Aromatase

Last updated
CYP19A1
Protein PGR PDB 1a28.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases CYP19A1 , ARO, ARO1, CPV1, CYAR, CYP19, CYPXIX, P-450AROM, cytochrome P450 family 19 subfamily A member 1
External IDs OMIM: 107910 MGI: 88587 HomoloGene: 30955 GeneCards: CYP19A1
Orthologs
SpeciesHumanMouse
Entrez

1588

13075

Ensembl

ENSG00000137869

ENSMUSG00000032274

UniProt

P11511

P28649

RefSeq (mRNA)

NM_007810
NM_001348171
NM_001348172
NM_001348173

RefSeq (protein)

NP_001335100
NP_001335101
NP_001335102
NP_031836

Location (UCSC) Chr 15: 51.21 – 51.34 Mb Chr 9: 54.07 – 54.18 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Aromatase (EC 1.14.14.14), 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.[ citation needed ] It is an important factor in sexual development.

Function

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+Estrone + Formate + 4H2O + 3NADP+
Testosterone + 3O2 + 3NADPH + 3H+17β-estradiol + Formate + 4H2O + 3NADP+
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. 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.
Catalytic mechanism of aromatase for the conversion of androstenedione to estrone. The methyl group is oxidized and subsequently eliminated. Aromatase mechanism.png
Catalytic mechanism of aromatase for the conversion of androstenedione to estrone. The methyl group is oxidized and subsequently eliminated.

Expression

Aromatase is expressed in the gonads, placenta, brain, adipose tissue, bone, and other tissues.[ citation needed ] It is almost undetectable in adult human liver. [6]

Genomics

The gene expresses two transcript variants. [7] In humans, the gene CYP19, located on chromosome 15q21.1, encodes aromatase. [8] The gene has nine coding exons and a number of alternative non-coding first exons that regulate tissue specific expression. [9]

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

Aromatase activity is increased by age, obesity, insulin, gonadotropins, and alcohol. [10] It also appears to be enhanced in certain estrogen-dependent local tissue next to breast tissue, endometrial cancer, endometriosis, and uterine fibroids. [10]

Aromatase activity is decreased or antagonized by prolactin, anti-Müllerian hormone and glyphosate. [10]

Role in sex-determination

Aromatase is generally highly present during the differentiation of ovaries. [11] [12] 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. [11] 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). [11] 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 [11] (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. [13]

Role in neuroprotection

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. [14] It has also been shown to decrease apoptosis following brain injury in zebra finches. [15] 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. [16]

Disorders

Aromatase excess syndrome

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. [17] It is inherited in an autosomal dominant fashion. [18] It has been suggested that the pharaoh Akhenaten and other members of his family may have had from this disorder, [19] but more recent genetic tests suggest otherwise. [20] It is one of the causes of familial precocious puberty—a condition first described in 1937. [21]

Aromatase deficiency syndrome

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 aromatase

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

Extracts of certain (white button variety: Agaricus bisporus ) mushrooms have been shown to inhibit aromatase in vitro. [32]

Pharmaceutical aromatase inhibitors

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. [33] 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 as a way to keep estrogen levels from spiking once doses of testosterone are introduced to their systems.

See also

Related Research Articles

<span class="mw-page-title-main">Estrogen</span> Primary female sex hormone

Estrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal activity: estrone (E1), estradiol (E2), and estriol (E3). Estradiol, an estrane, is the most potent and prevalent. Another estrogen called estetrol (E4) is produced only during pregnancy.

<span class="mw-page-title-main">Anastrozole</span> Chemical compound

Anastrozole, sold under the brand name Arimidex among others, is an antiestrogenic medication used in addition to other treatments for breast cancer. Specifically it is used for hormone receptor-positive breast cancer. It has also been used to prevent breast cancer in those at high risk. It is taken by mouth.

