Aromatase

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Cytochrome P450, family 19, subfamily A, polypeptide 1

Crystallographic structure of the human aromatase cytochrome P450 (rainbow colored cartoon, N-terminus = blue, C-terminus = red) in complex with the cofactor protoporphyrin IX (top) and the substrate androstenedione (bottom) depicted as stick diagrams (carbon = white, oxygen = red, nitrogen = blue, iron = orange).[1]
Available structures
PDBOrtholog search: PDBe, RCSB
Identifiers
SymbolsCYP19A1 ; ARO; ARO1; CPV1; CYAR; CYP19; CYPXIX; P-450AROM
External IDsOMIM107910 MGI88587 HomoloGene30955 ChEMBL: 1978 GeneCards: CYP19A1 Gene
EC number1.14.14.1
RNA expression pattern
PBB GE CYP19A1 203475 at tn.png
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez158813075
EnsemblENSG00000137869ENSMUSG00000032274
UniProtP11511P28649
RefSeq (mRNA)NM_000103NM_007810
RefSeq (protein)NP_000094NP_031836
Location (UCSC)Chr 15:
51.5 – 51.63 Mb
Chr 9:
54.17 – 54.19 Mb
PubMed search[1][2]
 
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Cytochrome P450, family 19, subfamily A, polypeptide 1

Crystallographic structure of the human aromatase cytochrome P450 (rainbow colored cartoon, N-terminus = blue, C-terminus = red) in complex with the cofactor protoporphyrin IX (top) and the substrate androstenedione (bottom) depicted as stick diagrams (carbon = white, oxygen = red, nitrogen = blue, iron = orange).[1]
Available structures
PDBOrtholog search: PDBe, RCSB
Identifiers
SymbolsCYP19A1 ; ARO; ARO1; CPV1; CYAR; CYP19; CYPXIX; P-450AROM
External IDsOMIM107910 MGI88587 HomoloGene30955 ChEMBL: 1978 GeneCards: CYP19A1 Gene
EC number1.14.14.1
RNA expression pattern
PBB GE CYP19A1 203475 at tn.png
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez158813075
EnsemblENSG00000137869ENSMUSG00000032274
UniProtP11511P28649
RefSeq (mRNA)NM_000103NM_007810
RefSeq (protein)NP_000094NP_031836
Location (UCSC)Chr 15:
51.5 – 51.63 Mb
Chr 9:
54.17 – 54.19 Mb
PubMed search[1][2]

Aromatase, also called estrogen synthetase or estrogen synthase, is an enzyme responsible for a key step in the biosynthesis of estrogens. It is a member of the cytochrome P450 superfamily (EC 1.14.14.1), which are monooxygenases that catalyze many reactions involved in steroidogenesis. In particular, aromatase is responsible for the aromatization of androgens into estrogens. The aromatase enzyme can be found in many tissues including gonads, brain, adipose tissue, placenta, blood vessels, skin, and bone, as well as in tissue of endometriosis, uterine fibroids, breast cancer, and endometrial cancer.[citation needed] It is an important factor in sexual development.[citation needed]

Function[edit]

Aromatase is localized in the endoplasmic reticulum where it is regulated by tissue-specific promoters that are in turn controlled by hormones, cytokines, and other factors. It catalyzes the last steps of estrogen biosynthesis from androgens (specifically, it transforms androstenedione to estrone and testosterone to estradiol). These steps include three successive hydroxylations of the 19-methyl group of androgens, followed by simultaneous elimination of the methyl group as formate and aromatization of the A-ring.

