Information on EC 3.1.4.53 - 3',5'-cyclic-AMP phosphodiesterase and Organism(s) Homo sapiens and UniProt Accession Q13946

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Homo sapiens
UNIPROT: Q13946


The expected taxonomic range for this enzyme is: Eukaryota, Bacteria


The taxonomic range for the selected organisms is: Homo sapiens

EC NUMBER
COMMENTARY hide
3.1.4.53
-
RECOMMENDED NAME
GeneOntology No.
3',5'-cyclic-AMP phosphodiesterase
-
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
adenosine 3',5'-cyclic phosphate + H2O = AMP
show the reaction diagram
catalytic reaction mechanism, overview
-
PATHWAY
BRENDA Link
KEGG Link
MetaCyc Link
Purine metabolism
-
-
SYSTEMATIC NAME
IUBMB Comments
3',5'-cyclic-AMP 5'-nucleotidohydrolase
Requires Mg2+ or Mn2+ for activity [2]. This enzyme is specific for 3',5'-cAMP and does not hydrolyse other nucleoside 3',5'-cyclic phosphates such as cGMP (cf. EC 3.1.4.17, 3,5-cyclic-nucleotide phosphodiesterase and EC 3.1.4.35, 3,5-cyclic-GMP phosphodiesterase). It is involved in modulation of the levels of cAMP, which is a mediator in the processes of cell transformation and proliferation [3].
CAS REGISTRY NUMBER
COMMENTARY hide
9036-21-9
-
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
malfunction
-
PDE4 inhibition together with transforming growth factor-beta1 results in augmented PGE2 production together with increased expression of COX mRNA and protein. inhibitors may attenuate fibroblast activities that can lead to fibrosis, PDE4 inhibitors may be particularly effective in the presence of transforming growth factor-beta1-induced fibroblast stimulation
metabolism
-
PKA, EPAC1, and PDE4D differentially regulate humanarterial endothelial cell vascular endothelial cadherin-based structures, overview. Protein-protein interactions between EPAC1 and PDE4D serve to foster their integration into vascular endothelial cadherin-based complexes and allow robust local regulation of EPAC1-based stabilization of vascular endothelial cadherin-based adhesions
physiological function
additional information
-
PDE4 is a cAMP-specific PDE which has four subfamilies, A thru D, that include over 50 isoforms
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
3',5'-cAMP + H2O
5'-AMP
show the reaction diagram
specific substrate
-
-
?
3',5'-cAMP + H2O
5'-AMP
show the reaction diagram
3',5'-cGMP + H2O
5'-AMP
show the reaction diagram
-
low activity
-
-
?
3',5'-cGMP + H2O
5'-GMP
show the reaction diagram
-
activity with 3',5'-cAMP is much higher than activity with 3',5'-cGMP, PDE7
-
-
?
adenosine 3',5'-cyclic phosphate + H2O
adenosine 5'-phosphate
show the reaction diagram
cAMP + H2O
5'-AMP
show the reaction diagram
-
-
-
?
cAMP + H2O
AMP
show the reaction diagram
-
-
-
?
cGMP + H2O
5'-GMP
show the reaction diagram
-
-
-
?
guanosine 3',5'-cyclic phosphate + H2O
guanosine 5'-phosphate
show the reaction diagram
-
-
-
?
additional information
?
-
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
3',5'-cAMP + H2O
5'-AMP
show the reaction diagram
-
-
-
-
?
adenosine 3',5'-cyclic phosphate + H2O
adenosine 5'-phosphate
show the reaction diagram
-
determination of reaction rate and mechanism using computational modeling, quantum mechanical/molecular mechanical-free energy perturbation, QM/MM-FE, and QM/MM-Poisson-Boltzmann surface area, PBSA, calculations. The onQM/MMreaction-coordinate calculations including the protein environment of any PDE-catalyzed reaction system identifies a unique catalytic reaction mechanism, overview
-
-
?
additional information
?
