P11511 (CP19A_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Cytochrome P450 19A1
EC=1.14.14.1

Alternative name(s):
Aromatase
CYPXIX
Cytochrome P-450AROM
Estrogen synthase

Gene names

Name:	CYP19A1
Synonyms:	ARO1, CYAR, CYP19

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	503 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Catalyzes the formation of aromatic C18 estrogens from C19 androgens.
Catalytic activity	RH + reduced flavoprotein + O2 = ROH + oxidized flavoprotein + H2O.
Cofactor	Heme group.
Subcellular location	Membrane; Peripheral membrane protein.
Tissue specificity	Brain, placenta and gonads. Ref.10 Ref.12 Ref.13 Ref.15
Involvement in disease	Aromatase excess syndrome (AEXS) [MIM:139300]: An autosomal dominant disorder characterized by increased extraglandular aromatization of steroids that presents with heterosexual precocity in males and isosexual precocity in females. Note: The disease is caused by mutations affecting the gene represented in this entry. Aromatase deficiency (AROD) [MIM:613546]: A rare disease in which fetal androgens are not converted into estrogens due to placental aromatase deficiency. Thus, pregnant women exhibit a hirsutism, which spontaneously resolves after post-partum. At birth, female babies present with pseudohermaphroditism due to virilization of extern genital organs. In adult females, manifestations include delay of puberty, breast hypoplasia and primary amenorrhoea with multicystic ovaries. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.17 Ref.18 Ref.19
Sequence similarities	Belongs to the cytochrome P450 family.

Ontologies

Keywords
Cellular component	Membrane
Coding sequence diversity	Polymorphism
Disease	Disease mutation Pseudohermaphroditism
Ligand	Heme Iron Metal-binding
Molecular function	Monooxygenase Oxidoreductase
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	androgen metabolic process Inferred from electronic annotation. Source: Compara estrogen biosynthetic process Traceable author statement. Source: Reactome prostate gland growth Inferred from electronic annotation. Source: Compara small molecule metabolic process Traceable author statement. Source: Reactome xenobiotic metabolic process Traceable author statement. Source: Reactome
Cellular_component	endoplasmic reticulum membrane Traceable author statement. Source: Reactome
Molecular_function	aromatase activity Inferred from direct assay Ref.16. Source: UniProtKB electron carrier activity Traceable author statement Ref.3. Source: UniProtKB heme binding Inferred from direct assay Ref.16. Source: UniProtKB iron ion binding Inferred from electronic annotation. Source: InterPro oxygen binding Traceable author statement Ref.3. Source: ProtInc
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 503

503

Cytochrome P450 19A1

PRO_0000051955

Sites

Metal binding

437

1

Iron (heme axial ligand)

Binding site

309

1

Substrate

Binding site

374

1

Substrate; via amide nitrogen

Natural variations

Natural variant

39

1

W → R. Ref.8
Corresponds to variant rs2236722 [ dbSNP | Ensembl ].

VAR_023428

Natural variant

201

1

T → M. Ref.8 Ref.9
Corresponds to variant rs28757184 [ dbSNP | Ensembl ].

VAR_023429

Natural variant

264

1

R → C. Ref.3 Ref.8 Ref.11
Corresponds to variant rs700519 [ dbSNP | Ensembl ].

VAR_018406

Natural variant

365

1

R → Q in AROD; 0.4% of wild-type activity. Ref.19

VAR_016962

Natural variant

375

1

R → C in AROD. Ref.18

VAR_016963

Natural variant

375

1

R → L. Ref.20

VAR_054152

Natural variant

435

1

R → C in AROD; 1.1% of wild-type activity. Ref.17

VAR_016964

Natural variant

437

1

C → Y in AROD; complete loss of activity. Ref.17

VAR_016965

Experimental info

Sequence conflict

496

1

N → S in AAA35557. Ref.1

Sequence conflict

496

1

N → S in CAA31929. Ref.1

Secondary structure

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503

Helix Strand Turn

Details...

