Ароматаза
| CYP19A1 | |||||||||||||||||||||||||||||||||||||||||||||||||
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| Идентификаторы | |||||||||||||||||||||||||||||||||||||||||||||||||
| Псевдонимы | CYP19A1 , ARO, ARO1, CPV1, CYAR, CYP19, CYPXIX, P-450Arom, Cytochrome P450 Семейство 19 Подсемейство А. Член 1 | ||||||||||||||||||||||||||||||||||||||||||||||||
| Внешние идентификаторы | Омим : 107910 ; MGI : 88587 ; Гомологен : 30955 ; GeneCards : CYP19A1 ; OMA : CYP19A1 - ортологи | ||||||||||||||||||||||||||||||||||||||||||||||||
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Ароматаза ( EC 1.14.14.14 ), также называемая синтетазой или эстрогенсинтазой , является ферментом, ответственным за ключевую стадию в биосинтезе эстрогенов эстрогеновой . Это CYP19A1 , член суперсемейства цитохрома P450 , которые являются монооксигеназами , которые катализируют многие реакции, связанные с стероидогенезом . , ароматаза отвечает за ароматизацию андрогенов В частности в эстрогены . Фермент ароматаза может быть обнаружена во многих тканях, включая гонады ( клетки гранулезы ), мозг , жировую ткань , плаценту , кровеносные сосуды , кожу и кость , а также в ткани эндометриоза , миомы матки , рака молочной железы и рака эндометрия . [ Цитация необходима ] Это важный фактор сексуального развития .
Функция
[ редактировать ]Ароматаза локализована в эндоплазматической ретикулуме , где она регулируется тканеспецифическими промоторами , которые, в свою очередь, контролируются гормонами , цитокинами и другими факторами. Он катализирует последние шаги биосинтеза эстрогена из андрогенов (в частности, он превращает андростендиона в эстрон и тестостерон в эстрадиол ). Эти шаги включают три последовательных гидроксилирования 19-метильной группы андрогенов, за которыми следовало одновременная элиминация метильной группы в качестве формиата и ароматизации A-кольца.
- Androstenedione + 3O2 + 3NADPH + 3H+ Estrone + Formate + 4H2O + 3NADP+
- Testosterone + 3O2 + 3NADPH + 3H+ 17β-estradiol + Formate + 4H2O + 3NADP+
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Expression
[edit]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
[edit]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
[edit]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
[edit]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
[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.[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
[edit]Aromatase excess syndrome
[edit]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
[edit]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
[edit]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
[edit]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
[edit]References
[edit]- ^ Jump up to: a b c GRCh38: Ensembl release 89: ENSG00000137869 – Ensembl, May 2017
- ^ Jump up to: a b c GRCm38: Ensembl release 89: ENSMUSG00000032274 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ Vaz AD (2003). "Chapter 1: Cytochrome activation by cytochromes P450: a role for multiple oxidants in the oxidation of substrates". In Fisher M, Lee JK, Obach RE (eds.). Drug metabolizing enzymes: cytochrome P450 and other enzymes in drug discovery and development. Lausanne, Switzerland: FontisMedia SA. ISBN 978-0-8247-4293-5.
- ^ Hata S, Miki Y, Saito R, Ishida K, Watanabe M, Sasano H (June 2013). "Aromatase in human liver and its diseases". Cancer Med. 2 (3): 305–15. doi:10.1002/cam4.85. PMC 3699842. PMID 23930207.
- ^ "Entrez Gene: CYP19A1 cytochrome P450, family 19, subfamily A, polypeptide 1".
- ^ 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". European Journal of Biochemistry. 213 (1): 383–9. doi:10.1111/j.1432-1033.1993.tb17772.x. PMID 8477708.
- ^ Czajka-Oraniec I, Simpson ER (2010). "Aromatase research and its clinical significance". Endokrynologia Polska. 61 (1): 126–34. PMID 20205115.
- ^ Jump up to: a b c Hussain A, Gilloteaux J (September 2020). "The human testes: Estrogen and ageing outlooks". Translational Research in Anatomy. 20: 100073. doi:10.1016/j.tria.2020.100073. ISSN 2214-854X. S2CID 219001284.
