Information on EC 3.4.24.79 - pappalysin-1

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The expected taxonomic range for this enzyme is: Bilateria

EC NUMBER
COMMENTARY
3.4.24.79
-
RECOMMENDED NAME
GeneOntology No.
pappalysin-1
-
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
Cleavage of the Met135-/-Lys bond in insulin-like growth factor binding protein (IGFBP)-4, and the Ser143-/-Lys bond in IGFBP-5
show the reaction diagram
a 400-kDa disulfide-linked dimer that circulates in human pregnancy mainly as a complex with the proform of eosinophil major basic protein, which acts as an inhibitor of the peptidase
-
Cleavage of the Met135-/-Lys bond in insulin-like growth factor binding protein (IGFBP)-4, and the Ser143-/-Lys bond in IGFBP-5
show the reaction diagram
mechanism
-
Cleavage of the Met135-/-Lys bond in insulin-like growth factor binding protein (IGFBP)-4, and the Ser143-/-Lys bond in IGFBP-5
show the reaction diagram
the mechanism of IGF-modulated proteolysis of IGFBP-4 and -5 involves changes in both the recognition of substrate and the turnover rate
-
Cleavage of the Met135-/-Lys bond in insulin-like growth factor binding protein (IGFBP)-4, and the Ser143-/-Lys bond in IGFBP-5
show the reaction diagram
-
-
-
-
SYNONYMS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IGF binding protein-4 protease
-
-
-
-
IGF binding protein-4 specific proteinase
-
-
-
-
IGF-BP-4 proteinase
-
-
-
-
IGFBP proteinase
-
-
IGFBP-4 protease
-
-
-
-
IGFBP-4 protease
Q13219
-
insulin-like growth factor binding protein-4 protease
-
-
-
-
PAPP-A
-
-
-
-
PAPP-A
-
-
pregnancy associated plasma protein-A
-
-
pregnancy-associated plasma protein A
-
-
pregnancy-associated plasma protein A
Q13219
-
pregnancy-associated plasma protein-A
-
-
-
-
pregnancy-associated plasma protein-A
-
-
pregnancy-associated plasma protein-A
-
-
pregnancy-associated plasma protein-A
Q13219
-
pregnancy-associated plasma protein-A
-
-
pregnancy-associated plasma protein-A2
-
-
pregnancy-related serine protease
-
-
-
-
protein IGF-BP 4 proteinase
-
-
-
-
insulin-like growth factor-binding protein proteinase
-
-
additional information
-
PAPP-A and PAPP-A2 are unique members in the group of laminin G proteins, the pappalysins represent examples where LG modules are associated with proteinases
CAS REGISTRY NUMBER
COMMENTARY
151662-33-8
-
GENERAL INFORMATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
physiological function
-
pregnancy-associated plasma protein-A (PAPP-A) increases local insulin-like growth factor-I bioavailability through cleavage of inhibitory insulin-like growth factor binding protein. Expression of human PAPP-A localized to arterial smooth muscle accelerates lesion progression in a mouse model of atherosclerosis
physiological function
-
pregnancy-associated plasma protein-A (PAPP-A) acts to enhance tumor growth in vivo. Overexpression of PAPP-A favored development of mature tumor vasculature. PAPP-A proteolytic activity enhances the tumorigenic potential of ovarian cancer cells
SUBSTRATE
PRODUCT                      
REACTION DIAGRAM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
IGF-binding protein-2 + H2O
?
show the reaction diagram
-
-
-
-
?
IGF-binding protein-2 + H2O
?
show the reaction diagram
-
i.e. IGFBP-2, low activity
-
-
?
IGF-binding protein-4 + H2O
?
show the reaction diagram
-
-
-
-
?
IGF-binding protein-4 + H2O
?
show the reaction diagram
-
i.e. IGFBP-4
-
-
?
IGF-binding protein-4 + H2O
?
show the reaction diagram
-
i.e. IGFBP-4
-
-
?
IGF-binding protein-4 + H2O
?
show the reaction diagram
-
PAPP-A promotes cell growth causing the release of bound insulin-like growth factors
-
-
?
IGF-binding protein-4 + H2O
?
show the reaction diagram
-
regulation of insulin-like growth factor bioavailability through cleavage of the inhibitory binding protein is an important mechanism for the control of growth and development of vertebrate cells
-
-
?