-
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Mn2+
-
the enzyme requires the presence of at least 1 mM Mn2+ or Mg2+ for maximal activity in vitro
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
4-[(2-chloro-4-nitrophenyl)thio]-pyridine
-
N-[2-(5-chloro-2-nitrophenylthio)phenyl]acetamide
lead compound for Parkinson's disease treatment
(2R,3R)-3-(6-amino-9H-purin-9-yl)nonan-2-ol
-
IC50: 0.31 mM, PDE4
(2Z)-9,10-dimethoxy-3-methyl-2-[(2,4,6-trimethylphenyl)imino]-2,3,6,7-tetrahydro-4H-pyrimido[6,1-a]isoquinolin-4-one
-
IC50: 0.00043 mM, PDE4
(4aS,8aR)-4-(3,4-dimethoxyphenyl)-4a,5,8,8a-tetrahydrophthalazin-1(2H)-one
-
-
(R)-rolipram
-
-
3-(1-methyl-7-oxo-3-propyl-4,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-propoxybenzenesulfonamide
-
-
3-(6-aminopurin-9-yl)nonan-2-ol hydrochloride
-
-
3-isobutyl-1-methyl-xanthine
-
-
3-isobutyl-1-methylxanthine
3-isobuytl-1-methylxanthine
-
-
4-[(2-chloro-4-nitrophenyl)thio]-pyridine
-
4-[8-(3-nitrophenyl)-[1,7]naphthyridin-6-yl]benzoic acid
i.e. NVP
6-(3,4-dimethoxyphenyl)-2-[4-(morpholinomethyl)benzyl]-4,5-dihydropyridazin-3(2H)-one
-
-
apigenin
-
-
apigenin-7-O-glucoside
-
-
apremilast
-
CC-10004, i.e. (S)-N-[2-[1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]acetamide, oral phosphodiesterase-4 inhibitor, apremilast shows no marked selectivity among PDE4 isozymes
avanafil
-
-
AWD 12-250
-
-
AWD12-281
-
-
BRL-50481
-
PDE7 inhibitor
BRL50481
-
-
cAMP-N1-oxide
-
-
cGMP
-
5% inhibition at 0.1 mM
chamomile
-
inhibits cAMP-PDE activity
cilomilast
Cilostamide
-
IC50: 0.099 mM, PDE4
cis-(+)-4-(3,4-dimethoxyphenyl)-2-[4-(morpholinomethyl)benzyl]-4a,5,8,8a-tetrahydrophthalazin-1(2H)-one
-
-
cis-(+)-4-(3,4-dimethoxyphenyl)-4a,5,8,8a-tetrahydrophthalazin-1(2H)-one
-
-
cis-(+/-)-4-(3,4-dimethoxyphenyl)-4a,5,8,8a-tetrahydrophthalazin-1(2H)-one
-
-
cis-(-)-4-(3,4-dimethoxyphenyl)-2-[4-(morpholinomethyl)benzyl]-4a,5,8,8a-tetrahydrophthalazin-1(2H)-one
-
-
cis-(-)-4-(3,4-dimethoxyphenyl)-4a,5,8,8a-tetrahydrophthalazin-1(2H)-one
-
-
cis-2-[(E)-4-(1H-imidazol-1-yl)but-2-enyl]-4-(3,4-dimethoxyphenyl)-4a,5,8,8a-tetrahydrophthalazin-1(2H)-one
-
-
cis-2-[2-[2-(1H-imidazol-1-yl)ethoxy]ethyl]-4-(3,4-dimethoxyphenyl)-4a,5,8,8a-tetrahydrophthalazin-1(2H)-one
-
-
cis-2-[4-(1,4-dioxa-8-azaspiro[4.5]decan-8-ylmethyl)-benzyl]-4-(3,4-dimethoxyphenyl)-4a,5,8,8a-tetrahydrophthalazin-1(2H)-one
-
-
cis-2-[4-[(1H-imidazol-1-yl)methyl]benzyl]-4-(3,4-dimethoxyphenyl)-4a,5,8,8a-tetrahydrophthalazin-1(2H)-one
-
-
cis-4-(3,4-dimethoxyphenyl)-2-[2-(morpholinomethyl)benzyl]-4a,5,8,8a-tetrahydrophthalazin-1(2H)-one
-
-
cis-4-(3,4-dimethoxyphenyl)-2-[3-(morpholinomethyl)benzyl]-4a,5,8,8a-tetrahydrophthalazin-1(2H)-one
-
-
cis-4-(3,4-dimethoxyphenyl)-2-[4-(morpholinomethyl)benzyl]-4a,5,6,7,8,8a-hexahydrophthalazin-1(2H)-one
-
-
cis-4-(3,4-dimethoxyphenyl)-2-[4-(morpholinomethyl)benzyl]-4a,5,8,8a-tetrahydrophthalazin-1(2H)-one
-
-
cis-4-(3,4-dimethoxyphenyl)-2-[4-(piperidin-1-ylmethyl)benzyl]-4a,5,8,8a-tetrahydrophthalazin-1(2H)-one
-
-
cis-4-(3,4-dimethoxyphenyl)-2-[4-[(4-methylpiperazin-1-yl)methyl]benzyl]-4a,5,8,8a-tetrahydrophthalazin-1(2H)-one
-
-
cis-4-(3,4-dimethoxyphenyl)-2-[4-[(4-oxopiperidin-1-yl)-methyl]benzyl]-4a,5,8,8a-tetrahydrophthalazin-1(2H)-one
-
-
cis-4-(3,4-dimethoxyphenyl)-2-[4-[(dimethylamino)-methyl]benzyl]-4a,5,8,8a-tetrahydrophthalazin-1(2H)-one
-
-
cis-5-(3,4-dimethoxyphenyl)-3-[4-(morpholinomethyl)benzyl]-3,4-diazabicyclo[4.1.0]hept-4-en-2-one
-
-
cis-5-(3,4-dimethoxyphenyl)-3-[4-(morpholinomethyl)benzyl]-3,4-diazabicyclo[4.2.0]oct-4-en-2-one hydrochloride
-
-
D-22888
-
-
denbufylline
-
-
dipyridamole
dipyridimole
-
-
E4021
-
-
erythro-9-(2-hydroxy-3-nonyl)adenine
-
7.4% inhibition at 0.1 mM
erythro-9-[3-(2-hydroxynonyl)]adenine
-
0.1 mM, 12% inhibition, wild-type enzyme
etazolate
-
-
ethyl 2-([4-(3-carbamoylpiperazin-1-yl)-6-[4-(dimethylamino)piperidin-1-yl]pyrimidin-2-yl]amino)-4-methyl-1,3-thiazole-5-carboxylate
-
-