- ^ Jump up to: 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". Journal of Experimental Zoology Part A. 313 (7): 421–31. Bibcode:2010JEZA..313..421D. doi:10.1002/jez.612. PMID 20623799.
- ^ 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". Sexual Development. 4 (1–2): 73–87. doi:10.1159/000260374. PMC 2855287. PMID 19940440.
- ^ Gilbert SF (2010). Developmental biology. Sunderland, Mass: Sinauer Associates. ISBN 978-0-87893-384-6.
- ^ Garcia-Segura LM, Wozniak A, Azcoitia I, Rodriguez JR, Hutchison RE, Hutchison JB (March 1999). "Aromatase expression by astrocytes after brain injury: implications for local estrogen formation in brain repair". Neuroscience. 89 (2): 567–78. doi:10.1016/s0306-4522(98)00340-6. PMID 10077336. S2CID 24689059.
- ^ Saldanha CJ, Rohmann KN, Coomaralingam L, Wynne RD (August 2005). "Estrogen provision by reactive glia decreases apoptosis in the zebra finch (Taeniopygia guttata)". Journal of Neurobiology. 64 (2): 192–201. doi:10.1002/neu.20147. PMID 15818556.
- ^ Duncan KA, Saldanha CJ (July 2011). "Neuroinflammation induces glial aromatase expression in the uninjured songbird brain". Journal of Neuroinflammation. 8 (81): 81. doi:10.1186/1742-2094-8-81. PMC 3158750. PMID 21767382.
- ^ Fukami M, Shozu M, Ogata T (2012). "Molecular bases and phenotypic determinants of aromatase excess syndrome". International Journal of Endocrinology. 2012: 584807. doi:10.1155/2012/584807. PMC 3272822. PMID 22319526.
- ^ Fukami M, Shozu M, Soneda S, Kato F, Inagaki A, Takagi H, et al. (June 2011). "Aromatase excess syndrome: identification of cryptic duplications and deletions leading to gain of function of CYP19A1 and assessment of phenotypic determinants". The Journal of Clinical Endocrinology and Metabolism. 96 (6): E1035-43. doi:10.1210/jc.2011-0145. PMID 21470988.
- ^ 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. doi:10.7326/0003-4819-150-8-200904210-00010. PMID 19380856. S2CID 24766974.
- ^ Seshadri KG (May 2012). "The breasts of Tutankhamun". Indian Journal of Endocrinology and Metabolism. 16 (3): 429–30. doi:10.4103/2230-8210.95696. PMC 3354854. PMID 22629513.
- ^ Ziora K, Oświecimska J, Geisler G, Broll-Waśka K, Szalecki M, Dyduch A (2006). "[Familial precocious puberty -- a variant of norm or pathology?]". Endokrynologia, Diabetologia I Choroby Przemiany Materii Wieku Rozwojowego (in Polish). 12 (1): 53–8. PMID 16704862.
- ^ Jump up to: a b c d Balunas MJ, Su B, Brueggemeier RW, Kinghorn AD (August 2008). "Natural products as aromatase inhibitors". Anti-Cancer Agents in Medicinal Chemistry. 8 (6): 646–82. doi:10.2174/1871520610808060646. PMC 3074486. PMID 18690828.
- ^ Satoh K, Sakamoto Y, Ogata A, Nagai F, Mikuriya H, Numazawa M, et al. (July 2002). "Inhibition of aromatase activity by green tea extract catechins and their endocrinological effects of oral administration in rats". Food and Chemical Toxicology. 40 (7): 925–33. doi:10.1016/S0278-6915(02)00066-2. PMID 12065214.
- ^ Kapiszewska M, Miskiewicz M, Ellison PT, Thune I, Jasienska G (May 2006). "High tea consumption diminishes salivary 17beta-estradiol concentration in Polish women". The British Journal of Nutrition. 95 (5): 989–95. doi:10.1079/BJN20061755. hdl:11315/483. PMID 16611391.
- ^ Le Bail JC, Pouget C, Fagnere C, Basly JP, Chulia AJ, Habrioux G (January 2001). "Chalcones are potent inhibitors of aromatase and 17beta-hydroxysteroid dehydrogenase activities". Life Sciences. 68 (7): 751–61. doi:10.1016/S0024-3205(00)00974-7. PMID 11205867.
