Information on EC 1.14.14.14 - aromatase

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The enzyme appears in viruses and cellular organisms

EC NUMBER
COMMENTARY hide
1.14.14.14
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RECOMMENDED NAME
GeneOntology No.
aromatase
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REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
19-hydroxyandrost-4-ene-3,17-dione + O2 + [reduced NADPH-hemoprotein reductase] = 19-oxo-androst-4-ene-3,17-dione + 2 H2O + [oxidized NADPH-hemoprotein reductase]
show the reaction diagram
(2b)
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-
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19-hydroxytestosterone + O2 + [reduced NADPH-hemoprotein reductase] = 19-oxotestosterone + 2 H2O + [oxidized NADPH-hemoprotein reductase]
show the reaction diagram
(1b)
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-
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19-oxoandrost-4-ene-3,17-dione + O2 + [reduced NADPH-hemoprotein reductase] = estrone + formate + H2O + [oxidized NADPH-hemoprotein reductase]
show the reaction diagram
catalytic reaction mechanism, detailed overview
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-
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19-oxotestosterone + O2 + [reduced NADPH-hemoprotein reductase] = 17beta-estradiol + formate + H2O + [oxidized NADPH-hemoprotein reductase]
show the reaction diagram
(1c)
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-
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androst-4-ene-3,17-dione + 3 O2 + 3 [reduced NADPH-hemoprotein reductase] = estrone + formate + 4 H2O + 3 [oxidized NADPH-hemoprotein reductase]
show the reaction diagram
(2)
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-
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androst-4-ene-3,17-dione + O2 + [reduced NADPH-hemoprotein reductase] = 19-hydroxyandrost-4-ene-3,17-dione + H2O + [oxidized NADPH-hemoprotein reductase]
show the reaction diagram
(2a)
-
-
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testosterone + 3 O2 + 3 [reduced NADPH-hemoprotein reductase] = 17beta-estradiol + formate + 4 H2O + 3 [oxidized NADPH-hemoprotein reductase]
show the reaction diagram
(1)
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-
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testosterone + O2 + [reduced NADPH-hemoprotein reductase] = 19-hydroxytestosterone + H2O + [oxidized NADPH-hemoprotein reductase]
show the reaction diagram
(1a)
-
-
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PATHWAY
BRENDA Link
KEGG Link
MetaCyc Link
Steroid hormone biosynthesis
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Metabolic pathways
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SYSTEMATIC NAME
IUBMB Comments
testosterone monooxygenase (17beta-estradiol-forming)
A cytochrome P-450. The enzyme catalyses three sequential hydroxylations of the androgens androst-4-ene-3,17-dione and testosterone, resulting in their aromatization and forming the estrogens estrone and 17beta-estradiol, respectively. The direct electron donor to the enzyme is EC 1.6.2.4, NADPH---hemoprotein reductase.
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
brain aromatase
UniProt
Manually annotated by BRENDA team
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-
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Manually annotated by BRENDA team
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UniProt
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
metabolism
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in a male mouse model overexpressing the aromatase enzyme, adipose tissue estradiol levels are increased while circulating sex steroid levels are unaffected. The overexpressing male mice are more insulin sensitive compared with wild-type mice and exhibit increased serum adiponectin levels and upregulated expression of Glut4 and Irs1 in white adipose tissue. The expression of markers of macrophages and immune cell infiltration is markedly decreased in their white adipose tissue
physiological function
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
16alpha-hydroxytestosterone + 3 O2 + 3 reduced flavoprotein
(16alpha,17beta)-estra-1(10),2,4-triene-3,16,17-triol + formate + 4 H2O + 3 oxidized flavoprotein
show the reaction diagram
-
overall reaction
-
-
?
19-hydroxyandrost-4-ene-3,17-dione + O2 + a reduced flavoprotein
19-oxo-androst-4-ene-3,17-dione + 2 H2O + an oxidized flavoprotein
show the reaction diagram
-
-
-
-
?
19-oxoandrost-4-ene-3,17-dione + O2 + a reduced flavoprotein
estrone + formate + H2O + an oxidized flavoprotein
show the reaction diagram
-
-
-
-
?
7-methoxy-4-trifluoromethyl coumarin + H2O + oxidized flavoprotein
? + O2 + reduced flavoprotein
show the reaction diagram
-
-
-
-
?
androst-4-ene-3,17-dione + 3 O2 + 3 reduced flavoproteins
estrone + formate + 4 H2O + 3 oxidized flavoproteins
show the reaction diagram
androst-4-ene-3,17-dione + O2 + a reduced flavoprotein
19-hydroxyandrost-4-ene-3,17-dione + H2O + an oxidized flavoprotein
show the reaction diagram
-
-
-
-
?
testosterone + 3 O2 + 3 reduced flavoproteins
17beta-estradiol + formate + 4 H2O + 3 oxidized flavoproteins
show the reaction diagram
additional information
?