ethyl 2-([4-[(3,4-dimethoxybenzyl)amino]-6-(piperazin-1-yl)pyrimidin-2-yl]amino)-4-methyl-1,3-thiazole-5-carboxylate
-
-
ethyl 2-([4-[4-(dimethylamino)piperidin-1-yl]-6-(4-hydroxypiperidin-1-yl)pyrimidin-2-yl]amino)-4-methyl-1,3-thiazole-5-carboxylate
-
-
ethyl 2-([4-[4-(dimethylamino)piperidin-1-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-yl]amino)-4-methyl-1,3-thiazole-5-carboxylate
-
-
ethyl 2-([4-[4-(dimethylamino)piperidin-1-yl]-6-(morpholin-4-yl)pyrimidin-2-yl]amino)-4-methyl-1,3-thiazole-5-carboxylate
-
-
ethyl 2-([4-[4-(dimethylamino)piperidin-1-yl]-6-[3-(hydroxymethyl)piperidin-1-yl]pyrimidin-2-yl]amino)-4-methyl-1,3-thiazole-5-carboxylate
-
-
ethyl 2-([7-ethyl-6-[(4-sulfamoylbenzyl)amino]-7H-purin-2-yl]amino)-4-methyl-1,3-thiazole-5-carboxylate
-
-
ethyl 2-[[4,6-bis(4-hydroxypiperidin-1-yl)pyrimidin-2-yl]amino]-4-methyl-1,3-thiazole-5-carboxylate
-
-
ethyl 2-[[4-[4-[2-(dimethylamino)ethyl]piperazin-1-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-yl]amino]-4-methyl-1,3-thiazole-5-carboxylate
-
-
ethyl 3,5-dimethyl-1-phenyl-1H-pyrazole-4-carboxylate
-
IC50: 0.00027 mM, PDE4D; IC50: 0.00031 mM, PDE4B
ethyl 3,5-dimethyl-1-quinolin-8-yl-1H-pyrazole-4-carboxylate
-
IC50: 0.017 mM, PDE4B; IC50: 0.019 mM, PDE4D
ethyl 3,5-dimethyl-1H-pyrazole-4-carboxylate
-
IC50: 0.015 mM, PDE4B; IC50: 0.019 mM, PDE4D
ethyl 3-(4-chlorophenyl)-1-phenyl-1H-pyrazole-4-carboxylate
-
IC50: 0.00088 mM, PDE4D; IC50: 0.0015 mM, PDE4B
ethyl 3-methyl-5-(4-methylphenyl)-1H-pyrazole-4-carboxylate
-
IC50: 0.06 mM, PDE4B; IC50: 0.082 mM, PDE4D
ethyl 4-methyl-2-([4-(4-methylpiperazin-1-yl)-6-[methyl(3,4,5-trimethoxybenzyl)amino]pyrimidin-2-yl]amino)-1,3-thiazole-5-carboxylate
-
-
ethyl 4-methyl-2-([4-(methylamino)-6-[(4-sulfamoylbenzyl)amino]pyrimidin-2-yl]amino)-1,3-thiazole-5-carboxylate
-
-
ethyl 4-methyl-2-([4-(piperazin-1-yl)-6-[(4-sulfamoylbenzyl)amino]pyrimidin-2-yl]amino)-1,3-thiazole-5-carboxylate
-
-
ethyl 4-methyl-2-([4-[(4-sulfamoylbenzyl)amino]pyrimidin-2-yl]amino)-1,3-thiazole-5-carboxylate
-
-
ethyl 4-methyl-2-([4-[methyl(3,4,5-trimethoxybenzyl)amino]-6-(piperazin-1-yl)pyrimidin-2-yl]amino)-1,3-thiazole-5-carboxylate
-
-
ethyl 4-methyl-2-[[4-(piperazin-1-yl)-7-(3,4,5-trimethoxybenzyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]-1,3-thiazole-5-carboxylate
-
-
ethyl 5-amino-1-(4a,5,6,7,8,9a-hexahydro[1]benzothieno[2,3-d]pyrimidin-4-yl)-1H-pyrazole-4-carboxylate
-
IC50: 0.025 mM, PDE4B; IC50: 0.05 mM, PDE4D
hyperoside
-
-
IR-202
-
PDE7 inhibitor
IR-284
-
dual PDE4/PDE7 inhibitor
LAS-31025
-
-
lodenafil
-
-
luteolin
-
-
luteolin-7-O-glucoside
-
-
Milrinone
mirodenafil
-
-
MK298
-
-
N-[2-(5-chloro-2-nitrophenylthio)phenyl]acetamide
N-[3-(1H-imidazol-1-yl)propyl]-2-[cis-4-(3,4-dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydrophthalazin-2(1H)-yl]acetamide
-
-
N6-Monobutyryl-cAMP
-
-
N6-monobutyyl-cAMP
-
-
papaverine
-
-
patuletin-7-O-glucoside
-
-
quazinone
-
0.1 mM, 26% inhibition, wild-type enzyme
quinazolinamine
-
IC50: 0.34 mM, PDE4
R-rolipram
-
-
Ro-20-1724
-
inhibition of PDE4, resulting in increased intacelular cAMP
Ro20-1724
roflumilast
rolipram
RP-73401
-
IC50: 0.0000016 mM, PDE4
RPR-73401
-
-
RS-25344
-
phosphorylation of PDE-4D3 increases the sensitivity of the enzyme to inhibition by RS-25344 about 100fold
RS-33793
-
phosphorylation of PDE-4D3 increases the sensitivity of the enzyme to inhibition by RS-33793 about 330fold
SB 207499
-
-
SCH 351591
-
-
SCH51866
-
-
sildenafil
tadalafil
theophylline
-
weak inhibitior
vardenafil
vinpocetine
zaprinast
zardaverine
Zn2+
-
more than 90% inhibition at 0.05 mM Zn2+ in the presence of 0.1 mM EDTA, inhibition can be greatly relieved with EDTA at 0.30 mM
additional information
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
EDTA
-
EDTA at 0.10 mM slightly activates PDE4
isoproterenol
-
0.001 mM isoproterenol triggers a sustained, 2fold increase in PDE4 activity
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0007 - 0.0088
3',5'-cAMP
1.6
3',5'-cGMP
-
wild type PDE8A1 catalytic domain, in 20 mM Tris-HCl, pH 7.5, 4 mM MnCl2, at 24°C