General reaction for the conversion of testosterone to estradiol catalyzed by aromatase. Steroids are composed of four fused rings (labeled A-D). Aromatase converts the ring labeled "A" into an aromatic state.
Catalytic mechanism of aromatase. The methyl group is oxidized and subsequently eliminated.[2]

Genomics[edit]

The gene expresses two transcript variants.[3] In humans, the gene CYP19, located on chromosome 15q21.1, encodes the aromatase enzyme.[4] The gene has nine coding exons and a number of alternative non-coding first exons that regulate tissue specific expression.[5]

CYP19 is present in an early-diverging chordate, the cephalochordate amphioxus (the Florida lancelet, Branchiostoma floridae), but not in the earlier diverging tunicate Ciona intestinalis. Thus, the aromatase gene evolved early in chordate evolution and does not appear to be present in nonchordate invertebrates (e.g. insects, molluscs, echinoderms, sponges, corals). However, estrogens may be synthesized in some of these organisms, via other unknown pathways.

Activity[edit]

Factors known to increase aromatase activity include age, obesity, insulin, gonadotropins, and alcohol. Aromatase activity is decreased by prolactin, anti-Müllerian hormone and the common herbicide glyphosate.[6] Aromatase activity appears to be enhanced in certain estrogen-dependent local tissue next to breast tissue, endometrial cancer, endometriosis, and uterine fibroids.

Role in sex-determination[edit]

Aromatase is generally highly present during the differentiation of ovaries.[7][8] It is also susceptible to environmental influences, particularly temperature. In species with temperature-dependent sex determination, aromatase is expressed in higher quantities at temperatures that yield female offspring.[7] Despite the fact that data suggest temperature controls aromatase quantities, other studies have shown that aromatase can overpower the effects of temperature: if exposed to more aromatase at a male-producing temperature, the organism will develop female and conversely, if exposed to less aromatase at female-producing temperatures, the organism will develop male (see sex reversal).[7] In organisms that develop through genetic sex determination, temperature does not affect aromatase expression and function, suggesting that aromatase is the target molecule for temperature during TSD[7] (for challenges to this argument, see temperature-dependent sex determination). It varies from species to species whether it is the aromatase protein that has different activity at different temperatures or whether the amount of transcription undergone by the aromatase gene is what is temperature-sensitive, but in either case, differential development is observed at different temperatures.[9]

Role in neuroprotection[edit]

Aromatase in the brain is usually only expressed in neurons. However, following penetrative brain injury of both mice and zebra finches, it has been shown to be expressed in astrocytes.[10] Furthermore, it has also been shown to decrease apoptosis following brain injury in zebra finches.[11] This is thought to be due to the neuroprotective actions of estrogens, including estradiol. Research has found that two pro-inflammatory cytokines, interleukin-1β (IL-1β) and interleukin-6 (IL-6), are responsible for the induction of aromatase expression in astrocytes following penetrative brain injury in the zebra finch.[12]

Disorders[edit]

Aromatase excess syndrome[edit]

A number of investigators have reported on a rather rare syndrome of excess aromatase activity. In boys, it can lead to gynecomastia, and in girls to precocious puberty and gigantomastia. In both sexes, early epiphyseal closure leads to short stature. This condition is due to mutations in the CYP19A1 gene which encodes aromatase.[13] It is inherited in an autosomal dominant fashion.[14] It has been suggested that the pharaoh Akhenaten and other members of his family may have suffered from this disorder,[15] but more recent genetic tests suggest otherwise.[16] It is one of the causes of familial precocious puberty—a condition first described in 1937.[17]

Aromatase deficiency syndrome[edit]

Main article: Aromatase deficiency

This syndrome is due to a mutation of gene CYP19 and inherited in an autosomal recessive way. Accumulations of androgens during pregnancy may lead to virilization of a female at birth (males are not affected). Females will have primary amenorrhea. Individuals of both sexes will be tall, as lack of estrogen does not bring the epiphyseal lines to closure.

Aromatase inhibitors[edit]

Main article: Aromatase inhibitor

The inhibition of the enzyme leads to profound hypoestrogenism (low estrogen levels). Thus, aromatase inhibitors have become useful in the management of patients with breast cancer whose lesion was found to be estrogen receptor positive. An example of an aromatase inhibitor is letrozole, marketed originally under the name 'Femara.' Aromatase inhibitors are also beginning to be prescribed to men on testosterone replacement therapy as a way to keep estrogen levels from spiking once doses of testosterone are introduced to their systems.