IGF-binding protein-4 + H2O
?
show the reaction diagram
-
i.e. IGFBP-4, PAPP-A cleaves IGFBP-4 at a single site in the central domain causing the release of bioactive IGF
-
-
?
IGF-binding protein-5 + H2O
?
show the reaction diagram
-
-
-
-
?
IGF-binding protein-5 + H2O
?
show the reaction diagram
-
i.e. IGFBP-5
-
-
?
IGF-binding protein-5 + H2O
?
show the reaction diagram
-
PAPP-A promotes cell growth causing the release of bound insulin-like growth factors
-
-
?
IGF-binding protein-5 + H2O
?
show the reaction diagram
-
regulation of insulin-like growth factor bioavailability through cleavage of the inhibitory binding protein is an important mechanism for the control of growth and development of vertebrate cells
-
-
?
IGF-binding protein-5 + H2O
?
show the reaction diagram
-
i.e. IGFBP-5, PAPP-A cleaves IGFBP-5 at a single site in the central domain causing the release of bioactive IGF
-
-
?
inhibitory insulin-like growth factor binding protein-4 + H2O
?
show the reaction diagram
-
-
-
-
?
insulin-like growth factor binding protein + H2O
?
show the reaction diagram
-
-
-
-
?
insulin-like growth factor binding protein-4 + H2O
?
show the reaction diagram
-
-
-
-
?
insulin-like growth factor binding protein-4 + H2O
?
show the reaction diagram
Q13219
-
-
-
-
insulin-like growth factor binding protein-4 + H2O
?
show the reaction diagram
-
-
-
-
-
insulin-like growth factor binding protein-4 + H2O
?
show the reaction diagram
-
-
-
-
?
insulin-like growth factor binding protein-4 + H2O
?
show the reaction diagram
-
-
-
-
?
insulin-like growth factor binding protein-4 + H2O
?
show the reaction diagram
-
-
-
-
?
insulin-like growth factor binding protein-4 + H2O
?
show the reaction diagram
-
-
-
-
?
insulin-like growth factor binding protein-4 + H2O
?
show the reaction diagram
-
-
-
-
?
insulin-like growth factor binding protein-4 + H2O
?
show the reaction diagram
Q13219
-
is cleaved into a 14 kDa and a 18 kDa fragment
?
insulin-like growth factor binding protein-4 + H2O
?
show the reaction diagram
-
substrate may be human or recombinant mouse protein, cleavage at carboxy-terminal side of Met131 of the rat protein
-
-
?
insulin-like growth factor binding protein-4 + H2O
?
show the reaction diagram
-
cleavage at Met135 of the human substrate
-
-
?
insulin-like growth factor binding protein-4 + H2O
?
show the reaction diagram
-
mutants of insulin-like growth factor binding protein-4
-
-
?
insulin-like growth factor binding protein-5 + H2O
?
show the reaction diagram
-
-
-
-
-
insulin-like growth factor binding protein-5 + H2O
?
show the reaction diagram
-
cleavage occurs between Ser143 and Lys144
-
-
-
insulin-like growth factor binding protein-5 + H2O
?
show the reaction diagram
-
cleavage by PAPP-A and PAPP-A2
-
-
?
insulin-like growth factor binding protein-5 + H2O
?
show the reaction diagram
-
substrate of PAPP-A
-
-
?
additional information
?
-
-
no substrate: insulin-like growth factor binding protein-3
-
-
-
additional information
?
-
-
serine protease
-
-
-
additional information
?
-
-
cleavage of insulin-like growth factor binding protein-5 does not require insulin-like growth factor
-
-
-
additional information
?
-
-
cleavage of insulin-like growth factor binding protein-4 occurs only in presence of insulin-like growth factor-II
-
-
-
additional information
?
-
-
enzyme activity is a determinant of follicular fate
-
-
-
additional information
?
-
-
enzyme enhances bioactivity of insulin-like growth factors in vitro
-
-
-
additional information
?
-
-
enzyme may be involved in modulating cellular response to insulin-like growth factor-I
-
-
-
additional information
?
-
-
interaction between insulin-like growth factor-II and insulin-like growth factor binding protein-4 is required for proteolysis
-
-
-
additional information
?
-
-
activated macrophage regulation of PAPP-A expression, co-localization of macophages and PAPP-A is involved in development of vulnerable plaques, overview
-
-
-
additional information
?
