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Information on EC 5.3.99.4 - prostaglandin-I synthase
for references in articles please use BRENDA:EC5.3.99.4
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EC Tree 5 Isomerases
5.3 Intramolecular oxidoreductases
5.3.99 Other intramolecular oxidoreductases
5.3.99.4 prostaglandin-I synthase
IUBMB Comments
A cytochrome P-450 heme-thiolate enzyme. Converts prostaglandin H2 into prostaglandin I2 (prostacyclin).
The enzyme appears in viruses and cellular organisms
- 5.3.99.4
-
thromboxane
-
cyclooxygenase
- endothelial
-
arachidonic
- artery
- platelet
- cox-2
-
vasodilator
- hypertension
-
prostanoids
-
endoperoxide
-
eicosanoids
- pulmonary
- vessel
- indomethacin
- aorta
-
6-keto-pgf1
- tranylcypromine
- peroxynitrite
-
vasoconstriction
-
endothelium-dependent
-
6-keto-prostaglandin
-
6-keto-pgf1alpha
-
phosphoglucose
-
iloprost
- tx
- mpges-1
- medicine
-
6-keto
-
antithrombotic
-
5-lipoxygenase
- dazoxiben
-
heme-thiolate
- ptges
- f1alpha
- synthase-1
-
beraprost
- 15-hpete
Reaction Schemes
showSynonyms
pgis, prostacyclin synthase, pgi2 synthase, ptgis, prostacyclin synthetase, pgi2 synthetase, cyp8a1, pgi synthase, prostaglandin i2 synthase, pgi2-s, more
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
Aortic cytochrom P450
-
-
-
-
PGI synthase
PGI2 synthase
PGI2 synthetase
-
-
-
-
PGIS
prostacyclin synthase
Prostacyclin synthetase
-
-
-
-
Prostacycline synthetase
-
-
-
-
Prostaglandin I2 synthase
Prostaglandin I2 synthetase
-
-
-
-
Synthetase, prostacyclin
-
-
-
-
PGI2 synthase
-
-
-
-
PGIS
-
-
-
-
PGIS
-
-
prostacyclin synthase
-
-
-
-
prostacyclin synthase
-
-
Prostaglandin I2 synthase
-
-
-
-
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REACTION
REACTION DIAGRAM
COMMENTARY
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
(5Z,13E,15S)-9alpha,11alpha-epidioxy-15-hydroxyprosta-5,13-dienoate = (5Z,13E,15S)-6,9alpha-epoxy-11alpha,15-dihydroxyprosta-5,13-dienoate
mechanism
-
(5Z,13E,15S)-9alpha,11alpha-epidioxy-15-hydroxyprosta-5,13-dienoate = (5Z,13E,15S)-6,9alpha-epoxy-11alpha,15-dihydroxyprosta-5,13-dienoate
mechanism
-
(5Z,13E,15S)-9alpha,11alpha-epidioxy-15-hydroxyprosta-5,13-dienoate = (5Z,13E,15S)-6,9alpha-epoxy-11alpha,15-dihydroxyprosta-5,13-dienoate
mechanism
-
(5Z,13E,15S)-9alpha,11alpha-epidioxy-15-hydroxyprosta-5,13-dienoate = (5Z,13E,15S)-6,9alpha-epoxy-11alpha,15-dihydroxyprosta-5,13-dienoate
prostaglandin endoperoxyde PGH2 prostacyclin PGI2 , a mechanism with the participation of a heme-thiolate protein is proposed
-
(5Z,13E,15S)-9alpha,11alpha-epidioxy-15-hydroxyprosta-5,13-dienoate = (5Z,13E,15S)-6,9alpha-epoxy-11alpha,15-dihydroxyprosta-5,13-dienoate
radical-mediated isomerizytion with high product fidelity
-
(5Z,13E,15S)-9alpha,11alpha-epidioxy-15-hydroxyprosta-5,13-dienoate = (5Z,13E,15S)-6,9alpha-epoxy-11alpha,15-dihydroxyprosta-5,13-dienoate
-
-
-
-
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
intramolecular oxidoreduction
-
-
-
-
isomerization
isomerization
-
-
-
-
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PATHWAY SOURCE
PATHWAYS
BRENDA
MetaCyc
arachidonate metabolites biosynthesis, C20 prostanoid biosynthesis, icosapentaenoate metabolites biosynthesis
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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).
