-2-[3-[4-(dimethylamino)phenyl]isoxazol-5-yl]propanoyl)-L-alpha-glutamyl-L-alpha-glutamine
-
-
0.00000019
N-[3-[(4-bromophenyl)(hydroxy)phosphoryl]-2-[3-(3'-chlorobiphenyl-4-yl)isoxazol-5-yl]propanoyl]-L-alpha-glutamyl-L-alpha-glutamine
-
-
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
149
(1S,5S,7R)-3-aza-6,8-dioxa-bicyclo[3.2.1]octane-3,7-dicarboxylic acid 7-[(biphenyl-4-ylmethyl)-amide] 3-hydroxyamide
-
pH 7.0, 25C, recombinant enzyme
0.954
(1S,5S,7R)-3-biphenyl-4-ylmethyl-2-oxo-3-aza-6,8-dioxa-bicyclo[3.2.1]octane-7-carboxylic acid
-
pH 7.0, 25C, recombinant enzyme
425
(1S,5S,7R)-3-biphenyl-4-ylmethyl-2-oxo-3-aza-6,8-dioxa-bicyclo[3.2.1]octane-7-carboxylic acid hydroxyamide
-
pH 7.0, 25C, recombinant enzyme
835
(1S,5S,7R)-3-biphenyl-4-ylmethyl-3-aza-6,8-dioxabicyclo[3.2.1]octane-7-carboxylic acid
-
pH 7.0, 25C, recombinant enzyme
399
(1S,5S,7R)-3-biphenyl-4-ylmethyl-3-aza-6,8-dioxabicyclo[3.2.1]octane-7-carboxylic acid hydroxyamide
-
pH 7.0, 25C, recombinant enzyme
0.000024
(3R)-3-([[4-(4'-acetylbiphenyl-4-yl)-5-fluorothiophen-2-yl]carbonyl]amino)-3-phenylpropanoic acid
-
pH and temperature not specified in the publication
0.000013
(3R)-3-[([5-fluoro-4-[4-(pyridin-4-yl)phenyl]thiophen-2-yl]carbonyl)amino]-3-phenylpropanoic acid
-
pH and temperature not specified in the publication
0.0002
(3R)-3-[([5-fluoro-4-[4-(trifluoromethoxy)phenyl]thiophen-2-yl]carbonyl)amino]-3-phenylpropanoic acid
-
pH and temperature not specified in the publication
0.000085
N-[(1R)-3-amino-3-oxo-1-phenylpropyl]-5-fluoro-4-[4-(trifluoromethoxy)phenyl]thiophene-2-carboxamide
-
pH and temperature not specified in the publication
0.000007
trans-4-[([[4-(4'-acetylbiphenyl-4-yl)-5-fluorothiophen-2-yl]carbonyl]amino)methyl]cyclohexanecarboxylic acid
-
pH and temperature not specified in the publication
0.0036
trans-4-[[([3-[4-(trifluoromethoxy)phenyl]-1,2-thiazol-5-yl]carbonyl)amino]methyl]cyclohexanecarboxylic acid
-
pH and temperature not specified in the publication
0.0004
trans-4-[[([4-[4-(trifluoromethoxy)phenyl]thiophen-2-yl]carbonyl)amino]methyl]cyclohexanecarboxylic acid
-
pH and temperature not specified in the publication
0.00014
trans-4-[[([5-fluoro-4-[4-(trifluoromethoxy)phenyl]thiophen-2-yl]carbonyl)amino]methyl]cyclohexanecarboxylic acid
-
pH and temperature not specified in the publication
0.031
trans-4-[[([5-[4-(trifluoromethoxy)phenyl]-1,2-thiazol-3-yl]carbonyl)amino]methyl]cyclohexanecarboxylic acid
-
pH and temperature not specified in the publication
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
-
-
additional information
-
specific activity 265 cpm/microgram
additional information
-
quantitative enzyme expression analysis by RT-PCR, overview
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
6.8
-
assay at
7
-
assay at
7.4
-
assay at
7.4
-
antimicrobial activity assay at
7.5
-
assay at
8
-
enzyme form B
8
-
assay at
8.5
-
assay at
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
25
-
assay at
33
-
assay at
37
-
assay at
37
-
assay at
37
-
assay at
37
-
assay at
37
-
assay at
37
-
assay at
37
-
antimicrobial activity assay at
37
-
assay at
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
-
MMP-12/tissue inhibitor of metalloproteinase-1 ratio is significantly increased in the CSF of Angiostrongylus cantonensis-infected mice from day 10 p.i., and reaches high levels on days 20 and 25 p.i. MMP-12 production is correlated with elastin degradation, eosinophil count, blood-CSF barrier permeability and pathological changes in the subarachnoid space
Manually annotated by BRENDA team
-
the catalytic domain of human recombinant MMP-12 expressed in Escherichia coli
Manually annotated by BRENDA team
-
airway epithelia
Manually annotated by BRENDA team
-
HME protein levels are 4.50-7.15fold increased in gastric carcinoma samples compared with the non-cancerous controls
Manually annotated by BRENDA team
-
irregular glomerular basement membrane that characterizes Alport syndrome may be mediated, in part, by focal degradation of glomerular basement membrane due to MMP dysregulation, in particular, MMP-12