0.000055 - 0.0244
adenosine 3',5'-cyclic phosphate
0.0001 - 0.0058
cAMP
0.24 - 0.427
cGMP
0.124
guanosine 3',5'-cyclic phosphate
-
-
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
4 - 4.3
3',5'-cAMP
1.6
3',5'-cGMP
-
wild type PDE8A1 catalytic domain, in 20 mM Tris-HCl, pH 7.5, 4 mM MnCl2, at 24°C
0.3 - 6.7
cAMP
0.48 - 1.19
cGMP
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.000085
(R)-rolipram
-
-
0.000068
apremilast
-
PDE4 purified from U-937 cells, using 0.001 mM cAMP as substrate, pH and temperature not specified in the publication
0.000114
cilomilast
30°C
0.00025 - 0.00038
R-rolipram
0.000037 - 0.0016
rolipram
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.00018
4-[(2-chloro-4-nitrophenyl)thio]-pyridine
Homo sapiens;
Q13946
pH not specified in the publication, 30°C
0.0021
N-[2-(5-chloro-2-nitrophenylthio)phenyl]acetamide
Homo sapiens;
Q13946
pH not specified in the publication, 30°C
0.31
(2R,3R)-3-(6-amino-9H-purin-9-yl)nonan-2-ol
Homo sapiens;
-
IC50: 0.31 mM, PDE4
0.00043
(2Z)-9,10-dimethoxy-3-methyl-2-[(2,4,6-trimethylphenyl)imino]-2,3,6,7-tetrahydro-4H-pyrimido[6,1-a]isoquinolin-4-one
Homo sapiens;
-
IC50: 0.00043 mM, PDE4
0.000085
(4aS,8aR)-4-(3,4-dimethoxyphenyl)-4a,5,8,8a-tetrahydrophthalazin-1(2H)-one
Homo sapiens;
-
in Tris-HCl (pH 7.6), 100 mM NaCl, 150 mM MgCl2, and 0.5% (w/v) polyethylene glycol 6000, at 30°C
0.0322 - 0.175
3-isobutyl-1-methyl-xanthine
0.00737 - 0.698
3-isobutyl-1-methylxanthine
0.0059
3-isobuytl-1-methylxanthine
Homo sapiens;
-
-
0.0066 - 0.0073
4-[(2-chloro-4-nitrophenyl)thio]-pyridine
0.00057 - 0.0057
4-[8-(3-nitrophenyl)-[1,7]naphthyridin-6-yl]benzoic acid
0.0041
apigenin
Homo sapiens;
-
-
0.0102
apigenin-7-O-glucoside
Homo sapiens;
-
-
0.00002 - 0.000074
apremilast
0.0004 - 0.0097
AWD 12-250
0.000015 - 0.0205
AWD12-281
0.0002
BRL-50481
Homo sapiens;
-
pH and temperature not specified in the publication
2.401 - 2.91
cAMP-N1-oxide
0.000101
cilomilast
Homo sapiens;
P27815
-
0.099
Cilostamide
Homo sapiens;
-
IC50: 0.099 mM, PDE4
0.0000003
cis-(+)-4-(3,4-dimethoxyphenyl)-2-[4-(morpholinomethyl)benzyl]-4a,5,8,8a-tetrahydrophthalazin-1(2H)-one
Homo sapiens;
-
in Tris-HCl (pH 7.6), 100 mM NaCl, 150 mM MgCl2, and 0.5% (w/v) polyethylene glycol 6000, at 30°C
0.0000088
cis-(-)-4-(3,4-dimethoxyphenyl)-2-[4-(morpholinomethyl)benzyl]-4a,5,8,8a-tetrahydrophthalazin-1(2H)-one
Homo sapiens;
-
in Tris-HCl (pH 7.6), 100 mM NaCl, 150 mM MgCl2, and 0.5% (w/v) polyethylene glycol 6000, at 30°C
0.0000004
cis-2-[(E)-4-(1H-imidazol-1-yl)but-2-enyl]-4-(3,4-dimethoxyphenyl)-4a,5,8,8a-tetrahydrophthalazin-1(2H)-one
Homo sapiens;
-
in Tris-HCl (pH 7.6), 100 mM NaCl, 150 mM MgCl2, and 0.5% (w/v) polyethylene glycol 6000, at 30°C
0.0000052
cis-2-[2-[2-(1H-imidazol-1-yl)ethoxy]ethyl]-4-(3,4-dimethoxyphenyl)-4a,5,8,8a-tetrahydrophthalazin-1(2H)-one
Homo sapiens;
-
in Tris-HCl (pH 7.6), 100 mM NaCl, 150 mM MgCl2, and 0.5% (w/v) polyethylene glycol 6000, at 30°C
0.0000013
cis-2-[4-(1,4-dioxa-8-azaspiro[4.5]decan-8-ylmethyl)-benzyl]-4-(3,4-dimethoxyphenyl)-4a,5,8,8a-tetrahydrophthalazin-1(2H)-one
Homo sapiens;
-
in Tris-HCl (pH 7.6), 100 mM NaCl, 150 mM MgCl2, and 0.5% (w/v) polyethylene glycol 6000, at 30°C
0.0000007
cis-2-[4-[(1H-imidazol-1-yl)methyl]benzyl]-4-(3,4-dimethoxyphenyl)-4a,5,8,8a-tetrahydrophthalazin-1(2H)-one
Homo sapiens;
-
in Tris-HCl (pH 7.6), 100 mM NaCl, 150 mM MgCl2, and 0.5% (w/v) polyethylene glycol 6000, at 30°C
0.0000013
cis-4-(3,4-dimethoxyphenyl)-2-[2-(morpholinomethyl)benzyl]-4a,5,8,8a-tetrahydrophthalazin-1(2H)-one
Homo sapiens;
-
in Tris-HCl (pH 7.6), 100 mM NaCl, 150 mM MgCl2, and 0.5% (w/v) polyethylene glycol 6000, at 30°C
0.0000014
cis-4-(3,4-dimethoxyphenyl)-2-[3-(morpholinomethyl)benzyl]-4a,5,8,8a-tetrahydrophthalazin-1(2H)-one
Homo sapiens;
-
in Tris-HCl (pH 7.6), 100 mM NaCl, 150 mM MgCl2, and 0.5% (w/v) polyethylene glycol 6000, at 30°C
0.000001
cis-4-(3,4-dimethoxyphenyl)-2-[4-(morpholinomethyl)benzyl]-4a,5,6,7,8,8a-hexahydrophthalazin-1(2H)-one