Extracts of certain (white button variety: Agaricus bisporus) mushrooms have been shown to inhibit aromatase in vitro.[18]

References[edit]

  1. ^ PDB 3EQM; Ghosh D, Griswold J, Erman M, Pangborn W (January 2009). "Structural basis for androgen specificity and oestrogen synthesis in human aromatase". Nature 457 (7226): 219–23. doi:10.1038/nature07614. PMID 19129847. 
  2. ^ Vaz ADN (2003). "Chapter 1: Cytochrome activation by cytochromes P450: a role for multiple oxidants in the oxidation of substrates". In Fisher, Michael; Lee, Jae Kyu; Obach, Robert E. Drug metabolizing enzymes: cytochrome P450 and other enzymes in drug discovery and development. Lausanne, Switzerland: FontisMedia SA. ISBN 0-8247-4293-1. 
  3. ^ "Entrez Gene: CYP19A1 cytochrome P450, family 19, subfamily A, polypeptide 1". 
  4. ^ Toda K, Shizuta Y (April 1993). "Molecular cloning of a cDNA showing alternative splicing of the 5'-untranslated sequence of mRNA for human aromatase P-450". Eur. J. Biochem. 213 (1): 383–9. doi:10.1111/j.1432-1033.1993.tb17772.x. PMID 8477708. 
  5. ^ Czajka-Oraniec I, Simpson ER (2010). "Aromatase research and its clinical significance". Endokrynol Pol 61 (1): 126–34. PMID 20205115. 
  6. ^ http://www.sciencedirect.com/science/article/pii/S0300483X09003047
  7. ^ a b c d Duffy TA, Picha ME, Won ET, Borski RJ, McElroy AE, Conover DO (August 2010). "Ontogenesis of gonadal aromatase gene expression in atlantic silverside (Menidia menidia) populations with genetic and temperature-dependent sex determination". J Exp Zool A Ecol Genet Physiol 313 (7): 421–31. doi:10.1002/jez.612. PMID 20623799. 
  8. ^ Kohno S, Katsu Y, Urushitani H, Ohta Y, Iguchi T, Guillette LJ (2010). "Potential contributions of heat shock proteins to temperature-dependent sex determination in the American alligator". Sex Dev 4 (1-2): 73–87. doi:10.1159/000260374. PMC 2855287. PMID 19940440. 
  9. ^ Gilbert SF (2010). Developmental biology. Sunderland, Mass: Sinauer Associates. ISBN 978-0-87893-384-6. 
  10. ^ Garcia-Segura, L.M.; Wozniak, A.; Azcoitia, I.; Rodriguez, J.R.; Hutchison, R.E.; J.B. Hutchison (1999). "Aromatase expression by astrocytes after brain injury: Implications for local estrogen formation in brain repair". Journal of Neuroscience 89 (2): 567–578. 
  11. ^ Saldanha, C.J.; Rohmann, K.N.; Coomaralingam, L.; R.D. Wynne (2005). "Estrogen provision by reactive glia decreases apoptosis in the zebra finch (Taeniopygia guttata)". Journal of Neurobiology 64 (2): 192–201. 
  12. ^ Duncan, K.A.; Saldanha, C.J. (2011). "Neuroinflammation induces glial aromatase expression in the uninjured songbird brain". Journal of Neuroinflammation 8 (81). 
  13. ^ Fukami M, Shozu M, Ogata T (2012). "Molecular bases and phenotypic determinants of aromatase excess syndrome". Int J Endocrinol 2012: 584807. doi:10.1155/2012/584807. PMC 3272822. PMID 22319526. 
  14. ^ Fukami M, Shozu M, Soneda S, Kato F, Inagaki A, Takagi H, Hanaki K, Kanzaki S, Ohyama K, Sano T, Nishigaki T, Yokoya S, Binder G, Horikawa R, Ogata T (June 2011). "Aromatase excess syndrome: identification of cryptic duplications and deletions leading to gain of function of CYP19A1 and assessment of phenotypic determinants". J. Clin. Endocrinol. Metab. 96 (6): E1035–43. doi:10.1210/jc.2011-0145. PMID 21470988. 
  15. ^ Braverman IM, Redford DB, Mackowiak PA (April 2009). "Akhenaten and the strange physiques of Egypt's 18th dynasty". Annals of Internal Medicine 150 (8): 556–60. PMID 19380856. 
  16. ^ Seshadri, Krishna G. (May–June 2012). "The breasts of Tutankhamun". Indian Journal of Endocrinology and Metabolism. 16(3): 429–430. doi:10.4103/2230-8210.95696. PMC 3354854. PMID 22629513. Retrieved July 2012. 
  17. ^ Ziora K, Oświecimska J, Geisler G, Broll-Waśka K, Szalecki M, Dyduch A (2006). "[Familial precocious puberty -- a variant of norm or pathology?]". Endokrynol Diabetol Chor Przemiany Materii Wieku Rozw (in Polish) 12 (1): 53–8. PMID 16704862. 
  18. ^ Chen S, Oh SR, Phung S, Hur G, Ye JJ, Kwok SL, Shrode GE, Belury M, Adams LS, Williams D (December 2006). "Anti-aromatase activity of phytochemicals in white button mushrooms (Agaricus bisporus)". Cancer Res. 66 (24): 12026–34. doi:10.1158/0008-5472.CAN-06-2206. PMID 17178902. 