Manually annotated by BRENDA team
-
only in glomerulonephritic ICGN strain, not in non-glomerulonephritic mouse (immunohistochemistry)
Manually annotated by BRENDA team
-
cigarette smoke increases the expression of MMP-12 in lungs of mice
Manually annotated by BRENDA team
-
MMP-12 suppresses the growth of lung metastases. Mice deficient in macrophage elastase develop significantly more gross Lewis lung carcinoma pulmonary metastases than wild-type counterparts
Manually annotated by BRENDA team
-
patients with chronic obstructive pulmonary disease produce greater quantities of MMP-12 than controls, which may be a critical step in the pathogenesis of chronic obstructive pulmonary disease and emphysema
Manually annotated by BRENDA team
-
increased expression of alveolar mucosa macrophage MMP-12 in HIV-healthy smokers compared to HIV1- healthy nonsmokers. MMP-12 expression is further significantly increased in HIV1- smokers with early emphysema in comparison with both HIV1- healthy nonsmokers and HIV1- healthy smokers. Expression of alveolar mucosa MMP-12 is further increased in HIV1+ smokers with early emphysema over and above the increase in HIV1- smokers with early emphysema
Manually annotated by BRENDA team
-
preferential expression of MMP12 in lung macrophages. MMP12 is predominantly produced by airway epithelia and alveolar macrophages
Manually annotated by BRENDA team
-
tissue culture medium of colchicin-treated inflammatory peritoneal macrophages
Manually annotated by BRENDA team
-
serum-free culture medium conditioned by thioglycollate-elicited peritoneal exudative macrophages
Manually annotated by BRENDA team
-
alveolar macrophages
Manually annotated by BRENDA team
-
alveolar macrophages
Manually annotated by BRENDA team
-
specific for
Manually annotated by BRENDA team
-
MMP-12 is secreted by macrophages at sites of inflammation
Manually annotated by BRENDA team
-
MMP12 is an enzyme predominantly expressed in mature tissue macrophages
Manually annotated by BRENDA team
-
macrophage-like
Manually annotated by BRENDA team
-
ICGN strain, small amounts during early pogression of renal disease, increasing amounts with progressing renal disease (immunohistochemistry)
Manually annotated by BRENDA team
-
16-50 SCCs, in situ detection, overview
Manually annotated by BRENDA team
-
HME is expressed in chronic gastritis with atypical hyperplasia and normal gastric epithelium mucosa. HME protein levels are 4.50-7.15fold increased in gastric carcinoma samples compared with the non-cancerous controls
Manually annotated by BRENDA team
-
mainly expressed by inflammatory macrophages in the rhematoid arthritis synovial membrane. Rheumatoid synovial tissue contains higher levels of MMP-12 messenger RNA than does osteoarthritis synovial tissue. Macrophage-derived MMP-12 may play an important role in the destructive process in rheumatoid arthritis
Manually annotated by BRENDA team
Mus musculus C57BL/6
-
alveolar
-
Manually annotated by BRENDA team
additional information
-
immunohistochemical expression analysis
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
-
recombinant enzyme from Escherichia coli
Manually annotated by BRENDA team
-
native enzyme
-
Manually annotated by BRENDA team
-
secretion from macrophages
-
Manually annotated by BRENDA team
Mus musculus C57BL/6
-
secretion from macrophages
-
-
Manually annotated by BRENDA team
-
glomerular basement membrane. Irregular glomerular basement membrane that characterizes Alport syndrome may be mediated, in part, by focal degradation of glomerular basement membrane due to MMP dysregulation, in particular, MMP-12
Manually annotated by BRENDA team
additional information
-
MMP12, in contrast to other MMPs, can act intracellularly rather than extracellularly. The majority of MMP12 is secreted, MMP12 might then bind to the bacteria outside the cell prior to phagocytosis
-
Manually annotated by BRENDA team
PDB
SCOP
CATH
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
22000
-
mouse, form B and C, gel filtration, sucrose density gradient centrifugation
