Information on EC 5.3.99.4 - prostaglandin-I synthase

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The expected taxonomic range for this enzyme is: Euteleostomi

EC NUMBER
COMMENTARY hide
5.3.99.4
-
RECOMMENDED NAME
GeneOntology No.
prostaglandin-I synthase
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
(5Z,13E,15S)-9alpha,11alpha-epidioxy-15-hydroxyprosta-5,13-dienoate = (5Z,13E,15S)-6,9alpha-epoxy-11alpha,15-dihydroxyprosta-5,13-dienoate
show the reaction diagram
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
intramolecular oxidoreduction
-
-
-
-
isomerization
PATHWAY
BRENDA Link
KEGG Link
MetaCyc Link
arachidonic acid metabolism
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-
Arachidonic acid metabolism
-
-
C20 prostanoid biosynthesis
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Metabolic pathways
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-
SYSTEMATIC NAME
IUBMB Comments
(5Z,13E)-(15S)-9alpha,11alpha-Epidioxy-15-hydroxyprosta-5,13-dienoate 6-isomerase
A cytochrome P-450 heme-thiolate enzyme. Converts prostaglandin H2 into prostaglandin I2 (prostacyclin).
CAS REGISTRY NUMBER
COMMENTARY hide
65802-86-0
-
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
-
-
Manually annotated by BRENDA team
ram
-
-
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
physiological function
-
PGIS over-expressed mesenchymal stem cells are more resistant to free radical stress-induced apoptosis, secrete paracrine factors to enhance immunemodulation and, thus, provide cardiac protection
additional information
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
(5Z,13E)-(15S)-9alpha,11alpha-epidioxy-15-hydroxyprosta-5,13-dienoate
(5Z,13E)-(15S)-6,9alpha-epoxy-11a,15-dihydroxyprosta-5,13-dienoate
show the reaction diagram
-
i.e. prostaglandin H2
prostaglandin I2
?
10-hydroperoxyoctadeca-8,12-dienoic acid
10-oxooctadeca-8,12-dienoic acid + 10-oxodec-8-enoic acid + 10-hydroxyoctadeca-8,12-dienoic acid
show the reaction diagram
-
-
-
-
?
15-hydroperoxyeicosatetraenoic acid
13-hydroxy-14,15-epoxy-5,8,11-eicosatrienoic acid + 15-ketoeicosatetraenoic acid + 13-hydroxy-14,15-epoxy-5,8,11-eicosatrienoic acid + 15-ketoeicosatetraenoic acid
show the reaction diagram
-
13-hydroxy-14,15-epoxy-5,8,11-eicosatrienoic acid and 15-ketoeicosatetraenoic acid result from homolytic cleavage of the O-O bond, whereas 13-hydroxy-14,15-epoxy-5,8,11-eicosatrienoic acid + 15-ketoeicosatetraenoic acid results from heterolytic cleavage. About 80% of substrate is cleaved homolytically, and maximal velocity of homolytic cleavage is about 1.4fold faster than heterolytic cleavage
-
?
15-oxo-Prostaglandin H2
15-oxo-Prostaglandin I2 + ?
show the reaction diagram
5-trans-Prostaglandin H2
?
show the reaction diagram
-
-
-
-
-
8-iso-Prostaglandin H2
?
show the reaction diagram
Prostaglandin G2
Prostaglandin I2 + 15-hydroperoxyprostacyclin
show the reaction diagram
prostaglandin H1
12-hydroxy-8,10-heptadecadienoic acid + malondialdehyde
show the reaction diagram
-
-
-
-
?
prostaglandin H1
12-hydroxyheptadecadienoic acid + malondialdehyde
show the reaction diagram
prostaglandin H2
6-keto prostaglandin F1-alpha
show the reaction diagram
-
-
-
-
?
Prostaglandin H2
?
show the reaction diagram
prostaglandin H2
prostacyclin
show the reaction diagram
Prostaglandin H2
Prostaglandin I2
show the reaction diagram
Prostaglandin H3
Prostaglandin I3
show the reaction diagram
additional information
?
-
-
fusion protein linking cyclooxygenase COX-2 and prostacyclin synthase together, is able to convert arachidonic acid to prostaglandin G2, prostaglandin H2 and prostaglandin I2. Fusion protein may directly synthesize prostaglandin I2 from arachidonic acid with Km value of 0.0032 mM
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-
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NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
(5Z,13E)-(15S)-9alpha,11alpha-epidioxy-15-hydroxyprosta-5,13-dienoate
(5Z,13E)-(15S)-6,9alpha-epoxy-11a,15-dihydroxyprosta-5,13-dienoate
show the reaction diagram
-
i.e. prostaglandin H2
prostaglandin I2
?