- ^ Ye L, Chan FL, Chen S, Leung LK (October 2012). "The citrus flavonone hesperetin inhibits growth of aromatase-expressing MCF-7 tumor in ovariectomized athymic mice". The Journal of Nutritional Biochemistry. 23 (10): 1230–7. doi:10.1016/j.jnutbio.2011.07.003. PMID 22209285.
- ^ Doering IL, Richter E (April 2009). "Inhibition of human aromatase by myosmine". Drug Metabolism Letters. 3 (2): 83–6. doi:10.2174/187231209788654045. PMID 19601869.
- ^ Biegon A, Kim SW, Logan J, Hooker JM, Muench L, Fowler JS (April 2010). "Nicotine blocks brain estrogen synthase (aromatase): in vivo positron emission tomography studies in female baboons". Biological Psychiatry. 67 (8): 774–7. doi:10.1016/j.biopsych.2010.01.004. PMC 2904480. PMID 20188349.
- ^ Wang Y, Lee KW, Chan FL, Chen S, Leung LK (July 2006). "The red wine polyphenol resveratrol displays bilevel inhibition on aromatase in breast cancer cells". Toxicological Sciences. 92 (1): 71–7. doi:10.1093/toxsci/kfj190. PMID 16611627.
- ^ Siler U, Barella L, Spitzer V, Schnorr J, Lein M, Goralczyk R, et al. (June 2004). "Lycopene and vitamin E interfere with autocrine/paracrine loops in the Dunning prostate cancer model". FASEB Journal. 18 (9): 1019–21. doi:10.1096/fj.03-1116fje. PMID 15084515. S2CID 26424745.
- ^ Om AS, Chung KW (April 1996). "Dietary zinc deficiency alters 5 alpha-reduction and aromatization of testosterone and androgen and estrogen receptors in rat liver". The Journal of Nutrition. 126 (4): 842–8. doi:10.1093/jn/126.4.842. PMID 8613886.
- ^ Chen S, Oh SR, Phung S, Hur G, Ye JJ, Kwok SL, et al. (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.
- ^ "Aromatase Inhibitors". Breastcancer.org. 29 October 2020.
Further reading
[edit]- Attar E, Bulun SE (May 2006). "Aromatase inhibitors: the next generation of therapeutics for endometriosis?". Fertility and Sterility. 85 (5): 1307–18. doi:10.1016/j.fertnstert.2005.09.064. PMID 16647373.
- Chen S (August 1998). "Aromatase and breast cancer". Frontiers in Bioscience. 3 (4): d922–33. doi:10.2741/A333. PMID 9696881.
- Strobel HW, Thompson CM, Antonovic L (June 2001). "Cytochromes P450 in brain: function and significance". Current Drug Metabolism. 2 (2): 199–214. doi:10.2174/1389200013338577. PMID 11469726.
- Simpson ER, Clyne C, Rubin G, Boon WC, Robertson K, Britt K, et al. (2002). "Aromatase--a brief overview". Annual Review of Physiology. 64: 93–127. doi:10.1146/annurev.physiol.64.081601.142703. PMID 11826265.
- Bulun SE, Yang S, Fang Z, Gurates B, Tamura M, Zhou J, et al. (December 2001). "Role of aromatase in endometrial disease". The Journal of Steroid Biochemistry and Molecular Biology. 79 (1–5): 19–25. doi:10.1016/S0960-0760(01)00134-0. PMID 11850203. S2CID 7642211.
- Balthazart J, Baillien M, Ball GF (December 2001). "Phosphorylation processes mediate rapid changes of brain aromatase activity". The Journal of Steroid Biochemistry and Molecular Biology. 79 (1–5): 261–77. doi:10.1016/S0960-0760(01)00143-1. PMID 11850233. S2CID 34269540.
- Richards JA, Petrel TA, Brueggemeier RW (February 2002). "Signaling pathways regulating aromatase and cyclooxygenases in normal and malignant breast cells". The Journal of Steroid Biochemistry and Molecular Biology. 80 (2): 203–12. doi:10.1016/S0960-0760(01)00187-X. PMID 11897504. S2CID 12728545.