31409
45000
-
MMp-12 active enzyme
652869
54000
-
MMp-12 proenzyme
652869
57000
-
mouse, form A, sucrose density gradient centrifugation, gel filtration
31409
59000
-
SDS-PAGE
699886
additional information
-
the open-reading frames predict proenzymes of MW 53000
31411
additional information
-
the open-reading frames predict proenzymes of MW 54000
31412
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
?
-
x * 22000, human, SDS-PAGE
?
-
x * 22000, mature recombinant enzyme without domain I, SDS-PAGE
?
-
x * 54000, inactive MMP-12 protenzyme, SDS-PAGE
?
-
x * 54000, inactive proenzyme, x * 45000, intermediate enzyme
?
-
x * 54000, inactive proenzyme, x * 45000, intermediate enzyme, x * 22000, mature active enzyme
?
-
x * 22000, active MMP-12
?
-
x * 54000, pro-MMP-12, x * 22000, active mature MMP-12
?
-
x * 54000, pro-MMP-12, x * 29000, mature active MMP-12
?
Mus musculus C57BL/6
-
x * 54000, inactive MMP-12 protenzyme, SDS-PAGE
-
monomer
-
1 * 22000, mouse, form B and C, SDS-PAGE
additional information
-
MMP-12 is synthesized as 54-kDa proenzyme that is processed into a 45-kDa and then a 22-kDa active form
additional information
-
NMR and mass spectrometry structure determination and anaylsis of the MMP-12 catalytic domain using the refolded recombinantly expressed protein, overview
additional information
-
NMR structure determination and analysis of unprocessed enzyme mutant E219A in absence of inhibitor, comparison to the enzyme crystal structure, PDB code 1JK3, active site structure, overview
additional information
-
pro-MMP-12 contains an N-terminal pro-domain, a catalytic domain, and a C-terminal hemopexin-like domain. The pro-domain is cleaved during maturation. The catalytic domain is essential for the substrate-converting activities of MMPs. Since MMP12 without C-terminal domain is still enzymatically active, the MMP12 C-terminal domain seems not to be required for substrate catalysis. A peptide sequence in the C-terminal domain is responsible for the anti-bacterial activity of MMP-12, but the catalytic domain is not required for the bactericidal property of MMP12, overview
additional information
-
the antimicrobial properties of MMP12 do not reside within its catalytic domain, but rather within the carboxy-terminal domain, which contains a unique four amino acid sequence on an exposed beta loop of the protein that is required for the observed antimicrobial activity, within the sequence designated SR-20, i.e. 344-SRNQLFLFKDEKYWLINNLV-363. Three-dimensional homology modeling of mouse MMP12 C-terminal domain, overview
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
no glycoprotein
-
-
proteolytic modification
-
MMP-12 is activated from a pro-MMP-12 form
proteolytic modification
-
pro-MMP-12 is activated to mature MMP-12
proteolytic modification
-
MMP-12 is synthesized as 54-kDa proenzyme that is processed into a 45-kDa and then a 22-kDa active form
proteolytic modification
-
the inactive MMP-12 protenzyme needs to be activated by cleavage to the mature form
proteolytic modification
-
MMP12 is produced and secreted as a latent pro-enzyme. The pro-domain keeps pro-MMP12 in a catalytically inactive state. After cleavage of the pro-domain, MMP12 becomes proteolytically active. MMP-12 undergoes further processing leading to C-terminal domain shedding, resulting in the mature active form of MMP12
proteolytic modification
-
pro-MMP-12 is activated to mature MMP-12
proteolytic modification
Mus musculus C57BL/6
-
the inactive MMP-12 protenzyme needs to be activated by cleavage to the mature form
-
Crystallization/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
hexagonal shaped crystals, crystal structure in complex with hydroxamic acid inhibitor, orthorhombic space group I222, unit cells dimensions a : 67.4 A, b : 87.2, c : 169.2
-
purified MMP-12 bound to hydroxamic acid, hanging drop vapour diffusion method, 20C, from protein solution containing 10 mg/ml protein in 0.1 M Tris-HCl, pH 8.0, 30% PEG 6000, 200 mM hydroxamic acid, and 1.0 M LiCl, a few days, X-ray diffraction structure determination and analysis at 1.3 A resolution