Prostaglandin H2
?
show the reaction diagram
prostaglandin H2
prostacyclin
show the reaction diagram
Prostaglandin H2
Prostaglandin I2
show the reaction diagram
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
cytochrome P450
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
(1R,2S)-2-phenylcyclopropanamine
13-Hydroperoxylinoleic acid
15-hydroperoxy-5,8,11,13-eicosatetraenoic acid
2,4-Diamino-6-piperidinopyrimidine-3-oxide
-
-
3-Hydroperoxy-3-methyl-2-phenyl-3H-indole
-
-
6-(1-Piperidyl)-2,4-diaminopyrimidine
9,11-Azoprosta-5,13-dienoic acid
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-
arachidonic acid
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-
clotrimazole
Hydroperoxy-fatty acids
-
lipoxygenase products
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Low density lipoprotein cholesterol
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0.5 mg/ml stimulates 27%. Inhibition at higher concentrations. Maximal inhibition by 2 mg/ml, 64.2%
-
miconazole
minoxidil
Monoclonal antibodies
-
against prostacyclin synthase
-
NO
-
activation at moderate concentration, reversible inhibition at high concentrations. Hemoglobin prevents both, activation and inhibition
peroxynitrite
Prostaglandin H1
-
slight inactivation
prostaglandin H2
rofecoxib
Tetranitromethane
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substrate analog U46619 partially prevents inhibition
trans-2-phenyl cyclopropylamine
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-
Tranylcypromine
U51605
additional information
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
13-cis-retinoic acid
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induces prostaglandin-I synthase activity and expression of mRNA and protein, mediated by retinoic acid receptor. Actinomycin and cycloheximide both inhibit the retinoic acid-induced expression. 13-cis-Retinoic acid additionally increases the release of prostaglandin I2, both spontaneous and thrombin-induced. Co-incubation with 13-cis-retinoic acid and interleukin-1beta results in a synergic increase in the release of prostaglandin I2
dithiothreitol
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increase in activity with increasing glutathione concentration from 0.1 mM up to 5 mM
High density lipoprotein cholesterol
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1.0 mg/ml stimulates 21%. Lower concentrations inhibit, 16% inhibition by 0.25 mg/ml
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interleukin-1
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-
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interleukin-6
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Low density lipoprotein cholesterol
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0.5 mg/ml stimulates 27%. Inhibition at higher concentrations
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NO
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activation at moderate concentration, inhibition at high concentrations. Hemoglobin prevents both, activation and inhibition
reduced glutathione
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increase in activity with increasing glutathione concentration from 0.1 mM up to 5 mM
TNFalpha
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-
-
additional information
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.059 - 0.065
15-hydroperoxyeicosatetraenoic acid
0.0094
Prostaglandin H1
-
-
0.0073 - 0.03
prostaglandin H2
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
26.5
Prostaglandin H1
Bos taurus
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2.45
prostaglandin H2
Bos taurus
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IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.001 - 0.01
rofecoxib
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
0.11
-
production of 6-keto-prostaglandin F1alpha
0.136
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-
0.975
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-
1.6
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solubilized microsomes
2.6
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after calcium phosphate gel
4.3
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after DEAE-sepharose chromatography
7.1
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after hydroxyapatite chromatography
15
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purified enzyme, at 24°C
46
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CM column, assayed at 23°C using 30 microM prostaglandin H1 as the substrate
additional information
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
6.8 - 7.5
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7.5
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kinetic assay
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
23
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kinetic assay
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
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ischemic cortex, ipsilateral penumbra area, pyriform cortex, hippocampus, leptomeninges
Manually annotated by BRENDA team
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study on involvement of enzyme polymorphism in adenomatous or hyperplastic colorectal polyps. The enzyme promoter polymorphism may affect risk of colorectal polyps and modify the effects of nonsteroidal anti-inflammatory drug use on polyp risk
Manually annotated by BRENDA team
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widely distributed among different cell types, specific binding sites which may mediate luteotropic actions of the enzyme are only present in small and large luteal cells
Manually annotated by BRENDA team
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constitutive expression of prostaglandin-I synthase and cyclooxygenase-1 in HK cells, while expression of cyclooxygenase-2 and prostaglandin-E synthase are up-regulated in response to tumor necrosis factor-alpha, tumor growth factor-beta, and lipopolysaccharide
Manually annotated by BRENDA team
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tendon, fascia and arteries leading to the muscle
Manually annotated by BRENDA team
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vascular and nonvascular
Manually annotated by BRENDA team
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of cyclic, pregnant, and pseudopregnant rats. Expression of prostacyclin synthase is increases during early pregnancy and decreases gradually from day 5.5 to 6.5. Later during pregnancy, expression of enzyme is maximal on day 12 and decrease to the end of pregnancy. During pseudopregnancy, both prostaglandin D synthase and prostacyclin synthase are increased in a time-dependent manner and are maximal at day 5. Both enzymes are found in luminal as well as glandular epithelial cells and in stroma during late pregnancy
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
48000
-
mutant C441H, SDS-PAGE; wild-type, SDS-PAGE
56500
determined by SDS-PAGE and Western Blot analysis
57100
-
calculated from the primary structure, deduced from the cDNA sequence
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
monomer
-
-
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