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CAS REGISTRY NUMBER
COMMENTARY
65802-86-0
-
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
LITERATURE
COMMENTARY
Reversibility
r=reversible
ir=irreversible
?=not specified
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
-
Substrates: i.e. prostaglandin H2
Products: prostaglandin I2
Products: prostaglandin I2
?
(5Z,13E,15S)-9alpha,11alpha-epidioxy-15-hydroxyprosta-5,13-dienoate
(5Z,13E,15S)-6,9alpha-epoxy-11alpha,15-dihydroxyprosta-5,13-dienoate
-
Substrates: -
Products: -
Products: -
?
10-hydroperoxyoctadeca-8,12-dienoic acid
10-oxooctadeca-8,12-dienoic acid + 10-oxodec-8-enoic acid + 10-hydroxyoctadeca-8,12-dienoic acid
-
Substrates: -
Products: -
Products: -
?
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
Substrates: -
Products: 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
Products: 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
?
prostaglandin H1
12-hydroxy-8,10-heptadecadienoic acid + malondialdehyde
-
Substrates: -
Products: -
Products: -
?
prostaglandin H1
12-hydroxyheptadecadienoic acid + malondialdehyde
-
Substrates: -
Products: -
Products: -
?
prostaglandin H2
6-keto prostaglandin F1-alpha
-
Substrates: -
Products: -
Products: -
?
additional information
?
-
-
Substrates: 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
Products: -
Products: -
?
prostaglandin G2
prostaglandin I2 + 15-hydroperoxyprostacyclin
-
Substrates: -
Products: -
Products: -
?
prostaglandin G2
prostaglandin I2 + 15-hydroperoxyprostacyclin
-
Substrates: -
Products: 15-hydroperoxyprostacyclin decomposes to 6,15-diketo-prostaglandin F1alpha
Products: 15-hydroperoxyprostacyclin decomposes to 6,15-diketo-prostaglandin F1alpha
?
Prostaglandin H2
?
-
Substrates: formation of prostaglandin I2, which is a powerful vasodilator and the most potent natural occuring inhibitor of platelet aggregation
Products: -
Products: -
?
Prostaglandin H2
?
-
Substrates: produces prostaglandin I2 which has opposite actions on platelet aggregatory and vasoconstrictive properties
Products: -
Products: -
?
Prostaglandin H2
?
-
Substrates: formation of prostaglandin I2 which is a powerful vasodilator and the most potent naturally occuring inhibitor of platlet aggregation. An imbalance in the ratio of prostaglandin I2 to thromboxane A2, a compound that has opposite biological properties may reflect some of the changes occuring in various pathological situations including thrombosis and ischemia
Products: -
Products: -
?
Prostaglandin H2
?
-
Substrates: formation of prostaglandin I2 which is a powerful vasodilator and the most potent naturally occuring inhibitor of platlet aggregation. An imbalance in the ratio of prostaglandin I2 to thromboxane A2, a compound that has opposite biological properties may reflect some of the changes occuring in various pathological situations including thrombosis and ischemia
Products: -
Products: -
?
Prostaglandin H2
Prostaglandin I2
-
Substrates: -
Products: 6-keto-prostaglandin F1alpha
Products: 6-keto-prostaglandin F1alpha
?
Prostaglandin H2
Prostaglandin I2
-
Substrates: -
Products: prostaglandin I2
Products: prostaglandin I2
?
Prostaglandin H2
Prostaglandin I2
-
Substrates: -
Products: prostaglandin I2 is readily hydrolyzed to 6-keto-prostaglandin F1alpha
Products: prostaglandin I2 is readily hydrolyzed to 6-keto-prostaglandin F1alpha
?
Prostaglandin H2
Prostaglandin I2
-
Substrates: -
Products: prostaglandin I2
Products: prostaglandin I2
?
Prostaglandin H2
Prostaglandin I2
-
Substrates: -
Products: -
Products: -
?