-
sitting drop vapor diffusion technique, crystallized in complex with inhibitor batimastat, BB-94, monoclinic space group C2, crystal cell constants a : 51.91 A, b : 60.26 A, c : 54.61 A
P45452
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
catalytic domain of MMP-12 exhibits higher activity, more rigidity of its backbone, and lower folding stability than its counterpart of the MMP-3 catalytic domain that has more internal motions throughout
-
Purification in the presence of EDTA prevents activation of proenzyme
-
Buffers with high concentration of Ca2+ stabilize during purification
-
Dialysis against 25 mM Tris-HCl, pH 7.6 inactivates, Ca2+ restores activity
-
Purified enzyme, not partially purified preparation, unstable in either glycerol or sucrose velocity gradients
-
Stable to freeze-thawing
-
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
-80C, in 50 mM Tris-HCl, pH 7.6, 150 mM NaCl, 50 mM CaCl2, at least 3 months
-
Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
partial, recombinant or native enzyme
-
recombinant F171D mutant fragment Gly106-Gly263 from Escherichia coli strain BL21 by gel filtration and anion exchange chromatography
-
refolded recombinant MMP-12 catalytic domain from Escherichia coli strain BL21(DE3) inclusion bodies by anion exchange chromatography
-
3 chromatographically distinct forms A, B and C, predominant form is B
-
recombinant MMP-12
-
Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
cloned and expressed in Escherichia coli BL21(DE3)
-
expressed in Escherichia coli
-
expression analysis
-
expression analysis of MMP12 in cancerous and healthy oral tissues, overview
-
expression of a cDNA encoding the fragment Gly106-Gly263 of the enzyme F171D mutant in Escherichia coli strain BL21
-
generation of transgenic rabbits that express human (h)MMP-12 gene under the control of a macrophage-specific promoter, the human scavenger receptor promoter. This transgenic rabbit model with increased expression of hMMP-12 may become a useful model for further mechanistic studies of MMP-12 in in inflammatory diseases and cancer invasion, it is also an ideal model for testing the in vivo action of MMP-12 inhibitors
-
MMP-12 catalytic domain, cd(EA)MMP-12 overexpressed in Escherichia coli strain BL21 (DE3)
P45452
molecular cloning of the proteinase domain of MMP12
-
overexpression of the MMP-12 catalytic domain, residues Phe100-Gly263, in Escherichia coli strain BL21(DE3) inclusion bodies
-
expressed in Escherichia coli
-
MMP-12 mRNA and protein level increased with the progression of renal disease in glomerulonephritic ICGN mouse compared to non-glomerulonephritic mouse
-
stable expression of MME domains 1 and 2 in enzyme-deficient murine CT-26 colon cancer cells suppresses orthotopic tumor growth, angiogenesis and vascular endothelial growth factor expression, expression analysis and orthotopic animal tumor model study, overview
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
MMP-12 expression is upregulated by other matrix components such as hyaluronan fragments, cytokines, and growth factors, for example by TGF-beta, IFN-gamma and EGF, and serine proteases such as thrombin and plasmin
-
UV radiation is known to induce the expression of MMP-12 in skin
-
MMP-12 expression is upregulated by other matrix components such as hyaluronan fragments, cytokines, and growth factors, for example by TGF-beta, IFN-gamma and EGF, and serine proteases such as thrombin and plasmin
-
MMP-12/tissue inhibitor of metalloproteinase-1 ratio is significantly increased in the CSF of Angiostrongylus cantonensis-infected mice from day 10 p.i., and reaches high levels on days 20 and 25 p.i. MMP-12 production is correlated with elastin degradation, eosinophil count, blood-CSF barrier permeability and pathological changes in the subarachnoid space
-
ENGINEERING
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
A164V
-
mutation inconsequential to elastolysis
A182G
-