Homo sapiens;
-
in Tris-HCl (pH 7.6), 100 mM NaCl, 150 mM MgCl2, and 0.5% (w/v) polyethylene glycol 6000, at 30°C
0.0000009
cis-4-(3,4-dimethoxyphenyl)-2-[4-(morpholinomethyl)benzyl]-4a,5,8,8a-tetrahydrophthalazin-1(2H)-one
Homo sapiens;
-
in Tris-HCl (pH 7.6), 100 mM NaCl, 150 mM MgCl2, and 0.5% (w/v) polyethylene glycol 6000, at 30°C
0.0000082
cis-4-(3,4-dimethoxyphenyl)-2-[4-(piperidin-1-ylmethyl)benzyl]-4a,5,8,8a-tetrahydrophthalazin-1(2H)-one
Homo sapiens;
-
in Tris-HCl (pH 7.6), 100 mM NaCl, 150 mM MgCl2, and 0.5% (w/v) polyethylene glycol 6000, at 30°C
0.000002
cis-4-(3,4-dimethoxyphenyl)-2-[4-[(4-methylpiperazin-1-yl)methyl]benzyl]-4a,5,8,8a-tetrahydrophthalazin-1(2H)-one
Homo sapiens;
-
in Tris-HCl (pH 7.6), 100 mM NaCl, 150 mM MgCl2, and 0.5% (w/v) polyethylene glycol 6000, at 30°C
0.0000009
cis-4-(3,4-dimethoxyphenyl)-2-[4-[(4-oxopiperidin-1-yl)-methyl]benzyl]-4a,5,8,8a-tetrahydrophthalazin-1(2H)-one
Homo sapiens;
-
in Tris-HCl (pH 7.6), 100 mM NaCl, 150 mM MgCl2, and 0.5% (w/v) polyethylene glycol 6000, at 30°C
0.0000097
cis-4-(3,4-dimethoxyphenyl)-2-[4-[(dimethylamino)-methyl]benzyl]-4a,5,8,8a-tetrahydrophthalazin-1(2H)-one
Homo sapiens;
-
in Tris-HCl (pH 7.6), 100 mM NaCl, 150 mM MgCl2, and 0.5% (w/v) polyethylene glycol 6000, at 30°C
0.0000459
cis-5-(3,4-dimethoxyphenyl)-3-[4-(morpholinomethyl)benzyl]-3,4-diazabicyclo[4.1.0]hept-4-en-2-one
Homo sapiens;
-
in Tris-HCl (pH 7.6), 100 mM NaCl, 150 mM MgCl2, and 0.5% (w/v) polyethylene glycol 6000, at 30°C
0.0000164
cis-5-(3,4-dimethoxyphenyl)-3-[4-(morpholinomethyl)benzyl]-3,4-diazabicyclo[4.2.0]oct-4-en-2-one hydrochloride
Homo sapiens;
-
in Tris-HCl (pH 7.6), 100 mM NaCl, 150 mM MgCl2, and 0.5% (w/v) polyethylene glycol 6000, at 30°C
0.00008 - 0.0048
D-22888
0.0005
denbufylline
Homo sapiens;
-
-
0.0011 - 0.00194
dipyridamole
0.009
dipyridimole
Homo sapiens;
-
-
0.015
E4021
Homo sapiens;
-
-
0.000082
ethyl 2-([4-(3-carbamoylpiperazin-1-yl)-6-[4-(dimethylamino)piperidin-1-yl]pyrimidin-2-yl]amino)-4-methyl-1,3-thiazole-5-carboxylate
Homo sapiens;
-
temperature not specified in the publication, in 20 mM Tris-HCl, pH 7.4
0.000031
ethyl 2-([4-[(3,4-dimethoxybenzyl)amino]-6-(piperazin-1-yl)pyrimidin-2-yl]amino)-4-methyl-1,3-thiazole-5-carboxylate
Homo sapiens;
-
temperature not specified in the publication, in 20 mM Tris-HCl, pH 7.4
0.000076
ethyl 2-([4-[4-(dimethylamino)piperidin-1-yl]-6-(4-hydroxypiperidin-1-yl)pyrimidin-2-yl]amino)-4-methyl-1,3-thiazole-5-carboxylate
Homo sapiens;
-
temperature not specified in the publication, in 20 mM Tris-HCl, pH 7.4
0.000083
ethyl 2-([4-[4-(dimethylamino)piperidin-1-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-yl]amino)-4-methyl-1,3-thiazole-5-carboxylate
Homo sapiens;
-
temperature not specified in the publication, in 20 mM Tris-HCl, pH 7.4
0.00013
ethyl 2-([4-[4-(dimethylamino)piperidin-1-yl]-6-(morpholin-4-yl)pyrimidin-2-yl]amino)-4-methyl-1,3-thiazole-5-carboxylate
Homo sapiens;
-
temperature not specified in the publication, in 20 mM Tris-HCl, pH 7.4
0.00012
ethyl 2-([4-[4-(dimethylamino)piperidin-1-yl]-6-[3-(hydroxymethyl)piperidin-1-yl]pyrimidin-2-yl]amino)-4-methyl-1,3-thiazole-5-carboxylate
Homo sapiens;
-
temperature not specified in the publication, in 20 mM Tris-HCl, pH 7.4
0.00001
ethyl 2-([7-ethyl-6-[(4-sulfamoylbenzyl)amino]-7H-purin-2-yl]amino)-4-methyl-1,3-thiazole-5-carboxylate
Homo sapiens;
-
temperature not specified in the publication, in 20 mM Tris-HCl, pH 7.4
0.000063
ethyl 2-[[4,6-bis(4-hydroxypiperidin-1-yl)pyrimidin-2-yl]amino]-4-methyl-1,3-thiazole-5-carboxylate
Homo sapiens;
-
temperature not specified in the publication, in 20 mM Tris-HCl, pH 7.4
0.000056
ethyl 2-[[4-[4-[2-(dimethylamino)ethyl]piperazin-1-yl]-6-(4-methylpiperazin-1-yl)pyrimidin-2-yl]amino]-4-methyl-1,3-thiazole-5-carboxylate
Homo sapiens;
-
temperature not specified in the publication, in 20 mM Tris-HCl, pH 7.4
0.00027 - 0.00031
ethyl 3,5-dimethyl-1-phenyl-1H-pyrazole-4-carboxylate
0.017 - 0.019