Prostaglandin H2
Prostaglandin I2
-
Substrates: -
Products: prostaglandin I2
Products: prostaglandin I2
?
Prostaglandin H2
Prostaglandin I2
-
Substrates: in vivo, this reaction is coupled to a previous one, where arachidonic acid is converted by cyclooxygenase and yields the substrate PGH2
Products: -
Products: -
?
Prostaglandin H2
Prostaglandin I2
-
Substrates: -
Products: prostaglandin I2
Products: prostaglandin I2
?
Prostaglandin H2
Prostaglandin I2
-
Substrates: -
Products: -
Products: -
?
Prostaglandin H2
Prostaglandin I2
Substrates: -
Products: -
Products: -
?
Prostaglandin H2
Prostaglandin I2
-
Substrates: -
Products: prostaglandin I2
Products: prostaglandin I2
?
Prostaglandin H2
Prostaglandin I2
-
Substrates: -
Products: prostaglandin I2
Products: prostaglandin I2
?
Prostaglandin H2
Prostaglandin I2
-
Substrates: -
Products: prostaglandin I2 is readily hydrolyzed to 6-keto-prostaglandin F1alpha
Products: prostaglandin I2 is readily hydrolyzed to 6-keto-prostaglandin F1alpha
?
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NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
LITERATURE
COMMENTARY
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
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
-
Substrates: i.e. prostaglandin H2
Products: prostaglandin I2
Products: prostaglandin I2
?
(5Z,13E,15S)-9alpha,11alpha-epidioxy-15-hydroxyprosta-5,13-dienoate
(5Z,13E,15S)-6,9alpha-epoxy-11alpha,15-dihydroxyprosta-5,13-dienoate
-
Substrates: -
Products: -
Products: -
?
Prostaglandin H2
?
-
Substrates: formation of prostaglandin I2, which is a powerful vasodilator and the most potent natural occuring inhibitor of platelet aggregation
Products: -
Products: -
?
Prostaglandin H2
?
-
Substrates: produces prostaglandin I2 which has opposite actions on platelet aggregatory and vasoconstrictive properties
Products: -
Products: -
?
Prostaglandin H2
?
-
Substrates: formation of prostaglandin I2 which is a powerful vasodilator and the most potent naturally occuring inhibitor of platlet aggregation. An imbalance in the ratio of prostaglandin I2 to thromboxane A2, a compound that has opposite biological properties may reflect some of the changes occuring in various pathological situations including thrombosis and ischemia
Products: -
Products: -
?
Prostaglandin H2
?
-
Substrates: formation of prostaglandin I2 which is a powerful vasodilator and the most potent naturally occuring inhibitor of platlet aggregation. An imbalance in the ratio of prostaglandin I2 to thromboxane A2, a compound that has opposite biological properties may reflect some of the changes occuring in various pathological situations including thrombosis and ischemia
Products: -
Products: -
?
Prostaglandin H2
Prostaglandin I2
-
Substrates: -
Products: -
Products: -
?
Prostaglandin H2
Prostaglandin I2
-
Substrates: in vivo, this reaction is coupled to a previous one, where arachidonic acid is converted by cyclooxygenase and yields the substrate PGH2
Products: -
Products: -
?
Prostaglandin H2
Prostaglandin I2
-
Substrates: -
Products: -
Products: -
?
Prostaglandin H2
Prostaglandin I2
Substrates: -
Products: -
Products: -
?