mutant retains similar activity toward substrate MCA-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2 (Km and kcat similar to wild-type, kcat/Km), mutant shows strong decreased (kcat/Km) toward fEln-100 compared to wild-type
D124Q
-
mutant retains similar activity toward substrate MCA-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2 (Km and kcat similar to wild-type, kcat/Km), mutant shows decreased (kcat/Km) toward fEln-100 compared to wild-type
D124Q/A182G
-
combination of two well-separated mutations further reduces activity toward both fEln-100 and elastin-fluorescein compared to the single mutations, mutant shows decreased activity towards MCA-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2
D124Q/I180S
-
combination of two well-separated mutations further reduces activity toward both fEln-100 and elastin-fluorescein compared to the single mutations, mutant shows decreased activity towards MCA-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2
D124Q/M156E
-
combination of two well-separated mutations further reduces activity toward both fEln-100 and elastin-fluorescein compared to the single mutations, mutant retains wild-type activity towards MCA-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2
D124Q/M156E/A182G
-
mutant confers a significantly greater loss of catalytic efficiency in digesting fEln-100 than the parental double mutant D124Q/M156E, catalytic activity toward MCA-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2 is highly decreased compared to wild-type, compared to triple mutant D124Q/M156E/F185Y and D124Q/M156E/T205K catalytic efficacy toward fEln-100 is highly decreased
D124Q/M156E/F185Y
-
mutant confers a significantly greater loss of catalytic efficiency in digesting fEln-100 than the parental double mutant D124Q/M156E, catalytic activity toward MCA-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2 is not affected compared to wild-type, compared to triple mutant D124Q/M156E/I180S and D124Q/M156E/A182G catalytic efficacy toward fEln-100 is moderately decreased
D124Q/M156E/I180S
-
mutant confers a significantly greater loss of catalytic efficiency in digesting fEln-100 than the parental double mutant D124Q/M156E, catalytic activity toward MCA-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2 is highly decreased compared to wild-type, compared to triple mutant D124Q/M156E/F185Y and D124Q/M156E/T205K catalytic efficacy toward fEln-100 is highly decreased
D124Q/M156E/T205K
-
mutant confers a significantly greater loss of catalytic efficiency in digesting fEln-100 than the parental double mutant D124Q/M156E, catalytic activity toward MCA-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2 is not affected compared to wild-type, compared to triple mutant D124Q/M156E/I180S and D124Q/M156E/A182G catalytic efficacy toward fEln-100 is moderately decreased
D200E
-
mutation inconsequential to elastolysis
E219A
-
site-directed mutagenesis, inactive mutant, autolysis of the mutant is prevented
E219A
-
NMR studies used MMP-12 preserved by E219A substitution of the general base
G166R
-
mutation inconsequential to elastolysis
I180S
-
mutant retains similar activity toward substrate MCA-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2 (Km and kcat similar to wild-type, kcat/Km), mutant shows strong decreased (kcat/Km) toward fEln-100 compared to wild-type
I255V
-
mutation inconsequential to elastolysis
K148T
-
mutation inconsequential to elastolysis
M103F
-
mutant retains similar activity toward substrate MCA-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2 (Km and kcat similar to wild-type, kcat/Km), mutant shows decreased catalytic efficacy (kcat/Km) toward fEln-100 compared to wild-type
M156E
-
mutant retains similar activity toward substrate MCA-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2 (Km and kcat similar to wild-type, kcat/Km), mutant shows strong decreased (kcat/Km) toward fEln-100 compared to wild-type
M156E/A182G
-
kcat (fEln-100) is twice that of wild-type, mutant retains wild-type activity towards MCA-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2
M156E/I180S