Beta strand

54 – 56

3

Helix

57 – 68

12

Helix

70 – 80

11

Beta strand

83 – 97

15

Helix

100 – 108

9

Helix

110 – 112

3

Helix

119 – 125

7

Beta strand

130 – 132

3

Helix

138 – 151

14

Helix

155 – 172

18

Helix

173 – 177

5

Beta strand

183 – 185

3

Helix

187 – 203

17

Helix

210 – 227

18

Helix

232 – 236

5

Helix

238 – 240

3

Helix

242 – 267

26

Turn

270 – 275

6

Helix

278 – 287

10

Turn

288 – 290

3

Helix

293 – 324

32

Helix

326 – 339

14

Turn

340 – 342

3

Helix

347 – 349

3

Turn

350 – 352

3

Helix

354 – 366

13

Beta strand

373 – 376

4

Beta strand

381 – 383

3

Beta strand

386 – 388

3

Beta strand

393 – 396

4

Helix

398 – 401

4

Turn

402 – 404

3

Helix

415 – 418

4

Turn

424 – 426

3

Helix

433 – 435

3

Helix

440 – 455

16

Beta strand

458 – 463

6

Turn

468 – 470

3

Beta strand

473 – 481

9

Beta strand

490 – 494

5

Sequences

	Sequence		Length	Mass (Da)
	P11511 [UniParc]. Last modified January 23, 2007. Version 3. Checksum: 9BD9B28651D9A69A	FASTA	503	57,883
	10 20 30 40 50 60 MVLEMLNPIH YNITSIVPEA MPAATMPVLL LTGLFLLVWN YEGTSSIPGP GYCMGIGPLI 70 80 90 100 110 120 SHGRFLWMGI GSACNYYNRV YGEFMRVWIS GEETLIISKS SSMFHIMKHN HYSSRFGSKL 130 140 150 160 170 180 GLQCIGMHEK GIIFNNNPEL WKTTRPFFMK ALSGPGLVRM VTVCAESLKT HLDRLEEVTN 190 200 210 220 230 240 ESGYVDVLTL LRRVMLDTSN TLFLRIPLDE SAIVVKIQGY FDAWQALLIK PDIFFKISWL 250 260 270 280 290 300 YKKYEKSVKD LKDAIEVLIA EKRRRISTEE KLEECMDFAT ELILAEKRGD LTRENVNQCI 310 320 330 340 350 360 LEMLIAAPDT MSVSLFFMLF LIAKHPNVEE AIIKEIQTVI GERDIKIDDI QKLKVMENFI 370 380 390 400 410 420 YESMRYQPVV DLVMRKALED DVIDGYPVKK GTNIILNIGR MHRLEFFPKP NEFTLENFAK 430 440 450 460 470 480 NVPYRYFQPF GFGPRGCAGK YIAMVMMKAI LVTLLRRFHV KTLQGQCVES IQKIHDLSLH 490 500 PDETKNMLEM IFTPRNSDRC LEH