<span class="mw-page-title-main">Cytochrome P450</span> Class of enzymes

Cytochromes P450 are a superfamily of enzymes containing heme as a cofactor that mostly, but not exclusively, function as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various compounds, as well as for hormone synthesis and breakdown. In 1963, Estabrook, Cooper, and Rosenthal described the role of CYP as a catalyst in steroid hormone synthesis and drug metabolism. In plants, these proteins are important for the biosynthesis of defensive compounds, fatty acids, and hormones.

<span class="mw-page-title-main">Aromatase inhibitor</span> Class of drugs

Aromatase inhibitors (AIs) are a class of drugs used in the treatment of breast cancer in postmenopausal women and in men, and gynecomastia in men. They may also be used off-label to reduce estrogen conversion when supplementing testosterone exogenously. They may also be used for chemoprevention in women at high risk for breast cancer.

<span class="mw-page-title-main">Estrogen receptor</span> Proteins activated by the hormone estrogen

Estrogen receptors (ERs) are a group of proteins found inside cells. They are receptors that are activated by the hormone estrogen (17β-estradiol). Two classes of ER exist: nuclear estrogen receptors, which are members of the nuclear receptor family of intracellular receptors, and membrane estrogen receptors (mERs), which are mostly G protein-coupled receptors. This article refers to the former (ER).

<span class="mw-page-title-main">Letrozole</span> Breast cancer drug

Letrozole, sold under the brand name Femara among others, is an aromatase inhibitor medication that is used in the treatment of breast cancer.

<span class="mw-page-title-main">CYP2C8</span> Gene-coded protein involved in metabolism of xenobiotics

Cytochrome P4502C8 (CYP2C8) is a member of the cytochrome P450 mixed-function oxidase system involved in the metabolism of xenobiotics in the body. Cytochrome P4502C8 also possesses epoxygenase activity, i.e. it metabolizes long-chain polyunsaturated fatty acids, e.g. arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, and Linoleic acid to their biologically active epoxides.

<span class="mw-page-title-main">Tibolone</span> Chemical compound

Tibolone, sold under the brand name Livial among others, is a medication which is used in menopausal hormone therapy and in the treatment of postmenopausal osteoporosis and endometriosis. The medication is available alone and is not formulated or used in combination with other medications. It is taken by mouth.

<span class="mw-page-title-main">CYP17A1</span> Mammalian protein found in Homo sapiens

Cytochrome P450 17A1 is an enzyme of the hydroxylase type that in humans is encoded by the CYP17A1 gene on chromosome 10. It is ubiquitously expressed in many tissues and cell types, including the zona reticularis and zona fasciculata of the adrenal cortex as well as gonadal tissues. It has both 17α-hydroxylase and 17,20-lyase activities, and is a key enzyme in the steroidogenic pathway that produces progestins, mineralocorticoids, glucocorticoids, androgens, and estrogens. More specifically, the enzyme acts upon pregnenolone and progesterone to add a hydroxyl (-OH) group at carbon 17 position (C17) of the steroid D ring, or acts upon 17α-hydroxyprogesterone and 17α-hydroxypregnenolone to split the side-chain off the steroid nucleus.

<span class="mw-page-title-main">CYP27A1</span> Protein-coding gene in the species Homo sapiens

CYP27A1 is a gene encoding a cytochrome P450 oxidase, and is commonly known as sterol 27-hydroxylase. This enzyme is located in many different tissues where it is found within the mitochondria. It is most prominently involved in the biosynthesis of bile acids.

<span class="mw-page-title-main">Estrogen receptor beta</span> Protein-coding gene in the species Homo sapiens

Estrogen receptor beta (ERβ) also known as NR3A2 is one of two main types of estrogen receptor—a nuclear receptor which is activated by the sex hormone estrogen. In humans ERβ is encoded by the ESR2 gene.

<span class="mw-page-title-main">PGRMC1</span> Protein-coding gene in the species Homo sapiens

Progesterone receptor membrane component 1 is a protein which co-purifies with progesterone binding proteins in the liver and ovary. In humans, the PGRMC1 protein is encoded by the PGRMC1 gene.

