Aromatase

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Aromatase (Template:EC number), also called estrogen synthetase or estrogen synthase, is an enzyme responsible for a key step in the biosynthesis of estrogens. It is CYP19A1, a member of the cytochrome P450 superfamily, which are monooxygenases that catalyze many reactions involved in steroidogenesis. In particular, aromatase is responsible for the aromatization of androgens into estrogens. The enzyme aromatase can be found in many tissues including gonads (granulosa cells), brain, adipose tissue, placenta, blood vessels, skin, and bone, as well as in tissue of endometriosis, uterine fibroids, breast cancer, and endometrial cancer.Template:Citation needed It is an important factor in sexual development.

FunctionEdit

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.

Androstenedione + 3O₂ + 3NADPH + 3H⁺ <math>\rightleftharpoons</math> Estrone + Formate + 4H₂O + 3NADP⁺

Testosterone + 3O₂ + 3NADPH + 3H⁺ <math>\rightleftharpoons</math> 17β-estradiol + Formate + 4H₂O + 3NADP⁺

File:Testosterone estradiol conversion.png

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.

File:Aromatase mechanism.png

Catalytic mechanism of aromatase for the conversion of androstenedione to estrone. The methyl group is oxidized and subsequently eliminated.<ref name="Vaz_2003">Template:Cite book</ref>

ExpressionEdit

Aromatase is expressed in the gonads, placenta, brain, adipose tissue, bone, and other tissues.Template:Citation needed It is almost undetectable in adult human liver.<ref name="pmid23930207">Template:Cite journal</ref>

GenomicsEdit

The gene expresses two transcript variants.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> In humans, the gene CYP19, located on chromosome 15q21.1, encodes aromatase.<ref name="pmid8477708">Template:Cite journal</ref> The gene has nine coding exons and a number of alternative non-coding first exons that regulate tissue specific expression.<ref name="pmid20205115">Template:Cite journal</ref>

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.

ActivityEdit

Aromatase activity is increased by age, obesity, insulin, gonadotropins, and alcohol.<ref name=":0">Template:Cite journal</ref> It also appears to be enhanced in certain estrogen-dependent local tissue next to breast tissue, endometrial cancer, endometriosis, and uterine fibroids.<ref name=":0" />

Aromatase activity is decreased or antagonized by prolactin, anti-Müllerian hormone and glyphosate.<ref name=":0" />

Role in sex-determinationEdit

Aromatase is generally highly present during the differentiation of ovaries.<ref name="pmid20623799">Template:Cite journal</ref><ref name="pmid19940440">Template:Cite journal</ref> 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.<ref name="pmid20623799"/> 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).<ref name="pmid20623799"/> 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<ref name="pmid20623799"/> (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.<ref name="Gilbert_2010">Template:Cite book</ref>

Role in neuroprotectionEdit

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.<ref>Template:Cite journal</ref> It has also been shown to decrease apoptosis following brain injury in zebra finches.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref>

DisordersEdit

Aromatase excess syndromeEdit

{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}} A number of investigators have reported on a rather rare syndrome of excess aromatase activity. In boys, it creates gynecomastia, and in girls, 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.<ref name=Fukami2012>Template:Cite journal</ref> It is inherited in an autosomal dominant fashion.<ref name=Fukami2011>Template:Cite journal</ref> It has been suggested that the pharaoh Akhenaten and other members of his family may have had from this disorder,<ref name=Braverman2009>Template:Cite journal</ref> but more recent genetic tests suggest otherwise.<ref name=Seshadri2012>Template:Cite journal</ref> It is one of the causes of familial precocious puberty—a condition first described in 1937.<ref name=Ziora2006>Template:Cite journal</ref>

Aromatase deficiency syndromeEdit

{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}} 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.

Inhibition of aromataseEdit

The inhibition of aromatase can cause hypoestrogenism (low estrogen levels). The following natural products have been found to have inhibiting effects on aromatase. Template:Div col

Apigenin<ref name=pmid18690828>Template:Cite journal</ref>
Catechin<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>
Chalcones<ref>Template:Cite journal</ref>
Eriodictyol<ref name=pmid18690828/>
Hesperetin<ref>Template:Cite journal</ref>
Isoliquiritigenin<ref name=pmid18690828/>
Mangostin<ref name=pmid18690828/>
Myosmine<ref>Template:Cite journal</ref>
Nicotine<ref>Template:Cite journal</ref>
Resveratrol<ref name="pmid16611627">Template:Cite journal</ref>
Vitamin E<ref name="pmid15084515">Template:Cite journal</ref>
Zinc<ref>Template:Cite journal</ref>

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Extracts of certain (white button variety: Agaricus bisporus) mushrooms have been shown to inhibit aromatase in vitro.<ref name="pmid17178902">Template:Cite journal</ref>

Pharmaceutical aromatase inhibitorsEdit

{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}} Aromatase inhibitors, which stop the production of estrogen in postmenopausal women, have become useful in the management of patients with breast cancer whose lesion was found to be estrogen receptor positive.<ref name="urlAromatase Inhibitors">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Inhibitors that are in current clinical use include anastrozole, exemestane, and letrozole. Aromatase inhibitors are also beginning to be prescribed to men on testosterone replacement therapy Template:Citation needed as a way to keep estrogen levels from spiking once doses of testosterone are introduced to their systems.

ReferencesEdit

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External linksEdit

"U.S. study of gay sheep may shed light on sexuality", via WikiNews, 15 August 2005.
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