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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
androst-4-ene-3,17-dione + 3 O2 + 3 reduced flavoproteins
estrone + formate + 4 H2O + 3 oxidized flavoproteins
show the reaction diagram
-
overall reaction
-
-
?
testosterone + 3 O2 + 3 reduced flavoproteins
17beta-estradiol + formate + 4 H2O + 3 oxidized flavoproteins
show the reaction diagram
-
overall reaction
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
cytochrome P450
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INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
1,4,6-androstatriene-3,17-dione
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treatment with the aromatase inhibitor ATD results in significantly decreased aromatase activity in male and female brain,but has no significant impact on ovarian aromatase activity
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1-(3-bromo-4-methoxybenzene-1-sulfonyl)-3-[(1H-imidazol-1-yl)methyl]piperidine
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1-[3-(2-chloro-6-nitrophenyl)benzene-1-sulfonyl]-3-[(1H-imidazol-1-yl)methyl]piperidine
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19-hydroxyandrost-4-ene-3,17-dione
19-nortestosterone
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competitive inhibitor of both aromatization and cytochrome P450 binding of androst-4-ene-3,17-dione
19-oxoandrost-4-ene-3,17-dione
2-(pyridin-3-yl)-1H-indole
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2-phenyl-1H-indole-3-carbonitrile
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4-[3-[(1H-imidazol-1-yl)methyl]piperidine-1-sulfonyl]-2,1,3-benzothiadiazole
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5-nitro-2-phenyl-1H-indole
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compound is inhibitory toward aromatase and induces quinone reductase 1
7,8-Benzoflavone
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competitive inhibitor, induces spectral changes in the aromatase cytochrome P450
8-prenylnaringenin
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flavonoid isolated from hop, inhibits enzyme activity, no effect on enzyme expression
Aminoglutethimide
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0.005 mM, 54% residual activity
anastrozole
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azole inhibitor, binding is independent of pH
androst-4-ene-3,17-dione
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competitive inhibitor of both aromatization and cytochrome P450 binding of 19-nortestosterone
apigenin
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chrysin
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competitive inhibitor, induces spectral changes in the aromatase cytochrome P450
diethylaminoethyl-2,2-diphenylvalerate
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0.05 mM, 64% residual activity
exemestane
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steroidal inhibitor, binding is dependent of pH
flavanone
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flavone
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isoxanthohumol
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flavonoid isolated from hop, inhibits enzyme activity, no effect on enzyme expression
KCN
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5 mM, 80% residual activity
letrozole
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quercetin
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sildenafil
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partial and mixed inhibitor with a maximal inhibition of 35%, KD value 0.58 mM. Sildenafil binds to the heme iron via its 6th axial water ligand
SYN 20028567
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nonsteroidal lead compound for aromatase inhibition
xanthohumol
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flavonoid isolated from hop, inhibits enzyme activity, no effect on enzyme expression
additional information
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.058
16alpha-hydroxytestosterone
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pH 7.2, 37°C
0.00006
androst-4-ene-3,17-dione
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pH 7.2, 37°C
0.00021
testosterone
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pH 7.2, 37°C
additional information
androst-4-ene-3,17-dione
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the Km values increase 1.5fold from pH 6.5 to 7.4similar to the Kd values, temperature not specified in the publication
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.00038 - 0.00045
19-hydroxyandrost-4-ene-3,17-dione
0.0015 - 0.003
19-oxoandrost-4-ene-3,17-dione
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.000006
1-(3-bromo-4-methoxybenzene-1-sulfonyl)-3-[(1H-imidazol-1-yl)methyl]piperidine
Homo sapiens;
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pH not specified in the publication, temperature not specified in the publication
0.000009
1-[3-(2-chloro-6-nitrophenyl)benzene-1-sulfonyl]-3-[(1H-imidazol-1-yl)methyl]piperidine
Homo sapiens;
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pH not specified in the publication, temperature not specified in the publication
0.00305
2-(pyridin-3-yl)-1H-indole
Homo sapiens;
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pH not specified in the publication, temperature not specified in the publication
0.00161
2-phenyl-1H-indole-3-carbonitrile
Homo sapiens;
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pH not specified in the publication, temperature not specified in the publication
0.000007
4-[3-[(1H-imidazol-1-yl)methyl]piperidine-1-sulfonyl]-2,1,3-benzothiadiazole
Homo sapiens;
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pH not specified in the publication, temperature not specified in the publication
0.009
5-nitro-2-phenyl-1H-indole
Homo sapiens;
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pH not specified in the publication, temperature not specified in the publication
0.00006 - 0.00007
7,8-Benzoflavone
0.000065
8-prenylnaringenin
Homo sapiens;
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pH not specified in the publication, temperature not specified in the publication
0.001 - 0.0012
apigenin
0.0004 - 0.0005
chrysin
0.005 - 0.008
flavanone
0.005 - 0.008
flavone
0.081
isoxanthohumol
Homo sapiens;
-
pH not specified in the publication, temperature not specified in the publication
0.01 - 0.012
quercetin
0.000009
SYN 20028567
Homo sapiens;
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pH not specified in the publication, temperature not specified in the publication
0.0203
xanthohumol
Homo sapiens;