-
-
in human pregnancy, the majority of PAPP-A circulates as a disulfide-bonded complex with its inhibitor, the proform of eosinophil major basic protein, i.e. proMBP
-
-
-
additional information
?
-
-
inhibition of IGF signaling is relevant in human disease, and several drugs in development target the IGF receptor, overview
-
-
-
additional information
?
-
-
PAPP-A enhances IGF action by increasing its bioavailability, overview
-
-
-
additional information
?
-
-
PAPP-A is involved in acute coronary syndrome, and is associated with atherosclerotic peripheral arterial disease, PAD, i.e. chronic limb ischemia, overview
-
-
-
additional information
?
-
-
PAPP-A stimulated by follicle stimulating hormone plays a crucial role for the insulin-like growth factor-I system in bovine follicular development
-
-
-
additional information
?
-
-
pregnancy associated plasma protein-A is involved in regulation of IGF bioavailability and in skeletal development and injury repair, responses is necessary for expeditious fracture healing in mice, mechanism for PAPP-A regulation of IGF action, overview
-
-
-
additional information
?
-
-
pregnancy-associated plasma protein-A, PAPP-A, levels and the PAPP-A to eosinophile major basic protein, proMBP, ratio is increased in patients with acute coronary syndrome, overview
-
-
-
additional information
?
-
-
regulation of enzyme expression, e.g. by pro-inflammatory cytokines involved in repair responses, especially TNFalpha and interleukin 1-beta, the enzyme is involved in cardiovascular disease, overview
-
-
-
additional information
?
-
-
the enzyme is involved in coronary artery disease, e.g. angina pectoris or acute myocardia infarction, independent of gender or age, PAPP-A/proMBP levels do not correlate with cardiac troponin I in patients, the PAPP-A/proMBP complex is involved in processes preceding vulnerable plaque development in acute coronary syndrome, overview
-
-
-
additional information
?
-
-
domain structure and function, overview, the enzyme performs autocatalytic cleavage
-
-
-
NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
IGF-binding protein-2 + H2O
?
show the reaction diagram
-
-
-
-
?
IGF-binding protein-4 + H2O
?
show the reaction diagram
-
-
-
-
?
IGF-binding protein-4 + H2O
?
show the reaction diagram
-
i.e. IGFBP-4
-
-
?
IGF-binding protein-4 + H2O
?
show the reaction diagram
-
i.e. IGFBP-4
-
-
?
IGF-binding protein-4 + H2O
?
show the reaction diagram
-
PAPP-A promotes cell growth causing the release of bound insulin-like growth factors
-
-
?
IGF-binding protein-4 + H2O
?
show the reaction diagram
-
regulation of insulin-like growth factor bioavailability through cleavage of the inhibitory binding protein is an important mechanism for the control of growth and development of vertebrate cells
-
-
?
IGF-binding protein-5 + H2O
?
show the reaction diagram
-
-
-
-
?
IGF-binding protein-5 + H2O
?
show the reaction diagram
-
i.e. IGFBP-5
-
-
?
IGF-binding protein-5 + H2O
?
show the reaction diagram
-
PAPP-A promotes cell growth causing the release of bound insulin-like growth factors
-
-
?
IGF-binding protein-5 + H2O
?
show the reaction diagram
-
regulation of insulin-like growth factor bioavailability through cleavage of the inhibitory binding protein is an important mechanism for the control of growth and development of vertebrate cells
-
-
?
inhibitory insulin-like growth factor binding protein-4 + H2O
?
show the reaction diagram
-
-
-
-
?
insulin-like growth factor binding protein + H2O
?
show the reaction diagram
-
-
-
-
?
insulin-like growth factor binding protein-4 + H2O
?
show the reaction diagram
Q13219
-
-
-
-
insulin-like growth factor binding protein-4 + H2O
?
show the reaction diagram
-
-
-
-
-
additional information
?
-
-
enzyme activity is a determinant of follicular fate
-
-
-
additional information
?
-
-
enzyme enhances bioactivity of insulin-like growth factors in vitro
-
-
-
additional information
?
-
-
enzyme may be involved in modulating cellular response to insulin-like growth factor-I
-
-
-
additional information
?
-
-
interaction between insulin-like growth factor-II and insulin-like growth factor binding protein-4 is required for proteolysis
-
-
-
additional information
?
-
-
activated macrophage regulation of PAPP-A expression, co-localization of macophages and PAPP-A is involved in development of vulnerable plaques, overview
-
-
-
additional information
?