-
combination of two well-separated mutations further reduces activity toward both fEln-100 and elastin-fluorescein compared to the single mutations, mutant shows decreased activity towards MCA-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2
N153Y
-
mutation inconsequential to elastolysis
R117S
-
mutant retains similar activity toward substrate MCA-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2 (Km and kcat similar to wild-type, kcat/Km), mutant shows decreased (kcat/Km) toward fEln-100 compared to wild-type
S142E
-
mutation inconsequential to elastolysis
V144A
-
mutation inconsequential to elastolysis
V162S
-
mutation inconsequential to elastolysis
Y132A
-
mutation inconsequential to elastolysis
additional information
-
MMP-12 knockout mice, no mucosal damage when trinitrobenzene sulfonic acid is administered to the colons compared to severe colitis in wild type mice
additional information
-
administration of trinitrobenzene sulphonic acid to the colons of MMP-12 knockout mice for 7 days does not lead to mucosal damage in contrast to wild-type mice which show severe colitis, overview
additional information
-
construction of a mutant peptide identical to SR-20, i.e. 344-SRNQLFLFKDEKYWLINNLV-363, except that the Lys-Asp-Glu-Lys motif found in mouse MMP12 is replaced by the human MMP9 sequence, Ser-Gly-Arg-Gln. The Lys-Asp-Glu-Lys motif is essential for the antimicrobial properties of mouse MMP12 C-terminal domain. Mmp12-/- mice exhibit impaired bacterial clearance and increased mortality when challenged with both Gram-negative and Gram-positive bacteria at macrophage-rich portals of entry, such as the peritoneum and lung
additional information
-
development of pulmonary fibrosis in MMP-12 -/- knockout mice
additional information
-
mice lacking MMP12 have impaired ability to destroy bacteria in the phagolysosomes and die as a result of uncontrolled spread of the infection. The increased mortality is observed when the bacteria are injected through the airway, but not when the bacteria are injected into the blood
Renatured/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
recombinant fragment of mutant F171D from Escherichia coli inclusion bodies by solubilization in 20 mM Tris-HCl and 8 M urea at pH 8.0, refolding by multi-step dialysis, overview
-
recombinant MMP-12 catalytic domain from Escherichia coli strain BL21(DE3) inclusion bodies with refolding buffer, which contains 6 M urea, 20 mM Tris-HCl, 5 mM CaCl2, and 100 mM NaCl, pH 7.5, followed by a two-step dialysis against refolding buffer containing 0.1 mM ZnCl2, overview
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
analysis
-
the enzyme can be utilized for pharmacological evaluation of anti-inflammatory mechanisms of action
diagnostics
-
MMP12 is a no effect level oral cancer marker in neck tissue and gingiva
diagnostics
-
overexpression of HME is strongly correlated with the reduced angiogenesis and vascular invasion of gastric carcinoma, and may serve as a useful predictive indicator in patients with this disease
drug development
-
the enzyme is a target for drug development
drug development
-
the enzyme is a target in treatment of degradative disease processes in the skin
medicine
-
abnormal expression of HME may contribute to destructive processes such as pulmonary empysema and vascular aneurysm formation
medicine
-
inhibition of MMP-12 may be a potential modality for the treatment of rheumatoid arthritis
pharmacology
-
MMP-12 plays a predominant role in the inflammatory process induced by cigarette smoke, and therefore is potentially an important therapeutic target for the treatment of chronic obstructive pulmonary diseases
medicine
-
role in idiophathic diseases, may be even more important in the causation of inflammatory bowel disease than MMP-3, markedly upregulated in a T-cell-mediated model in inflammatory bowel disease, local immune response can increase MMP-12 expression in resident lamina propria macrophages
pharmacology
-
MMP-12 might be a target for the therapy against allergic bronchial asthma