BRENDA - Enzyme Database show

Biochemical, functional and pharmacological characterization of AT-56, an orally active and selective inhibitor of lipocalin-type prostaglandin d synthase

Irikura, D.; Aritake, K.; Nagata, N.; Maruyama, T.; Shimamoto, S.; Urade, Y.; J. Biol. Chem. 284, 7623-7630 (2009)

Data extracted from this reference:

Application
EC Number
Application
Commentary
Organism
5.3.99.2
medicine
orally administered AT-56, i.e. 4-dibenzo [a,d]cyclohepten-5-ylidene-1-[4-(2H-tetrazol-5-yl)-butyl]-piperidine, below 30 mg/kg body weight decreases the prostaglandin D2 production to 40% in the brain of H-PGDS-deficient mice after a stab-wound injury in a dose-dependent manner without affecting the production of prostaglandin E2 and prostaglandin F2alpha, and also suppresses the accumulation of eosinophils and monocytes in the bronco-alveolar lavage fluid from the antigen-induced lung inflammation model of human L-PGDS-transgenic mice
Mus musculus
Engineering
EC Number
Amino acid exchange
Commentary
Organism
5.3.99.2
C89A/C186A
mutant retains wild-type like activity and is stable
Mus musculus
5.3.99.2
W54A
mutant retains wild-type like activity and is stable
Mus musculus
Inhibitors
EC Number
Inhibitors
Commentary
Organism
Structure
5.3.99.2
4-dibenzo [a,d]cyclohepten-5-ylidene-1-[4-(2H-tetrazol-5-yl)-butyl]-piperidine
i.e. AT-56, inhibits the activity of lipocalin-type prostaglandin-D synthase in a concentration-dependent manner, but does not affect the activities of hematopoietic prostaglandin-D synthase, cyclooxygenase-1 and -2, and microsomal PGE synthase-1. AT-56 inhibits the lipocalin-type prostaglandin-D synthase activity in a competitive manner against the substrate prostaglandin H2 but does not inhibit the binding of 13-cis-retinoic acid. AT-56 occupies the catalytic pocket, but not the retinoid-binding pocket, of lipocalin-type prostaglandin-D synthase
Homo sapiens
5.3.99.2
4-dibenzo [a,d]cyclohepten-5-ylidene-1-[4-(2H-tetrazol-5-yl)-butyl]-piperidine
i.e. AT-56. Orally administered AT-56 below 30 mg/kg body weight decreases the prostaglandin D2 production to 40% in the brain of H-PGDS-deficient mice after a stab-wound injury in a dose-dependent manner without affecting the production of prostaglandin E2 and prostaglandin F2alpha, and also suppresses the accumulation of eosinophils and monocytes in the bronco-alveolar lavage fluid from the antigen-induced lung inflammation model of human L-PGDS-transgenic mice
Mus musculus
KM Value [mM]
EC Number
KM Value [mM]
KM Value Maximum [mM]
Substrate
Commentary
Organism
Structure
5.3.99.2
0.014
-
(5Z,13E)-(15S)-9alpha,11alpha-epidioxy-15-hydroxyprosta-5,13-dienoate
pH 8.0
Homo sapiens
5.3.99.2
0.014
-
(5Z,13E)-(15S)-9alpha,11alpha-epidioxy-15-hydroxyprosta-5,13-dienoate
pH 8.0
Mus musculus
Organism
EC Number
Organism
Primary Accession No. (UniProt)
Commentary
Textmining
5.3.99.2
Homo sapiens
-
-
-
5.3.99.2
Mus musculus
O09114
-
-
Source Tissue
EC Number
Source Tissue
Commentary
Organism
Textmining
5.3.99.2
brain
-
Mus musculus
-
Substrates and Products (Substrate)
EC Number
Substrates
Commentary Substrates
Literature (Substrates)
Organism
Products
Commentary (Products)
Literature (Products)
Organism (Products)
Reversibility
5.3.99.2
(5Z,13E)-(15S)-9alpha,11alpha-epidioxy-15-hydroxyprosta-5,13-dienoate
-
693254
Homo sapiens
(5Z,13E)-(15S)-9alpha,15-dihydroxy-11-oxoprosta-5,13-dienoate
-
-
-
?
5.3.99.2
(5Z,13E)-(15S)-9alpha,11alpha-epidioxy-15-hydroxyprosta-5,13-dienoate
-
693254
Mus musculus
(5Z,13E)-(15S)-9alpha,15-dihydroxy-11-oxoprosta-5,13-dienoate
-
-
-
?
Ki Value [mM]
EC Number
Ki Value [mM]
Ki Value maximum [mM]
Inhibitor
Commentary
Organism
Structure
5.3.99.2
0.075
-
4-dibenzo [a,d]cyclohepten-5-ylidene-1-[4-(2H-tetrazol-5-yl)-butyl]-piperidine
pH 8.0
Homo sapiens
IC50 Value
EC Number
IC50 Value
IC50 Value Maximum
Commentary
Organism
Inhibitor
Structure
5.3.99.2
0.003
-