ethyl 3,5-dimethyl-1-quinolin-8-yl-1H-pyrazole-4-carboxylate
0.015 - 0.019
ethyl 3,5-dimethyl-1H-pyrazole-4-carboxylate
0.00088 - 0.0015
ethyl 3-(4-chlorophenyl)-1-phenyl-1H-pyrazole-4-carboxylate
0.06 - 0.082
ethyl 3-methyl-5-(4-methylphenyl)-1H-pyrazole-4-carboxylate
0.000039
ethyl 4-methyl-2-([4-(4-methylpiperazin-1-yl)-6-[methyl(3,4,5-trimethoxybenzyl)amino]pyrimidin-2-yl]amino)-1,3-thiazole-5-carboxylate
Homo sapiens;
-
temperature not specified in the publication, in 20 mM Tris-HCl, pH 7.4
0.0001
ethyl 4-methyl-2-([4-(methylamino)-6-[(4-sulfamoylbenzyl)amino]pyrimidin-2-yl]amino)-1,3-thiazole-5-carboxylate
Homo sapiens;
-
temperature not specified in the publication, in 20 mM Tris-HCl, pH 7.4
0.00001
ethyl 4-methyl-2-([4-(piperazin-1-yl)-6-[(4-sulfamoylbenzyl)amino]pyrimidin-2-yl]amino)-1,3-thiazole-5-carboxylate
Homo sapiens;
-
temperature not specified in the publication, in 20 mM Tris-HCl, pH 7.4
0.00022
ethyl 4-methyl-2-([4-[(4-sulfamoylbenzyl)amino]pyrimidin-2-yl]amino)-1,3-thiazole-5-carboxylate
Homo sapiens;
-
temperature not specified in the publication, in 20 mM Tris-HCl, pH 7.4
0.00001
ethyl 4-methyl-2-([4-[methyl(3,4,5-trimethoxybenzyl)amino]-6-(piperazin-1-yl)pyrimidin-2-yl]amino)-1,3-thiazole-5-carboxylate
Homo sapiens;
-
temperature not specified in the publication, in 20 mM Tris-HCl, pH 7.4
0.000006
ethyl 4-methyl-2-[[4-(piperazin-1-yl)-7-(3,4,5-trimethoxybenzyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]-1,3-thiazole-5-carboxylate
Homo sapiens;
-
temperature not specified in the publication, in 20 mM Tris-HCl, pH 7.4
0.025 - 0.05
ethyl 5-amino-1-(4a,5,6,7,8,9a-hexahydro[1]benzothieno[2,3-d]pyrimidin-4-yl)-1H-pyrazole-4-carboxylate
0.0118
hyperoside
Homo sapiens;
-
-
0.000085
IR-202
Homo sapiens;
-
pH and temperature not specified in the publication
0.00421 - 0.00728
LAS-31025
0.0013
luteolin
Homo sapiens;
-
-
0.0149
luteolin-7-O-glucoside
Homo sapiens;
-
-
0.0033 - 0.00635
Milrinone
0.0000143
N-[3-(1H-imidazol-1-yl)propyl]-2-[cis-4-(3,4-dimethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydrophthalazin-2(1H)-yl]acetamide
Homo sapiens;
-
in Tris-HCl (pH 7.6), 100 mM NaCl, 150 mM MgCl2, and 0.5% (w/v) polyethylene glycol 6000, at 30°C
0.561 - 1.13
N6-monobutyyl-cAMP
0.0149
patuletin-7-O-glucoside
Homo sapiens;
-
-
0.34
quinazolinamine
Homo sapiens;
-
IC50: 0.34 mM, PDE4
0.000042 - 0.0022
Ro20-1724
0.00001 - 0.18
rolipram
0.0000016
RP-73401
Homo sapiens;
-
IC50: 0.0000016 mM, PDE4
0.000001 - 0.0178
RPR-73401
0.000113
SB 207499
Homo sapiens;
-
-
0.000105
SCH 351591
Homo sapiens;
-
-
0.0015
SCH51866
Homo sapiens;
-
PDE7B expressed in transfected COS-7 cells
0.00319 - 0.0861
sildenafil
0.01
tadalafil
Homo sapiens;
-
IC50: above 10000 nM, PDE4
0.002055 - 0.0046
vardenafil
0.059
vinpocetine
Homo sapiens;
-
-
0.0525
zaprinast
Homo sapiens;
-
mutant enzyme D440N
0.01
additional information
Homo sapiens;
-
IC 50 for sildenafil and tadalafil is above 10000 nM, PDE7
-
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
parietal, frontal, temporal cortex, hippocampus, striatum, thalamus, hypothalamus, substantia nigra, nucleus accumbens, cerebellum
Manually annotated by BRENDA team
-
lung epithelial cell
Manually annotated by BRENDA team
-
carcinoma of salivary gland
Manually annotated by BRENDA team
-
phosphodiesterase 4 is detected in smooth muscle cells of the wall, and in the cytoplasm of luminal endothelial cells of cavernous arteries
Manually annotated by BRENDA team
-
PDE4 is observed in the nonvascular smooth musculature of the corpus cavernosum clitoris, sinusoidal endothelial and subendothelial layers, and nerve fibers innervating the tissue; presence of isoform PDE4 in nonvascular smooth musculature of the corpus carnosum, in sinusoidal endothelial and subendothelial layers, and nerve fiber innervating the tissue
Manually annotated by BRENDA team
-
presence of isoform PDE4 in nonvascular smooth musculature of the corpus carnosum
Manually annotated by BRENDA team
-