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pH not specified in the publication, temperature not specified in the publication
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
57
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pH 7.2, 37°C
pH RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
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androstenedione binding is pH-dependent. The apparent pKa for Asp309 is 8.2, and the residue is protonated at physiological pH. A D309N mutant binds androstenedione across the entire pH range studied
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
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maternal ovaries and adrenals maintain high aromatase activity throughout gestation
Manually annotated by BRENDA team
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cell line expresses aromatase mRNA and shows a cytoplasmic pattern of aromatase immunoreactivity. In addition, the cell line expresses estrogen receptor alpha
Manually annotated by BRENDA team
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aromatase activity in the developing brains and gonads of embryos is comparable with measurements in oviparous reptiles. Aromatase activity in the embryonic gonads is low at embryonic stage 29-34, but increases significantly at mid-development and then remains high in late stage embryos
Manually annotated by BRENDA team
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in the female, activity is detecable throughout the year
Manually annotated by BRENDA team
A0A068CIW9;, A0A068CLX6;
high transcript abundance in the female brain, followed by gonads, liver, gill, kidney and muscle; high transcript abundance in the ovary and female brain, followed by the testis and male brain, and female liver and muscle
Manually annotated by BRENDA team
A0A068CIW9;, A0A068CLX6;
high transcript abundance in the female brain, followed by gonads, liver, gill, kidney and muscle; high transcript abundance in the ovary and female brain, followed by the testis and male brain, and female liver and muscle
Manually annotated by BRENDA team
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cell line expresses aromatase mRNA and shows a cytoplasmic pattern of aromatase immunoreactivity. In addition, the cell line expresses estrogen receptor alpha
Manually annotated by BRENDA team
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cell line expresses aromatase mRNA and shows a cytoplasmic pattern of aromatase immunoreactivity. In addition, the cell line expresses estrogen receptor alpha
Manually annotated by BRENDA team
additional information
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
PDB
SCOP
CATH
UNIPROT
ORGANISM
Homo sapiens;
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
55000
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x * 55000, SDS-PAGE
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
?
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x * 55000, SDS-PAGE
homodimer
multimer
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enzyme is composed of cytochrome P450 and NADPH-cytochrome P450 reductase components
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
phosphoprotein
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treatment with alkaline phosphatase results in loss of activity
Crystallization/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
free energy simulations of the entry/exit routes preferentially followed by substrate androstenedione and inhibitor letrozole. Two channels appear accessible to their entrance, while only one exit route appears to be preferential, ligand channeling is associated with large enzyme structural rearrangements
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molecular docking studies with inhibitors based on PDB entry 3EQM. The 2-arylindoles prefer binding with the 2-aryl group toward a small hydrophobic pocket within the active site. The C-5 electron withdrawing group on indole may have an important role and form a hydrogen bond with Ser478 (OH). Meta-pyridyl analogs may orient with the pyridyl 3'-nitrogen coordinating with the heme group
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molecular dynamics simulations of the dimeric interfaces, i.e.residues 45-496
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to 1.8 A resolution, in complex with its natural substrate androst-4-ene-3,17-dione. Aromatase has an androgen-specific cleft that binds the androstenedione molecule snugly. Hydrophobic and polar residues complement the steroid backbone
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molecular modeling of structure
Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
from microsome. Full enzymatic activity can be reconstituted with rabbit liver microsomal cytochrome P-450 reductase and Nonidet P-40
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Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
expression in Escherichia coli
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
Cyp19a expression is significantly lower at 52 days post-hatch at the male-producing temperature (19°C) and increases to similar levels as treatments at 13°C or 16°C at 66 days post-hatch. Expression levels later in juvenile development (66–191 days post-hatch) largely decrease with fish size
gene is expressed highly in the resting phase and gives the highest transcript abundance in the preparatory phase. Human chorionic gonadotropin administration stimulates the expression; gene is expressed highly in the resting phase and gives the highest transcript abundance in the preparatory phase. Human chorionic gonadotropin administration stimulates the expression
A0A068CIW9;, A0A068CLX6;
hypothalamic aromatase levels increase two times during annual gonadal cycle, once in a fully gravid fish and then in a reproductively quiescent fish
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phosphodiesterase type-5 inhibitor tadalafil inhibits aromatase mRNA and protein expression leading to an increase in testosterone levels in the supernatants
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ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
D309N
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mutant retains its ability to bind to androstenedione across the entire pH range studied
R192H
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homozygous CYP19A1 mutation identified in two siblings of consanguineous parents. Mutation causes a severe phenotype of aromatase deficiency in a 46,XX newborn and maybe hypospadias and cryptorchidism in a 46,XY, but no maternal androgen excess during pregnancy
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
medicine
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