-
-
in human pregnancy, the majority of PAPP-A circulates as a disulfide-bonded complex with its inhibitor, the proform of eosinophil major basic protein, i.e. proMBP
-
-
-
additional information
?
-
-
inhibition of IGF signaling is relevant in human disease, and several drugs in development target the IGF receptor, overview
-
-
-
additional information
?
-
-
PAPP-A enhances IGF action by increasing its bioavailability, overview
-
-
-
additional information
?
-
-
PAPP-A is involved in acute coronary syndrome, and is associated with atherosclerotic peripheral arterial disease, PAD, i.e. chronic limb ischemia, overview
-
-
-
additional information
?
-
-
PAPP-A stimulated by follicle stimulating hormone plays a crucial role for the insulin-like growth factor-I system in bovine follicular development
-
-
-
additional information
?
-
-
pregnancy associated plasma protein-A is involved in regulation of IGF bioavailability and in skeletal development and injury repair, responses is necessary for expeditious fracture healing in mice, mechanism for PAPP-A regulation of IGF action, overview
-
-
-
additional information
?
-
-
pregnancy-associated plasma protein-A, PAPP-A, levels and the PAPP-A to eosinophile major basic protein, proMBP, ratio is increased in patients with acute coronary syndrome, overview
-
-
-
additional information
?
-
-
regulation of enzyme expression, e.g. by pro-inflammatory cytokines involved in repair responses, especially TNFalpha and interleukin 1-beta, the enzyme is involved in cardiovascular disease, overview
-
-
-
additional information
?
-
-
the enzyme is involved in coronary artery disease, e.g. angina pectoris or acute myocardia infarction, independent of gender or age, PAPP-A/proMBP levels do not correlate with cardiac troponin I in patients, the PAPP-A/proMBP complex is involved in processes preceding vulnerable plaque development in acute coronary syndrome, overview
-
-
-
METALS and IONS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
Ca2+
-
-
Ca2+
-
-
Ca2+
-
the LNR module reversibly binds a calcium ion and that bound calcium is required for antibody binding
Zn2+
-
Zn2+ binding metalloprotease
Zn2+
-
-
Zn2+
-
PAPP-A is a metzincin metalloproteinase
Zn2+
-
PAPP-A is a zinc-binding metalloproteinase
Zn2+
-
zinc endoprotease, the enzyme contains the zinc-binding consensus sequence HEXXHXXGXXH
Zn2+
-
the enzyme is a metzincin metalloproteinase
Zn2+
-
zinc metalloproteinase
INHIBITORS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
1,10-phenanthroline
-
10 mM, complete inhibition
1,10-phenanthroline
-
-
3,4-Dichloroisocoumarin
-
-
alpha1-Antichymotrypsin
-
potent inhibitor
-
beta-mercaptoethanol
-
-
beta-phorbol-12,13-didecanoate
-
100 nM, time-dependent inhibition, possibly through induction of pro-eosinophil major basic protein
EDTA
-
5 mM
heparin
-
up to 60% inhibition
IGF-I
-
the rate of IGFBP-4 proteolysis is dramatically increased upon addition of IGF-I or -II with IGF-II being more potent than IGF-I, while IGFBP-5 cleavage is slightly inhibited, overview
-
PAC1
-
specific monoclonal antibody inhibiting PAPP-A activity against IGFBP-4, only slight inhibition of IGFBP-5 proteolysis
-
pro-eosinophil major basic protein
-
physiological inhibitor
-
proform of eosinophil major basic protein
-
i.e. proMBP, the glycosaminoglycan of proMBP is not required for PAPP-A-proMBP complex formation, while proMBP residues His137, Ser178, Arg179, and Asn181 are important for the recognition of PAPP-A, complex formation increases the half-life of enzyme and inhibitor, the PAPP-A-proMBP complex is formed at the cell surface in vivo rather than in the circulation, the redox potential of the tissue microenvironment controls the process, chondroitin or dermatan sulfate do not have any effect on complex formation