sinusoidal endothelial and subendothelialn layer of clitoris, presence of isoform PDE4
Manually annotated by BRENDA team
-
human middle ear epithelial cell
Manually annotated by BRENDA team
-
PDE4
Manually annotated by BRENDA team
-
gingiva-derived malignant melanoma cell, expression of variants PDE4B and PDE4D
Manually annotated by BRENDA team
-
monocytic cells may express different PDE4 isozymes, depending on their state of activation or differentiation. These isozymes could thus regulate intracellular cAMP levels at various stages of monocyte activation and could thereby be important in limiting the inflammatory response
Manually annotated by BRENDA team
-
human bronchial epithelial cell
Manually annotated by BRENDA team
-
cultured, PDE7
Manually annotated by BRENDA team
-
abundantly present in the fibromusclular stroma as well as in glandular structures of the transition zone
Manually annotated by BRENDA team
-
carcinoma of salivary gland
Manually annotated by BRENDA team
-
PDE4; PDE7
Manually annotated by BRENDA team
-
of central cavernous arteries
Manually annotated by BRENDA team
-
PDE4
Manually annotated by BRENDA team
-
PDE7
Manually annotated by BRENDA team
additional information
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
-
of luminal endothelial cells of cavernous arteries
Manually annotated by BRENDA team
small part of enzyme is associated with the plasma membrane
Manually annotated by BRENDA team
PDB
SCOP
CATH
UNIPROT
ORGANISM
Homo sapiens;
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
38800
-
x * 39000, SDS-PAGE, x * 38800, deduced from gene sequence, both N-terminally truncated enzyme
39000
-
x * 39000, SDS-PAGE, x * 38800, deduced from gene sequence, both N-terminally truncated enzyme
58000
x * 58000, SDS-PAGE of isoform PDE4B5
125000
x * 125000, SDS-PAGE, recombinant protein
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
phosphoprotein
Crystallization/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
catalytic domain of inactive mutant D201N in complex with substrate cAMP at 1.56 A resolution. Q369 forms only one hydrogen bond ith the adenine of cAMP. Structural comparison between isoform PDE4D2-cAMP and PDE10A2-cAMP shows an anti configuration of cAMP in PDE4, but syn in PDE10
-
hanging drop method, PDE4D2 in complex with the nonselective inhibitor 3-isobutyl-1-methylxanthine
-
hanging-drop vapor-diffusion method, crystal structures of the catalytic domain of phosphodiesterase 4B complexed with AMP (2.0 A), 8-Br-AMP (2.13 A), and rolipram (2.0 A)
-
in complex with inhibitor 4-[8-(3-nitrophenyl)-[1,7]naphthyridin-6-yl]benzoic acid, comparison with isoforms PDE4A, PDE4B, PDE4C. Inhibitor binds in the same conformation to the deep cAMP substrate pocket and interacts with the same residues in each instance. Detailed structural comparison
in complex with inhibitor 4-[8-(3-nitrophenyl)-[1,7]naphthyridin-6-yl]benzoic acid, comparison with isoforms PDE4A, PDE4C, PDE4D. Inhibitor binds in the same conformation to the deep cAMP substrate pocket and interacts with the same resiudues in each instance. Detailed structural comparison; unliganded, detailed structural comparison with isoforms PDE4A, PDE4B, PDE4C
in complex with inhibitor 4-[8-(3-nitrophenyl)-[1,7]naphthyridin-6-yl]benzoic acid, comparison with isoforms PDE4B, PDE4C, PDE4D. Inhibitor binds in the same conformation to the deep cAMP substrate pocket and interacts with the same residues in each instance. Detailed structural comparison
molecular dynamics simulations. The second bridging ligand in the active site is HO- rather than H2O, serving as a nucleophile to initialize the catalytic hydrolysis of cAMP
-
NMR and CD analysis of the N-terminal 38mer peptide of isoform PDE4D5 which contains the entire signaling scaffold protein RACK1 interaction domain together with a portion of the beta-arrestin binding site. The peptiode has a distinct amphipathic helical structure. Study on binding to RACK1 and to beta-arrestin
-