Further reading[edit]

  • Attar E, Bulun SE (May 2006). "Aromatase inhibitors: the next generation of therapeutics for endometriosis?". Fertil. Steril. 85 (5): 1307–18. doi:10.1016/j.fertnstert.2005.09.064. PMID 16647373. 
  • Chen S (2004). "Aromatase and breast cancer". Front. Biosci. 3: d922–33. PMID 9696881. 
  • Strobel HW, Thompson CM, Antonovic L (2001). "Cytochromes P450 in brain: function and significance". Curr. Drug Metab. 2 (2): 199–214. doi:10.2174/1389200013338577. PMID 11469726. 
  • Simpson ER, Clyne C, Rubin G, et al. (2002). "Aromatase--a brief overview". Annu. Rev. Physiol. 64: 93–127. doi:10.1146/annurev.physiol.64.081601.142703. PMID 11826265. 
  • Bulun SE, Yang S, Fang Z, et al. (2002). "Role of aromatase in endometrial disease". J. Steroid Biochem. Mol. Biol. 79 (1–5): 19–25. doi:10.1016/S0960-0760(01)00134-0. PMID 11850203. 
  • Balthazart J, Baillien M, Ball GF (2002). "Phosphorylation processes mediate rapid changes of brain aromatase activity". J. Steroid Biochem. Mol. Biol. 79 (1–5): 261–77. doi:10.1016/S0960-0760(01)00143-1. PMID 11850233. 
  • Richards JA, Petrel TA, Brueggemeier RW (2002). "Signaling pathways regulating aromatase and cyclooxygenases in normal and malignant breast cells". J. Steroid Biochem. Mol. Biol. 80 (2): 203–12. doi:10.1016/S0960-0760(01)00187-X. PMID 11897504. 
  • Balthazart J, Baillien M, Ball GF (2002). "Interactions between aromatase (estrogen synthase) and dopamine in the control of male sexual behavior in quail". Comp. Biochem. Physiol. B, Biochem. Mol. Biol. 132 (1): 37–55. doi:10.1016/S1096-4959(01)00531-0. PMID 11997208. 
  • Meinhardt U, Mullis PE (2002). "The aromatase cytochrome P-450 and its clinical impact". Horm. Res. 57 (5–6): 145–52. doi:10.1159/000058374. PMID 12053085. 
  • Carreau S, Bourguiba S, Lambard S, et al. (2003). "Reproductive system: aromatase and estrogens". Mol. Cell. Endocrinol. 193 (1–2): 137–43. doi:10.1016/S0303-7207(02)00107-7. PMID 12161013. 
  • Meinhardt U, Mullis PE (2003). "The essential role of the aromatase/p450arom". Semin. Reprod. Med. 20 (3): 277–84. doi:10.1055/s-2002-35374. PMID 12428207. 
  • Carreau S, Bourguiba S, Lambard S, Galeraud-Denis I (2003). "[Testicular aromatase]". J. Soc. Biol. 196 (3): 241–4. PMID 12462076. 
  • Carani C, Fabbi M, Zirilli L, Sgarbi I (2003). "[Estrogen resistance and aromatase deficiency in humans]". J. Soc. Biol. 196 (3): 245–8. PMID 12462077. 