<span class="mw-page-title-main">Aromatase deficiency</span> Medical condition

Aromatase deficiency is a rare condition characterized by extremely low levels or complete absence of the enzyme aromatase activity in the body. It is an autosomal recessive disease resulting from various mutations of gene CYP19 (P450arom) which can lead to ambiguous genitalia and delayed puberty in females, continued linear growth into adulthood and osteoporosis in males and virilization in pregnant mothers. As of 2020, fewer than 15 cases have been identified in genetically male individuals and at least 30 cases in genetically female individuals.

<span class="mw-page-title-main">Aromatase excess syndrome</span> Medical condition

Aromatase excess syndrome is a rarely diagnosed genetic and endocrine syndrome which is characterized by an overexpression of aromatase, the enzyme responsible for the biosynthesis of the estrogen sex hormones from the androgens, in turn resulting in excessive levels of circulating estrogens and, accordingly, symptoms of hyperestrogenism. It affects both sexes, manifesting itself in males as marked or complete phenotypical feminization and in females as hyperfeminization.

Steroidal aromatase inhibitors are a class of drugs that are mostly used for treating breast cancer in postmenopausal women. High levels of estrogen in breast tissue increases the risk of developing breast cancer and the enzyme aromatase is considered to be a good therapeutic target when treating breast cancer due to it being involved in the final step of estrogen biosynthetic pathway and also its inhibition will not affect production of other steroids. Aromatase Inhibitors are classified into two categories based on their structure, nonsteroidal and steroidal; the latter resemble the structure of androstenedione. Steroidal aromatase inhibitors irreversibly inhibit the enzyme by binding covalently to the binding site of aromatase so the substrate cannot access it.

Serdar Bulun is a gynecologist, with a special interest in the common gynecologic diseases, endometriosis and uterine fibroids.

<span class="mw-page-title-main">Hydroxylation of estradiol</span>

The hydroxylation of estradiol is one of the major routes of metabolism of the estrogen steroid hormone estradiol. It is hydroxylated into the catechol estrogens 2-hydroxyestradiol and 4-hydroxyestradiol and into estriol (16α-hydroxyestradiol), reactions which are catalyzed by cytochrome P450 enzymes predominantly in the liver, but also in various other tissues.

<span class="mw-page-title-main">Steroidogenic enzyme</span>

Steroidogenic enzymes are enzymes that are involved in steroidogenesis and steroid biosynthesis. They are responsible for the biosynthesis of the steroid hormones, including sex steroids and corticosteroids, as well as neurosteroids, from cholesterol. Steroidogenic enzymes are most highly expressed in classical steroidogenic tissues, such as the testis, ovary, and adrenal cortex, but are also present in other tissues in the body.

<span class="mw-page-title-main">Cytochrome p450 family 19 subfamily a member 1</span> Protein-coding gene in the species Homo sapiens

Cytochrome P450 family 19 subfamily A member 1 is a protein that in humans is encoded by the CYP19A1 gene.

<span class="mw-page-title-main">Non steroidal aromatase inhibitors</span>

Non-Steroidal Aromatase Inhibitors (NSAIs) are one of two categories of aromatase inhibitors (AIs). AIs are divided into two categories, steroidal aromatase inhibitors and non-steroidal aromatase inhibitors that is based on their mechanism of action and structure. NSAIs are mainly used to treat breast cancer in women. NSAIs binding is a reversible process where NSAIs binds to the aromatase enzyme through non-covalent interactions. When aromatase inhibitors (AIs) are used to treat breast cancer the main target is the aromatase enzyme which is responsible for the high estrogen level.

References

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  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000032274 - Ensembl, May 2017
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  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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  32. ↑ 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 Research. 66 (24): 12026–34. doi: 10.1158/0008-5472.CAN-06-2206 . PMID   17178902.
  33. ↑ "Aromatase Inhibitors". Breastcancer.org. 29 October 2020.

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