unliganded PDE8A1 and in complex with 3-isobuytl-1-methylxanthine, hanging drop vapour diffusion method, using 100 mM sodium cacodylate (pH 6.5), 15% 2-propanol, 30% ethylene glycol, and 8-10% PEG3350 at 4°C
-
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
55
-
soluble HSPDE4A10 is more thermostable (T0.5: 11 min) than the particulate enzyme (T0.5: 5 min)
Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
ammonium sulfate fractionation and amylose-resin column chromatography
-
from inclusion bodies
-
gel filtration
-
Ni-NTA column chromatography
-
Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
cloned and expressed in Sf9 cells with recombinant baculovirus infection
-
Epac1-camps-PDE4A1 fusion protein is expressed in HEK-293 cells
-
expressed in COS1 cells
-
expressed in Escherichia coli strain BL21
-
expressed in transfected COS7 cells. The human PDE4A species, h6.1 (HSPDE4A4C), which lacks the N-terminal extension of PDE-46, is an entirely soluble species when expressed in COS7 cells
-
expression in baculovirus transfected Sf9 cells
-
expression in COS-7 cell; When expressed in COS-7 cells, PDE4A8 localizes predominantly in the cytosol, but 20% of the enzyme was associated with membrane fractions
expression in Escherichia coli as N-terminal glutathione S-transferase-fusion protein
-
expression in Sf9 insect cells
expression in Spodoptera frugiperda
-
expression of the catalytic domain in Escherichia coli
-
recombinant PDE7B expressed in transfected COS-7 cells
-
the catalytic domain of human PDE4D is cloned from HL-60 cells and expressed in Escherichia coli JM109 cells
-
transient expression of the engineered human PDE4A10 open reading frame in COS7 cells allows detection of a 121000 Da protein in both soluble and particulate fractions. PDE4A10 is localized primarily to the perinuclear region of COS7 cells
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
2fold increased PDE7B mRNA expression in chronic lymphocytic leukemia correlates with a 10fold higher expression of PDE7B protein and results in an increased contribution of PDE7 to total PDE activity
-
ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
A590C
-
mutation has no significant influence on substrate affinity or specificity
D440A
-
unlike wild type enzyme, the mutant enzyme shows activity with cGMP
D440N
-
unlike wild type enzyme, the mutant enzyme shows activity with cGMP
F484Y
-
mutation has no significant influence on substrate affinity or specificity
H305P
the mutation is associated with micronodular adrenocortical disease
L391A
-
mutation has no significant influence on substrate affinity or specificity
P595I
-
mutation leads to 7fold decrease of substrate affinity and an 14fold decrease of the affinity towards the PDE4-specific inhibitor rolipram
T748F
-
the mutation increases the PDE8A1 sensitivity to several nonselective or family selective PDE inhibitors, the catalytic efficiency of the mutant is about 2fold better than that of the wild type PDE8A1
V501A
-
mutation has no significant influence on substrate affinity or specificity
W375Q
-
mutation abolishes catalytic activity
W605I
-
mutation abolishes catalytic activity
W605V
-
mutation abolishes catalytic activity
W605Y
-
mutation abolishes catalytic activity
Renatured/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
refolding is initiated by addition of 0.03 mg/ml protein to a buffer of 0.5 M Tris-HCl pH 7.0, 20 mM MgCl2, 20 mM MnCl2, 0.020 mM ZnSO4, 0.7 M arginine, 30% glycerol, 10 mM NaCl, 1 mM KCl, and 10 mM dithiothreitol, at 4°C for three days
-
refolding to active enzyme from inclusion bodies requires high concentrations of arginine hydrochloride, ethylene glycol, and magnesium chloride at pH 8.5
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
medicine
molecular biology
-
development of cell-permeable peptide reagents based upon the N-terminal region of PDE4D5 that allow for the selective disruption of PDE4D5 targeting to specific signalling scaffolds, namely beta-arrestin and RACK1