Information on EC 1.14.14.14 - aromatase

Steroid hormone biosynthesis

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Cyp19A3

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cytochrome P450 aromatase

P450arom

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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]

(2b)

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19-hydroxytestosterone + O2 + [reduced NADPH-hemoprotein reductase] = 19-oxotestosterone + 2 H2O + [oxidized NADPH-hemoprotein reductase]

(1b)

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19-oxoandrost-4-ene-3,17-dione + O2 + [reduced NADPH-hemoprotein reductase] = estrone + formate + H2O + [oxidized NADPH-hemoprotein reductase]

catalytic reaction mechanism, detailed overview

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19-oxotestosterone + O2 + [reduced NADPH-hemoprotein reductase] = 17beta-estradiol + formate + H2O + [oxidized NADPH-hemoprotein reductase]

(1c)

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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]

(2)

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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]

(2a)

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testosterone + 3 O2 + 3 [reduced NADPH-hemoprotein reductase] = 17beta-estradiol + formate + 4 H2O + 3 [oxidized NADPH-hemoprotein reductase]

(1)

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testosterone + O2 + [reduced NADPH-hemoprotein reductase] = 19-hydroxytestosterone + H2O + [oxidized NADPH-hemoprotein reductase]

(1a)

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KEGG

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.

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

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overall reaction

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?

19-hydroxyandrost-4-ene-3,17-dione + O2 + a reduced flavoprotein

19-oxo-androst-4-ene-3,17-dione + 2 H2O + an oxidized flavoprotein

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725327

-

?

19-oxoandrost-4-ene-3,17-dione + O2 + a reduced flavoprotein

estrone + formate + H2O + an oxidized flavoprotein

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725327

-

?

7-methoxy-4-trifluoromethyl coumarin + H2O + oxidized flavoprotein

? + O2 + reduced flavoprotein

-

-

?

androst-4-ene-3,17-dione + 3 O2 + 3 reduced flavoproteins

estrone + formate + 4 H2O + 3 oxidized flavoproteins

5 entries

androst-4-ene-3,17-dione + O2 + a reduced flavoprotein

19-hydroxyandrost-4-ene-3,17-dione + H2O + an oxidized flavoprotein

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725327

-

?

testosterone + 3 O2 + 3 reduced flavoproteins

17beta-estradiol + formate + 4 H2O + 3 oxidized flavoproteins

additional information

?

-

androst-4-ene-3,17-dione + 3 O2 + 3 reduced flavoproteins

estrone + formate + 4 H2O + 3 oxidized flavoproteins

-

overall reaction

724244, 725329

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?

testosterone + 3 O2 + 3 reduced flavoproteins

17beta-estradiol + formate + 4 H2O + 3 oxidized flavoproteins

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overall reaction

724244, 725329

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?

cytochrome P450

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1,4,6-androstatriene-3,17-dione

Tautogolabrus adspersus

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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

744150

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

725325

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

724244

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

725325

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

724244

diethylaminoethyl-2,2-diphenylvalerate

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0.05 mM, 64% residual activity

725325

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

745644

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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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

0.00038 - 0.00045

19-hydroxyandrost-4-ene-3,17-dione

0.0015 - 0.003

19-oxoandrost-4-ene-3,17-dione

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

-

pH not specified in the publication, temperature not specified in the publication

0.00305

2-(pyridin-3-yl)-1H-indole

Homo sapiens

-

pH not specified in the publication, temperature not specified in the publication

0.00161

2-phenyl-1H-indole-3-carbonitrile

Homo sapiens

-

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

57

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pH 7.2, 37°C

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

Carinascincus metallicus

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brain aromatase

UniProt

Homo sapiens ATCC HTB-144

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Mizuhopecten yessoensis

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724783

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Mus musculus

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743988, 743990, 744615

P28649

UniProt

Paralichthys dentatus

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UniProt

-

-

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UniProt

Tautogolabrus adspersus

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744150

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adrenal gland

Carinascincus metallicus

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maternal ovaries and adrenals maintain high aromatase activity throughout gestation

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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

726047

embryo

Carinascincus metallicus

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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

-

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in the female, activity is detecable throughout the year

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

745022

muscle

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

-

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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

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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

726047

additional information

-

724158, 724244, 725325, 725329, 725832

metabolism

Mus musculus

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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

743988

physiological function

4 entries

11 entries

55000

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x * 55000, SDS-PAGE

?

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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

725832

phosphoprotein

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treatment with alkaline phosphatase results in loss of activity

724158

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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745615

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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745643

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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726036

molecular modeling of structure

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

745768

-

-

725832, 726036

from microsome. Full enzymatic activity can be reconstituted with rabbit liver microsomal cytochrome P-450 reductase and Nonidet P-40

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expression in Escherichia coli

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

Paralichthys dentatus

A0A0H4KB14

744946

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

745022

hypothalamic aromatase levels increase two times during annual gonadal cycle, once in a fully gravid fish and then in a reproductively quiescent fish