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Cloning of a complete cDNA encoding human aromatase: immunochemical identification and sequence analysis." Harada N. Biochem. Biophys. Res. Commun. 156:725-732(1988) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Placenta.
[2]	"Human aromatase: cDNA cloning, Southern blot analysis, and assignment of the gene to chromosome 15." Chen S., Besman M.J., Sparkes R.S., Zollman S., Klisak I., Mohandas T., Hall P.F., Shively J.E. DNA 7:27-38(1988) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[3]	"Isolation of a full-length cDNA insert encoding human aromatase system cytochrome P-450 and its expression in nonsteroidogenic cells." Corbin C.J., Graham-Lorence S., McPhaul M., Mason J.I., Mendelson C.R., Simpson E.R. Proc. Natl. Acad. Sci. U.S.A. 85:8948-8952(1988) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT CYS-264.
[4]	"Alternative usage of different poly(A) addition signals for two major species of mRNA encoding human aromatase P-450." Toda K., Terashima M., Mitsuuchi Y., Yamasaki Y., Yokoyama Y., Nojima S., Ushiro H., Maeda T., Yamamoto Y., Sagara Y., Shizuta Y. FEBS Lett. 247:371-376(1989) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Placenta.
[5]	"Structural analysis of the gene encoding human aromatase cytochrome P-450, the enzyme responsible for estrogen biosynthesis." Means G.D., Mahendroo M.S., Corbin C.J., Mathis J.M., Powell F.E., Mendelson C.R., Simpson E.R. J. Biol. Chem. 264:19385-19391(1989) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[6]	"Expression of human placental aromatase in Saccharomyces cerevisiae." Pompon D., Liu R.Y., Besman M.J., Wang P.L., Shively J.E., Chen S. Mol. Endocrinol. 3:1477-1487(1989) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Placenta.
[7]	"Biochemical and molecular genetic analyses on placental aromatase (P-450AROM) deficiency." Harada N., Ogawa H., Shozu M., Yamada K., Suhara K., Nishida E., Takagi Y. J. Biol. Chem. 267:4781-4785(1992) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[8]	NIEHS SNPs program Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS ARG-39; MET-201 AND CYS-264.
[9]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT MET-201. Tissue: Placenta.
[10]	"Isolation and characterization of a complementary DNA specific for human aromatase-system cytochrome P-450 mRNA." Evans C.T., Ledesma D.B., Schulz T.Z., Simpson E.R., Mendelson C.R. Proc. Natl. Acad. Sci. U.S.A. 83:6387-6391(1986) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 85-503, TISSUE SPECIFICITY. Tissue: Placenta.
[11]	"Sequencing of cDNA inserts encoding aromatase cytochrome P-450 (P-450AROM)." Simpson E.R., Evans C.T., Corbin C.J., Powell F.E., Ledesma D.B., Mendelson C.R. Mol. Cell. Endocrinol. 52:267-272(1987) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 85-503, VARIANT CYS-264.
[12]	"Tissue-specific expression of human P-450AROM. The promoter responsible for expression in adipose tissue is different from that utilized in placenta." Mahendroo M.S., Means G.D., Mendelson C.R., Simpson E.R. J. Biol. Chem. 266:11276-11281(1991) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-49, TISSUE SPECIFICITY.
[13]	"Tissue-specific and hormonally controlled alternative promoters regulate aromatase cytochrome P450 gene expression in human adipose tissue." Mahendroo M.S., Mendelson C.R., Simpson E.R. J. Biol. Chem. 268:19463-19470(1993) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-49, TISSUE SPECIFICITY, ALTERNATIVE PROMOTER USAGE.
[14]	"Amino terminal sequence analysis of human placenta aromatase." Chen S., Shively J.E., Nakajin S., Shinoda M., Hall P.F. Biochem. Biophys. Res. Commun. 135:713-719(1986) [PubMed] [Europe PMC] [Abstract] Cited for: PRELIMINARY PROTEIN SEQUENCE OF N-TERMINUS. Tissue: Placenta.
[15]	"Novel exon 1 of the aromatase gene specific for aromatase transcripts in human brain." Honda S., Harada N., Takagi Y. Biochem. Biophys. Res. Commun. 198:1153-1160(1994) [PubMed] [Europe PMC] [Abstract] Cited for: ALTERNATIVE PROMOTER USAGE, TISSUE SPECIFICITY.
[16]	"Structural basis for androgen specificity and oestrogen synthesis in human aromatase." Ghosh D., Griswold J., Erman M., Pangborn W. Nature 457:219-223(2009) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS) IN COMPLEX WITH ANDROSTENEDIONE, HEME.
[17]	"Molecular basis of aromatase deficiency in an adult female with sexual infantilism and polycystic ovaries." Ito Y., Fisher C.R., Conte F.A., Grumbach M.M., Simpson E.R. Proc. Natl. Acad. Sci. U.S.A. 90:11673-11677(1993) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS AROD CYS-435 AND TYR-437.
[18]	"Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens." Morishima A., Grumbach M.M., Simpson E.R., Fisher C., Qin K. J. Clin. Endocrinol. Metab. 80:3689-3698(1995) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT AROD CYS-375.
[19]	"Effect of testosterone and estradiol in a man with aromatase deficiency." Carani C., Qin K., Simoni M., Faustini-Fustini M., Serpente S., Boyd J., Korach K.S., Simpson E.R. N. Engl. J. Med. 337:91-95(1997) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT AROD GLN-365.
[20]	"DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome." Ley T.J., Mardis E.R., Ding L., Fulton B., McLellan M.D., Chen K., Dooling D., Dunford-Shore B.H., McGrath S., Hickenbotham M., Cook L., Abbott R., Larson D.E., Koboldt D.C., Pohl C., Smith S., Hawkins A., Abbott S. , Locke D., Hillier L.W., Miner T., Fulton L., Magrini V., Wylie T., Glasscock J., Conyers J., Sander N., Shi X., Osborne J.R., Minx P., Gordon D., Chinwalla A., Zhao Y., Ries R.E., Payton J.E., Westervelt P., Tomasson M.H., Watson M., Baty J., Ivanovich J., Heath S., Shannon W.D., Nagarajan R., Walter M.J., Link D.C., Graubert T.A., DiPersio J.F., Wilson R.K. Nature 456:66-72(2008) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT [LARGE SCALE ANALYSIS] LEU-375.
+	Additional computationally mapped references.