-
proform of eosinophil major basic protein
-
i.e. proMBP, complex formation with PAPP-A
-
IGF-II
-
the rate of IGFBP-4 proteolysis is dramatically increased upon addition of IGF-I or -II with IGF-II being more potent than IGF-I, while IGFBP-5 cleavage is slightly inhibited, overview
-
additional information
-
not inhibitory: pepstatin A, E-64, chymostatin, aprotinin, PMSF
-
additional information
-
monoclonal phage-derived scFv antibodies selectively inhibit the cleavage of IGFBP-4 by PAPP-A, none of the antibodies inhibit the homologous proteinase PAPP-A2, which allowed mapping of antibody binding by means of chimeras between PAPP-A and PAPP-A2 to the C-terminal Lin12-Notch repeat module, separated from the proteolytic domain by almost 1000 amino acids, the LNR module requires bound calcium for antibody binding, selective inhibition of IGFBP-4 cleavage by interference with exosite binding, binding site mapping, overview
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
IGF
-
PAPP-A activity is dependent on presence of insulin-like growth factor-II
-
IGF
-
-
-
IGF
-
PAPP-A activity is dependent on presence of insulin-like growth factor
-
IGF-I
-
the rate of IGFBP-4 proteolysis is dramatically increased upon addition of IGF-I or -II with IGF-II being more potent than IGF-I, while IGFBP-5 cleavage is slightly inhibited, the mechanism of IGF-modulated proteolysis of IGFBP-4 and -5 involves changes in both the recognition of substrate and the turnover rate, overview
-
IGF-II
-
the rate of IGFBP-4 proteolysis is dramatically increased upon addition of IGF-I or -II with IGF-II being more potent than IGF-I, while IGFBP-5 cleavage is slightly inhibited, the mechanism of IGF-modulated proteolysis of IGFBP-4 and -5 involves changes in both the recognition of substrate and the turnover rate, overview
-
additional information
-
the enzyme expression in fibroblasts is stimulated by pro-inflammatory cytokines involved in repair responses, especially TNFalpha and interleukin 1-beta, the stimulation is inhibited by resveratrol
-
additional information
-
follicle stimulating hormone and 17beta-estradiol stimulate PAPP-A expression in granulosa cells, overview
-
KM VALUE [mM]
KM VALUE [mM] Maximum
SUBSTRATE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
0.00045
-
IGFBP-4
-
pH 7.5, 37C, in presence of IGF-II
-
0.00163
-
IGFBP-4
-
pH 7.5, 37C, in presence of IGF-I
-
0.00031
-
IGFBP-5
-
pH 7.5, 37C, in absence of IGF
-
0.00041
-
IGFBP-5
-
pH 7.5, 37C, in presence of IGF-I
-
0.00064
-
IGFBP-5
-
pH 7.5, 37C, in presence of IGF-II
-
additional information
-
additional information
-
kinetics
-
additional information
-
additional information
-
PAPP-A-proMBP complex formation kinetics, overview
-
TURNOVER NUMBER [1/s]
TURNOVER NUMBER MAXIMUM[1/s]
SUBSTRATE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
0.64
-
IGFBP-4
-
pH 7.5, 37C, in presence of IGF-II
-
0.89
-
IGFBP-4
-
pH 7.5, 37C, in presence of IGF-I
-
0.31
-
IGFBP-5
-
pH 7.5, 37C, in presence of IGF-I
-
0.47
-
IGFBP-5
-
pH 7.5, 37C, in presence of IGF-II
-
0.75
-
IGFBP-5
-
pH 7.5, 37C, in absence of IGF
-
Ki VALUE [mM]
Ki VALUE [mM] Maximum
INHIBITOR
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
1.2e-06
-
PAC1 antibody
-
pH 7.5, 37C, inhibition of PAPP-A
-
SPECIFIC ACTIVITY [µmol/min/mg]
SPECIFIC ACTIVITY MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
additional information
-
-
-
additional information
-
-
serum PAPP-A concentrations are measured with an enzymatically amplified 2-step sandwich-type immunoassay
additional information
-
-
immunohistochemic analysis of enzyme levels in patients with acute coronary disease
additional information
-
-
enzyme activity and enzyme-inhibitor complex levels in healthy persons and patients with coronary disease, overview