  • Kragie L (2003). "Aromatase in primate pregnancy: a review". Endocr. Res. 28 (3): 121–8. doi:10.1081/ERC-120015041. PMID 12489562. 
  • Simpson ER (2004). "Biology of aromatase in the mammary gland". Journal of Mammary Gland Biology and Neoplasia 5 (3): 251–8. doi:10.1023/A:1009590626450. PMID 14973387. 
  • Bulun SE, Takayama K, Suzuki T, et al. (2004). "Organization of the human aromatase p450 (CYP19) gene". Semin. Reprod. Med. 22 (1): 5–9. doi:10.1055/s-2004-823022. PMID 15083376. 
  • Simpson ER (2004). "Aromatase: biologic relevance of tissue-specific expression". Semin. Reprod. Med. 22 (1): 11–23. doi:10.1055/s-2004-823023. PMID 15083377. 
  • Bulun SE, Fang Z, Imir G, et al. (2004). "Aromatase and endometriosis". Semin. Reprod. Med. 22 (1): 45–50. doi:10.1055/s-2004-823026. PMID 15083380. 
  • Shozu M, Murakami K, Inoue M (2004). "Aromatase and leiomyoma of the uterus". Semin. Reprod. Med. 22 (1): 51–60. doi:10.1055/s-2004-823027. PMID 15083381. 
  • Chen S, Ye J, Kijima I, et al. (2005). "Positive and negative transcriptional regulation of aromatase expression in human breast cancer tissue". J. Steroid Biochem. Mol. Biol. 95 (1–5): 17–23. doi:10.1016/j.jsbmb.2005.04.002. PMID 15955695. 
  • Lambard S, Silandre D, Delalande C, et al. (2005). "Aromatase in testis: expression and role in male reproduction". J. Steroid Biochem. Mol. Biol. 95 (1–5): 63–9. doi:10.1016/j.jsbmb.2005.04.020. PMID 16019206. 
  • Bulun SE, Imir G, Utsunomiya H, et al. (2005). "Aromatase in endometriosis and uterine leiomyomata". J. Steroid Biochem. Mol. Biol. 95 (1–5): 57–62. doi:10.1016/j.jsbmb.2005.04.012. PMID 16024248. 
  • Lambard S, Carreau S (2005). "Aromatase and oestrogens in human male germ cells". Int. J. Androl. 28 (5): 254–9. doi:10.1111/j.1365-2605.2005.00546.x. PMID 16128984. 
  • Ellem SJ, Risbridger GP (2006). "Aromatase and prostate cancer". Minerva Endocrinol. 31 (1): 1–12. PMID 16498360. 
  • Brueggemeier RW, Díaz-Cruz ES (2006). "Relationship between aromatase and cyclooxygenases in breast cancer: potential for new therapeutic approaches". Minerva Endocrinol. 31 (1): 13–26. PMID 16498361. 
  • Jongen VH, Hollema H, Van Der Zee AG, Heineman MJ (2006). "Aromatase in the context of breast and endometrial cancer. A review". Minerva Endocrinol. 31 (1): 47–60. PMID 16498363. 
  • Hiltunen M, Iivonen S, Soininen H (2006). "Aromatase enzyme and Alzheimer's disease". Minerva Endocrinol. 31 (1): 61–73. PMID 16498364. 

External links[edit]