-
diabetes induces prostacyclin synthase nitration in carotid plaques
Crystallization/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
recombinant protein without ligand, in complex with inhibitor minoxidil, or with substrate analogue U51605. Upon stereo-specific binding of substrate, conformational changes take place at the proximal side and in the heme itself. Mechanism is a radical-mediated isomerization with high product fidelity
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TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
100
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5-7 min, destroys activity in crude enzyme extract
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
6 M guanidine-HCl inactivates enzyme in crude extract
-
ORGANIC SOLVENT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Triton X-100
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within 30 s, about 75% of PGH2 is presented to the PGIS active side and isomerized to PGI2 by the membrane-bound PGIS. In contrast, only about 20% of the substrate is isomerized to the product by the detergent-solubilized (Triton X-100) PGIS. Replacement of the membrane with detergent does not alter the PGIS active side conformation, but affects the substrate presentation
OXIDATION STABILITY
ORGANISM
UNIPROT
LITERATURE
destructive action of a nascent oxidizing agent released from prostaglandin G1, 15-hydroperoxy-prostaglandin E1, 15-hydroperoxy-5,8,11,13-eicosatetraenoic acid, and 12-hydroxy-5,8,10,14-eicosatetraenoic acid is prevented by 2-aminomethyl-4-tert-6-iodophenol
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37459
human PGIS is significantly unstable when the heme cofactor appears in the reduction and/or reduction-CO binding state
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662059
the prostacyclin synthase is unusually sensitive to the redox state or sulfhydryl oxidation of the enzyme
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3127
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
-80°C, partially purified enzyme, stable for 2-3 months
-
-90°C, gradual loss of activity of enzyme in crude extract
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Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
partial
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recombinant C-terminally His4-tagged modified enzyme from Escherichia coli strain BL21/(DE3)pLys by nickel affinity chromatography and carboxymethyl cation exchange chromatography to homogeneity
recombinant enzyme
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recombinant enzyme is purified to homogeneity
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to electrophoretic homogeneity
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Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
expressed in Mus musculus mesenchymal stem cells
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expression in alveolar and airway epithelial cells from Mus musculus
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expression in Cos-1 cells
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expression in COS-7 cells
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expression in Escherichia coli
expression in HEK 293 cells
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expression in Spodoptera frugiperda 21 cells
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expression with C-terminal His-tag and hydrophilic aminoterminal segment MAKKTSS
for expression in Escherichia coli cells
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from endothelilal cells
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fusion protein linking cyclooxygenase COX-2 and prostacyclin synthase together, separated by a transmembrane domain of 10 or 22 residues
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GFP-tagged cDNA containing the full-length rat prostacyclin synthase gene is inserted into an adenoviral DNA construct for in vitro gene transfer to murine and human mesenchymal stem cells
into the pcDNA3.1 vector for transfection of insulin-producing RINm5F cells
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recombinant expression of C-terminally His4-tagged enzyme with the first 16 amino acid residues in the N-terminal transmembrane domain replaced with a hydrophilic sequence, MAKKTSS, in Escherichia coli strain BL21/(DE3)pLys
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recombinant expression of C-terminally His4-tagged enzyme with the first 17 amino acid residues in the N-terminal transmembrane domain replaced with a hydrophilic sequence, MAKKTSS, in Escherichia coli strain BL21/(DE3)pLys
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specific transgenic expression in mouse kidney using rat KSP-cadherin promoter
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
a dramatic loss in PGIS mRNA levels is observed in primary lung tumor samples
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after 16 weeks the prostacyclin synthase mRNA levels are reduced
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after 8 weeks on fat diet, aortic arches from low-density lipoprotein receptor deficient, LDL r-KO, mice shows a significant increase in prostacyclin synthase levels
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angiotensin II (0.1 mM, 24 h incubation) induces PGIS mRNA expression. Pretreatment with losartan (0.01 mM), PD98059 (0.025 mM) or SB203580 (0.01 mM) prevents PGIS protein expression induced by the combination of angiotensin II and interleukin-1beta
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for overexpression of prostacyclin synthase transgenic mice, carrying the rat prostacyclin synthase gene, are developed
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hyperglycemia and palmitate increase prostacyclin synthase nitration and reduce its activity
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interleukin-1beta (10 ng/ml, 24 h incubation) does not alter PGIS protein expression
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PGIS mRNA and protein expression is increased in response to mechanical cyclical stretch in both spinal ligament and uterine myometrial cells, up-regulation is observed in umbilical vein endothelial cell treated with a thromboxane analogue
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ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
C441H
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no heme-binding ability, no activity
DELTA-20-PGIS
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PGH2 presentation to the membrane-bound mutant has a 2 to 3fold delay compared to that of membrane-bound wild-type PGIS
PGIS/TXAS(8-27)
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the first 20 membrane anchor residues of human PGIS are replaced by the corresponding membrane anchor region of human TXAS (thromboxane A2 synthase). Efficiency of the isomerization of PGH2 to PGI2 is slowed down with approximately 25, 65, and 85% at 30, 60, and 120 s reactions, compared to the wild-type PGIS, respectively
additional information
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
medicine