pH OPTIMUM
pH MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
7.4
-
-
assay at
7.5
-
-
assay at
7.6
-
-
assay at
TEMPERATURE OPTIMUM
TEMPERATURE OPTIMUM MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
37
-
-
assay at
37
-
-
assay at
37
-
-
assay at
SOURCE TISSUE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
SOURCE
-
the enzyme is extracted from plaque tissue samples of endarterectomy and aneurysm patients
Manually annotated by BRENDA team
-
PAPP-A is markedly elevated in the earliest hours after the onset of symptoms in patients with ST-elevated myocardial infarction treated with heparin and primary percutaneous coronary intervention
Manually annotated by BRENDA team
-
heparin administration is associated with a significant increase in PAPP-A levels, presumably because of the detachment of PAPP-A from the vessel wall
Manually annotated by BRENDA team
-
of bone fracture in the mid-shaft
Manually annotated by BRENDA team
-
enzyme expression during follicular development and in cell culture
Manually annotated by BRENDA team
-
coronary artery smooth muscle cells
Manually annotated by BRENDA team
-
expression analysis, overview
Manually annotated by BRENDA team
-
cell surface
Manually annotated by BRENDA team
-
PAPP-A and PAPP-A2 mRNA and protein levels are analysed in placenta and maternal sera from women with pre-eclampsia and compared them with samples from uncomplicated pregnancy. PAPP-A2 but not PAPP-A mRNA and protein are elevated in pre-eclamptic placenta; PAPP-A and PAPP-A2 mRNA and protein levels are analysed in placenta and maternal sera from women with pre-eclampsia and compared them with samples from uncomplicated pregnancy. PAPP-A2 but not PAPP-A mRNA and protein are elevated in pre-eclamptic placenta. PAPP-A2 is normally produced in placental syncytiotrophoblast cells and maternal decidua. PAPP-A2 in syncytiotrophoblast cells is dramatically increased in pre-eclampsia
Manually annotated by BRENDA team
-
PAPP-A and PAPP-A2 mRNA and protein levels are analysed in placenta and maternal sera from women with pre-eclampsia and compared them with samples from uncomplicated pregnancy. Maternal serum concentrations of PAPP-A2 but not PAPP-A are significantly elevated in pre-eclampsia as compared with uncomplicated pregnancy
Manually annotated by BRENDA team
additional information
-
in human pregnancy, the majority of PAPP-A circulates as a disulfide-bonded complex with its inhibitor, the proform of eosinophil major basic protein, i.e. proMBP, the PAPP-A-proMBP complex is unable to bind to the cell surface
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
-
surface association of PAPP-A accounts for its colocalization with activated macrophages in human atherosclerotic plaque, immunohistochemic analysis, overview
Manually annotated by BRENDA team
-
detachment of pregnancy-associated plasma protein-A requires the formation of intermolecular proteinase-inhibitor disulfide bonds and glycosaminoglycan covalently bound to the inhibitor, mechanism, overview, the PAPP-A-proMBP complex is unable to bind to the cell surface
Manually annotated by BRENDA team
-
PAPP-A reversibly binds to cell surface, while PAPP-A2 does not
-
Manually annotated by BRENDA team
additional information
-
the PAPP-A-proMBP complex is formed at the cell surface in vivo rather than in the circulation, the redox potential of the tissue microenvironment controls the process, chondroitin or dermatan sulfate do not have any effect on complex formation
-
Manually annotated by BRENDA team
MOLECULAR WEIGHT
MOLECULAR WEIGHT MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
400000
-
-
nonreducing SDS-PAGE
400000
-
-
more than, gel filtration
400000
-
-
-
SUBUNITS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
?