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COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
heme
-
heme conformation and heme protein matrix interactions for human and zebrafish enzymes in the presence and absence of ligands, overview. The heme group is in the ferric, six-coordinate, low-spin state for both resting and ligand-bound enzymes of boh species. Drastically different RR shifts with heme conformational changes in both hPGIS and zPGIS upon different ligand bindings, suggesting that PGIS exhibits a ligand-specific heme conformational change to accommodate the substrate binding
heme
-
heme conformation and heme protein matrix interactions for human and zebrafish enzymes in the presence and absence of ligands, overview. The heme group is in the ferric, six-coordinate, low-spin state for both resting and ligand-bound enzymes of boh species. Drastically different RR shifts with heme conformational changes in both hPGIS and zPGIS upon different ligand bindings, suggesting that PGIS exhibits a ligand-specific heme conformational change to accommodate the substrate binding
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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
Low density lipoprotein cholesterol
-
0.5 mg/ml stimulates 27%. Inhibition at higher concentrations. Maximal inhibition by 2 mg/ml, 64.2%
-
NO
-
activation at moderate concentration, reversible inhibition at high concentrations. Hemoglobin prevents both, activation and inhibition
13-hydroperoxylinoleic acid
-
9,11-azoprosta-5,13-dienoic acid prevents inactivation; rapid inactivation of purified enzyme during incubation with prostaglandin H2
13-hydroperoxylinoleic acid
-
rapid inactivation of purified enzyme during incubation with prostaglandin H2
miconazole
-
i.e. 1-[2,4-dichloro-beta-[(2,4-dichlorobenzyl)oxy]phenyl]imidazole
prostaglandin H2
-
9,11-azoprosta-5,13-dienoic acid prevents inactivation; rapid inactivation of purified enzyme during incubation with prostaglandin H2
prostaglandin H2
-
rapid inactivation of purified enzyme during incubation with prostaglandin H2
prostaglandin H2
-
9,11-azoprosta-5,13-dienoic acid prevents inactivation; inactivation originates primarily from a transition-state intermediate, not from malondialdehyde formed by hydrolysis of prostaglandin endoperoxides; rapid inactivation of purified enzyme during incubation with prostaglandin H2
rofecoxib
-
inhibitor of cyclooxygenase COX-2, additionally non-competitive inhibition of prostacyclin synthase in aortic microsomal fractions. No significant inhibition up to 0.001 mM
rofecoxib
-
inhibitor of cyclooxygenase COX-2, additionally non-competitive inhibition of prostacyclin synthase
tranylcypromine
-
10 mM, 90% inhibition in absence or presence of 2 mM reduced glutathione
U51605
-
culture of embryo in presence of U51605 decreases the implantation rate
additional information
-
the enzyme is deactivated by prostaglandin H2 and peroxides
-
additional information
-
the enzyme is deactivated by prostaglandin H2 and peroxides
-
additional information
-
proinflammatory C-reactive protein, CRP, selectively inhibits endothelium-dependent PGI2-induced dilation of coronary arterioles through peroxynitrite-mediated tyrosine nitration of prostacyclin synthase
-
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
13-cis-retinoic acid
-
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
-
increase in activity with increasing glutathione concentration from 0.1 mM up to 5 mM
High density lipoprotein cholesterol
-
1.0 mg/ml stimulates 21%. Lower concentrations inhibit, 16% inhibition by 0.25 mg/ml
-
Low density lipoprotein cholesterol
-
0.5 mg/ml stimulates 27%. Inhibition at higher concentrations
-
NO
-
activation at moderate concentration, inhibition at high concentrations. Hemoglobin prevents both, activation and inhibition
reduced glutathione
-
increase in activity with increasing glutathione concentration from 0.1 mM up to 5 mM
additional information
-
the extent of prostaglandin I2 production is determined by an appropriate ratio of COX-1/COX-2 to PGIS. Human vascular endothelial cells transfected with a construct that contains COX-1 and prostaglandin-I synthase cDNAs have an equivalent increase in COX-1 and PGIS, and produce a large quantity of prostaglandin-I synthase which is more than 200fold over that produced by untransfected cells
-
additional information
-
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
-
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.059
15-hydroperoxyeicosatetraenoic acid
pH 7.5, 23°C, heterolytic cleavage
0.065
15-hydroperoxyeicosatetraenoic acid
pH 7.5, 23°C, homolytic cleavage
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.001
rofecoxib
Homo sapiens
-
22°C, 0.001 mM rofecoxib completely blocks cyclooxygenase COX-2
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
46
-
CM column, assayed at 23°C using 30 microM prostaglandin H1 as the substrate
additional information
additional information
-
assay of prostacyclin synthase using [5,6-3H]prostaglandin H2
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
3127, 3200, 37460, 37461, 37465, 37468, 37469, 37472, 37474, 37476, 37477, 37478, 37479, 37480, 37482, 37485, 660924, 679435, 681029
-
-
brenda