inhibition of enzyme in lipocalin-type prostaglandin-D synthase-expressing TE-671 cells after stimulation with Ca2+-ionophore A23187
Homo sapiens
4-dibenzo [a,d]cyclohepten-5-ylidene-1-[4-(2H-tetrazol-5-yl)-butyl]-piperidine
Application (protein specific)
EC Number
Application
Commentary
Organism
5.3.99.2
medicine
orally administered AT-56, i.e. 4-dibenzo [a,d]cyclohepten-5-ylidene-1-[4-(2H-tetrazol-5-yl)-butyl]-piperidine, below 30 mg/kg body weight decreases the prostaglandin D2 production to 40% in the brain of H-PGDS-deficient mice after a stab-wound injury in a dose-dependent manner without affecting the production of prostaglandin E2 and prostaglandin F2alpha, and also suppresses the accumulation of eosinophils and monocytes in the bronco-alveolar lavage fluid from the antigen-induced lung inflammation model of human L-PGDS-transgenic mice
Mus musculus
Engineering (protein specific)
EC Number
Amino acid exchange
Commentary
Organism
5.3.99.2
C89A/C186A
mutant retains wild-type like activity and is stable
Mus musculus
5.3.99.2
W54A
mutant retains wild-type like activity and is stable
Mus musculus
IC50 Value (protein specific)
EC Number
IC50 Value
IC50 Value Maximum
Commentary
Organism
Inhibitor
Structure
5.3.99.2
0.003
-
inhibition of enzyme in lipocalin-type prostaglandin-D synthase-expressing TE-671 cells after stimulation with Ca2+-ionophore A23187
Homo sapiens
4-dibenzo [a,d]cyclohepten-5-ylidene-1-[4-(2H-tetrazol-5-yl)-butyl]-piperidine
Inhibitors (protein specific)
EC Number
Inhibitors
Commentary
Organism
Structure
5.3.99.2
4-dibenzo [a,d]cyclohepten-5-ylidene-1-[4-(2H-tetrazol-5-yl)-butyl]-piperidine
i.e. AT-56, inhibits the activity of lipocalin-type prostaglandin-D synthase in a concentration-dependent manner, but does not affect the activities of hematopoietic prostaglandin-D synthase, cyclooxygenase-1 and -2, and microsomal PGE synthase-1. AT-56 inhibits the lipocalin-type prostaglandin-D synthase activity in a competitive manner against the substrate prostaglandin H2 but does not inhibit the binding of 13-cis-retinoic acid. AT-56 occupies the catalytic pocket, but not the retinoid-binding pocket, of lipocalin-type prostaglandin-D synthase
Homo sapiens
5.3.99.2
4-dibenzo [a,d]cyclohepten-5-ylidene-1-[4-(2H-tetrazol-5-yl)-butyl]-piperidine
i.e. AT-56. Orally administered AT-56 below 30 mg/kg body weight decreases the prostaglandin D2 production to 40% in the brain of H-PGDS-deficient mice after a stab-wound injury in a dose-dependent manner without affecting the production of prostaglandin E2 and prostaglandin F2alpha, and also suppresses the accumulation of eosinophils and monocytes in the bronco-alveolar lavage fluid from the antigen-induced lung inflammation model of human L-PGDS-transgenic mice
Mus musculus
Ki Value [mM] (protein specific)
EC Number
Ki Value [mM]
Ki Value maximum [mM]
Inhibitor
Commentary
Organism
Structure
5.3.99.2
0.075
-
4-dibenzo [a,d]cyclohepten-5-ylidene-1-[4-(2H-tetrazol-5-yl)-butyl]-piperidine
pH 8.0
Homo sapiens
KM Value [mM] (protein specific)
EC Number
KM Value [mM]
KM Value Maximum [mM]
Substrate
Commentary
Organism
Structure
5.3.99.2
0.014
-
(5Z,13E)-(15S)-9alpha,11alpha-epidioxy-15-hydroxyprosta-5,13-dienoate
pH 8.0
Homo sapiens
5.3.99.2
0.014
-
(5Z,13E)-(15S)-9alpha,11alpha-epidioxy-15-hydroxyprosta-5,13-dienoate
pH 8.0
Mus musculus
Source Tissue (protein specific)
EC Number
Source Tissue
Commentary
Organism
Textmining
5.3.99.2
brain
-
Mus musculus
-
Substrates and Products (Substrate) (protein specific)
EC Number
Substrates
Commentary Substrates
Literature (Substrates)
Organism
Products
Commentary (Products)
Literature (Products)
Organism (Products)
Reversibility
5.3.99.2
(5Z,13E)-(15S)-9alpha,11alpha-epidioxy-15-hydroxyprosta-5,13-dienoate
-
693254
Homo sapiens
(5Z,13E)-(15S)-9alpha,15-dihydroxy-11-oxoprosta-5,13-dienoate
-
-
-
?
5.3.99.2
(5Z,13E)-(15S)-9alpha,11alpha-epidioxy-15-hydroxyprosta-5,13-dienoate
-
693254
Mus musculus
(5Z,13E)-(15S)-9alpha,15-dihydroxy-11-oxoprosta-5,13-dienoate
-
-
-
?