-
x * 400000, SDS-PAGE
dimer
-
2 x 200000, SDS-PAGE
dimer
-
homodimer, a laminin G-like module is contained within the N-terminal region, secondary structure prediction and sequence alignment, overview
additional information
-
primary sequence, structure motifs, and domain structure and function, the first 350 amino acid residues comprise the proteolytic domain, overview
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
glycoprotein
-
-
proteolytic modification
-
the enzyme performs autocatalytic cleavage
TEMPERATURE STABILITY
TEMPERATURE STABILITY MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
37
-
-
10 min, no loss of activity
55
-
-
10 min, no loss of activity
70
95
-
10 min, complete inactivation
GENERAL STABILITY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
half-life of circulating PAPP-A and proMBP in complex is severalfold higher than both of the uncomplexed proteins
-
high salt condition, SDS, or beta-mercaptoethanol inhibit
-
Triton X-100, Tween-20, NP-40, sodium azide, glycerol do not affect enzyme activity
-
STORAGE STABILITY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
-30C, 1 year, no loss of activity
-
4C, 3 days, no loss of activity
-
Purification/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
recombinant His-tagged wild-type and mutant chimeric PAPP-A and PAPP-A2 from HEK-293T cells
-
recombinant His6-tagged PAPP-A laminin G domain from Escherichia coli by nickel affinity chromatography
-
recombinant PAPP-A wild-type and mutant E483A from HEK-293T cells by immunoaffinity chromatography
-
Cloned/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
DNA and amino acid sequence determination and anaylsis, sequence comparisons
-
expressed in mouse arterial smooth muscle cells
-
expressed in SKOV-3 cells
-
expression of His-tagged wild-type and mutant chimeric PAPP-A and PAPP-A2 in HEK-293T cells
-
expression of PAPP-A wild-type and mutant E483A in HEK-293T cells, co-expression with inhibitor proMBP
-
expression of the enzyme in transgenic mice, expression of FLAG-tagged enzyme in primary mouse osteoblasts
-
expression of the His6-tagged PAPP-A laminin G domain in Escherichia coli, expression of wild-type andtruncation mutant enzymes, comparising residues 1-310, in HEK293T cells
-
overexpression in transgenic mice heart, brain, liver, kidney, forearm, and spleen, expression analysis, overview
-
EXPRESSION
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
after intravenous unfractionated heparin and low molecular weight heparin free PAPP-A increases significantly (85 to 310fold from baseline)
-
ENGINEERING
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
E483A
-
a proteolytically inactive PAPP-A mutant
E483Q
-
he proteolytic activity of the mutant is markedly reduced
additional information
-
a mutant chimeric variant of PAPP-A, which is replaced in part by PAPP-A2 sequences, retains functionality as a protease but is unable to bind surface-associated glycosaminoglycan and shows no macrophage association or internalization
additional information
-
construction of transgenic mice overexpressing the enzyme, osteoblasts of transgenic mice show increased IGFBP-4 proteolysis and increased free IGF-I concentration. Calvarial bone thickness, bone marrow cavity, and skull bone mineral density are significantly increased in transgenic mice, bone size-related parameters in femur and tibia such as total bone area and periosteal circumference are significantly increased in transgenic mice. Bone formation rate and osteoid surface are increased by more than 2fold, whereas bone resorbing surface is unaffected. These anabolic effects are sustained with aging, phenotype overview
additional information
-
PAPP-A overexpression in transgenic mice leads to increased somatic groath and skeletal muscle mass, phenotype, overview
additional information
-
construction of chimeras between PAPP-A and PAPP-A2 of human and murine sequences, overview
additional information
-
construction of enzyme knockout mice, dwarf phenotype with decreased body size and IGF-II deficiency, overview
additional information
-
construction of PAPP-A knockout mice, which show impaired post-fracture, bony bridging of a mid-shaft fracture callus, the mutant mice show reduced amount of intramembranous bone formation, cartilage production, endochondral ossification and remodeling compared to wild-type mice, overview
Renatured/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
microdialysis against water reverses high salt inhibition
-
readdition of 5 mM Ca2+, but not of 0.1 mM Zn2+, restores EDTA-treated enzyme
-
APPLICATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
diagnostics
-
the enzyme is a highly specific marker for coronary heart disease
diagnostics
-
increased pregnancy-associated plasma protein-A is a marker for peripheral atherosclerosis, Linz Peripheral Arterial Disease Study
diagnostics
-
PAPP-A is a circulating biomarker for acute coronary syndrome
medicine
-
enhancing IGF bioavailability by PAPP-A can be a powerful strategy in the treatment of certain metabolic diseases such as osteoporosis
medicine
-
PAPP-A levels in adults with growth hormone deficiency at baseline and after growth hormone replacement is evaluated: 14 growth hormone deficiency adults are evaluated at baseline and after 1 year of growth hormone therapy. All patients are compared at baseline with 28 age-, sex- and body mass index (BMI)-matched control subjects. At baseline, growth hormone deficiency adults show higher PAPP-A levels and higher leptin, fibrinogen and highly sensitive C-reactive protein values than controls. Therapy with growth hormone reduces PAPP-A and fibrinogen levels while increased BMI and reduced waist-hip ratio are observed