Web resources

Wikipedia

Aromatase entry

GeneReviews

NIEHS-SNPs

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

M22246 mRNA. Translation: AAA35557.1.
X13589 mRNA. Translation: CAA31929.1.
M18856 mRNA. Translation: AAA35556.1.
J04127 mRNA. Translation: AAA52132.1.
Y07508 mRNA. Translation: CAA68807.1.
M30804 , M30796, M30797, M30798, M30800, M30801, M30802, M30803 Genomic DNA. Translation: AAA35728.1.
AY957953 Genomic DNA. Translation: AAX44046.1.
BC107785 mRNA. Translation: AAI07786.1.
M28420 mRNA. Translation: AAA52141.1.

IPI

IPI00465065.

PIR

O4HU19. A34451.

RefSeq

NP_000094.2. NM_000103.3.
NP_112503.1. NM_031226.2.

UniGene

Hs.260074.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1TQA	model	-	A	53-495	[»]
3EQM	X-ray	2.90	A	1-503	[»]
3S79	X-ray	2.75	A	1-503	[»]
3S7S	X-ray	3.21	A	1-503	[»]
4GL5	X-ray	3.48	A	1-503	[»]
4GL7	X-ray	3.90	A	1-503	[»]

ProteinModelPortal

P11511.

ModBase

Search...

Protein-protein interaction databases

MINT

MINT-4054553.

STRING

9606.ENSP00000260433.

PTM databases

PhosphoSite

P11511.

Polymorphism databases

DMDM

117293.

Proteomic databases

PaxDb

P11511.

PRIDE

P11511.

Protocols and materials databases

DNASU

1588.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000260433; ENSP00000260433; ENSG00000137869.
ENST00000396402; ENSP00000379683; ENSG00000137869.
ENST00000396404; ENSP00000379685; ENSG00000137869.
ENST00000559878; ENSP00000453149; ENSG00000137869.

GeneID

1588.

KEGG

hsa:1588.

UCSC

uc001zyz.4. human.

Organism-specific databases

CTD

1588.

GeneCards

GC15M051500.

HGNC

HGNC:2594. CYP19A1.

HPA

CAB000355.

MIM

107910. gene.
139300. phenotype.
613546. phenotype.

neXtProt

NX_P11511.

Orphanet

91. Aromatase deficiency.
178345. Aromatase excess syndrome.

PharmGKB

PA27091.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG2124.

HOGENOM

HOG000111912.

HOVERGEN

HBG050750.

InParanoid

P11511.

KO

K07434.

OMA

MRRIMLD.

OrthoDB

EOG4ZCT4K.

PhylomeDB

P11511.

Enzyme and pathway databases

BioCyc

MetaCyc:HS06413-MONOMER.

Reactome

REACT_111217. Metabolism.
REACT_15493. Steroid hormones.

SABIO-RK

P11511.

Gene expression databases

ArrayExpress

P11511.

Bgee

P11511.

CleanEx

HS_CYP19A1.

Genevestigator

P11511.

GermOnline

ENSG00000137869. Homo sapiens.

Family and domain databases

Gene3D

1.10.630.10. 1 hit.

InterPro

IPR001128. Cyt_P450.
IPR017972. Cyt_P450_CS.
IPR002401. Cyt_P450_E_grp-I.
[Graphical view]

Pfam

PF00067. p450. 1 hit.
[Graphical view]

PRINTS

PR00463. EP450I.
PR00385. P450.

SUPFAM

SSF48264. Cytochrome_P450. 1 hit.

PROSITE

PS00086. CYTOCHROME_P450. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

P11511.

ChEMBL

CHEMBL1978.

ChiTaRS

CYP19A1. human.

DrugBank

DB00357. Aminoglutethimide.
DB01217. Anastrozole.
DB00286. Conjugated Estrogens.
DB01406. Danazol.
DB00255. Diethylstilbestrol.
DB00990. Exemestane.
DB01006. Letrozole.
DB00894. Testolactone.
DB00624. Testosterone.

EvolutionaryTrace

P11511.

GenomeRNAi

1588.

NextBio

6526.

SOURCE

Search...

Entry information

Entry name

CP19A_HUMAN

Accession

Primary (citable) accession number: P11511
Secondary accession number(s): Q16731, Q3B764, Q58FA0

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1989
Last sequence update:	January 23, 2007
Last modified:	May 1, 2013
This is version 151 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.