medicine
-
PAPP-A, IGF1, inflammatory markers and adiponectin concentrations in type 2 diabetic patients with and without carotid plaques are compared and the relationship between these serum parameters and ultrasound carotid markers of atherosclerosis is evaluated. 125 consecutive type 2 diabetic patients are examined. Serum PAPP-A and IGF1 do not appear to be useful serum biomarkers for carotid atherosclerosis in type 2 diabetic patients with stable glycemic control, despite scientific evidence of their local role in atherosclerosis
medicine
-
a prospective screening study for trisomy 21 in singleton pregnancies is carried out by a combination of maternal age, fetal nuchal translucency, free beta-hCG and PAPP-A in a one-stop-clinic for first-trimester assessment of risk at 11-13 weeks of gestation. All three trisomies (13,18 and 21) are associated with increased maternal age, increased fetal nuchal translucency and decreased maternal serum PAPP-A
medicine
-
a detailed analysis is performed of first trimester screening results in singleton pregnancies conceived using assisted reproductive technologies and non-assisted reproductive technologies pregnancies. A record linkage study compared outcomes in 1739 assisted reproductive technologies-conceived and 50.253 naturally conceived pregnancies. Assisted reproductive technologies pregnancies have reduced first trimester screening PAPP-A levels leading to an increased likelihood of receiving a false-positive result and having a CVS/amniocentesis. Lower PAPP-A may reflect impairment of early implantation with some forms of assisted reproductive technologies
medicine
-
the effect of smoking on three first trimester screening markers for Downs syndrome that constitute the Combined test, namely nuchal translucency (NT), PAPP-A and free beta human chorionic gonadotophin is examined. In addition it is determined which of these markers need to be adjusted for smoking and by how much. The effect of adjusting for smoking on the Combined test is small, with an estimated less than 0.5% increase in the detection rate for a 3% false-positive rate and less than 0.2% decrease in the false-positive rate for an 85% detection rate
medicine
-
levels of PAPP-A and C-reactive protein in pre-eclampsia and their association with the mean arterial blood pressure are determined. 67 women with pre-eclampsia symptoms are matched with 56 normal pregnant controls for gestational age, maternal age and parity. Both of the groups are third trimester. PAPP-A and C-reactive protein are measured in serum. Maternal serum levels of PAPP-A and C-reactive protein are increased in women with pre-eclampsia compared to controls
medicine
-
it is examined whether maternal Rhesus status has any effect on the levels of first-trimester markers free beta-human chorionic gonadotropin, PAPP-A and nuchal translucency. First-trimester markers from pregnant women are converted into multiples of medians and corrected for maternal weight, ethnicity, and smoking status. Totally, 15045 normal, singleton pregnancies are retrieved with full records. Maternal Rhesus status does not influence the levels of free beta-human chorionic gonadotropin and PAPP-A in the first trimester of pregnancy in this almost exclusively Caucasian population studied. Therefore, correction for maternal Rhesus status is not suggested
medicine
-
contribution of maternal variables that influence the measured concentration of free beta-human chorionic gonadotropin and PAPP-A, and the interaction between these covariates, in first-trimester biochemical screening for trisomy 21 are analysed. In a multicenter study of prospective first-trimester biochemical screening for trisomy 21 it is shown that it is essential to adjust the measured values of free beta-human chorionic gonadotropin and PAPP-A for maternal and pregnancy characteristics
medicine
-
the performance of first-trimester combined screening by maternal age, fetal nuchal translucency (NT) thickness and maternal serum free beta-human chorionic gonadotropin and PAPP-A is examined
medicine
-
pregnancy-associated plasma protein A is a cardiac risk marker
medicine
-
administation of insulin-like growth factor binding protein (IGFBP)-4 causes significant increase in bone formation parameters, possibly through increased IGF bioavailability via proteolysis of insulin-like growth factor binding protein (IGFBP)-4
molecular biology
-
heparin administration is associated with a significant increase in PAPP-A levels, presumably because of the detachment of PAPP-A from the vessel wall
molecular biology
-
mice born with the deletion of the gene for PAPP-A, a model of reduced local IGF activity, live approximately 30% longer than their wild-type littermates. Food intake, and total energy expenditure and resting energy expenditure as measured by calorimetry are not different between PAPP-A knockout and wild-type mice. There is an increase in spontaneous physical activity in PAPP-A knockout mice. Both wild-type and PAPP-A knockout mice exhibit mild insulin resistance with age. Oral glucose tolerance and insulin sensitivity are not significantly different between the two groups of mice, although there appeared to be a decrease in the average size of the pancreatic islets in PAPP-A knockout mice. Thus, neither reduced rate of living nor altered glucose-insulin homeostasis can be considered key determinants of the enhanced longevity of PAPP-A knockout mice