- Balthazart J, Baillien M, Ball GF (May 2002). "Interactions between aromatase (estrogen synthase) and dopamine in the control of male sexual behavior in quail". Comparative Biochemistry and Physiology. Part B, Biochemistry & Molecular Biology. 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". Hormone Research. 57 (5–6): 145–52. doi:10.1159/000058374 (inactive 2024-07-10). PMID 12053085. S2CID 24115725.
{{cite journal}}: CS1 maint: DOI inactive as of July 2024 (link) - Carreau S, Bourguiba S, Lambard S, Galeraud-Denis I, Genissel C, Levallet J (July 2002). "Reproductive system: aromatase and estrogens". Molecular and Cellular Endocrinology. 193 (1–2): 137–43. doi:10.1016/S0303-7207(02)00107-7. PMID 12161013. S2CID 34446206.
- Meinhardt U, Mullis PE (August 2002). "The essential role of the aromatase/p450arom". Seminars in Reproductive Medicine. 20 (3): 277–84. doi:10.1055/s-2002-35374. PMID 12428207. S2CID 25407830.
- Carreau S, Bourguiba S, Lambard S, Galeraud-Denis I (2003). "[Testicular aromatase]". Journal de la Société de Biologie. 196 (3): 241–4. doi:10.1051/jbio/2002196030241. PMID 12462076.
- Carani C, Fabbi M, Zirilli L, Sarbi I (2003). «[Эзоген, сопротивляющиеся ароматазам у людей]». Журнал Bilogia Societal . 196 (3): 245–8. Два : 10 1051/Jbio/2002196030245 . PMID 12462077 .
- Краги Л (август 2002 г.). «Ароматаза при приматах беременности: обзор». Эндокринные исследования . 28 (3): 121–8. doi : 10.1081/ERC-120015041 . PMID 12489562 . S2CID 8509882 .
- Симпсон ER (июль 2000 г.). «Биология ароматазы в молочной железе». Журнал биологии молочной железы и неоплазии . 5 (3): 251–8. doi : 10.1023/a: 1009590626450 . PMID 14973387 . S2CID 13296474 .
- Bulun SE, Takayama K, Suzuki T, Sasano H, Yilmaz B, Sebastian S (февраль 2004 г.). «Организация гена ароматазы человека P450 (CYP19)». Семинары в репродуктивной медицине . 22 (1): 5–9. doi : 10.1055/s-2004-823022 . PMID 15083376 . S2CID 260316748 .
- Симпсон ER (февраль 2004 г.). «Ароматаза: биологическая значимость тканевой специфической экспрессии». Семинары в репродуктивной медицине . 22 (1): 11–23. doi : 10.1055/s-2004-823023 . PMID 15083377 . S2CID 260319521 .
- Bulun SE, Fang Z, Imir G, Gurates B, Tamura M, Yilmaz B, et al. (Февраль 2004 г.). «Ароматаза и эндометриоз». Семинары в репродуктивной медицине . 22 (1): 45–50. doi : 10.1055/s-2004-823026 . PMID 15083380 . S2CID 260319473 .
- Shozu M, Murakami K, Inoue M (февраль 2004 г.). «Ароматаза и лейомиома матки». Семинары в репродуктивной медицине . 22 (1): 51–60. doi : 10.1055/s-2004-823027 . PMID 15083381 . S2CID 260319833 .
- Chen S, Ye J, Kijima I, Kinoshita Y, Zhou D (май 2005 г.). «Положительная и отрицательная регуляция транскрипции экспрессии ароматазы в тканях рака молочной железы человека». Журнал стероидной биохимии и молекулярной биологии . 95 (1–5): 17–23. doi : 10.1016/j.jsbmb.2005.04.002 . PMID 15955695 . S2CID 22138523 .
- Lambard S, Silandre D, Delalande C, Denis-Galeraud I, Bourguiba S, Carreau S (май 2005 г.). «Ароматаза в яичке: экспрессия и роль в мужской размножении». Журнал стероидной биохимии и молекулярной биологии . 95 (1–5): 63–9. doi : 10.1016/j.jsbmb.2005.04.020 . PMID 16019206 . S2CID 40087589 .
- Bulun SE, Imir G, Utsunomiya H, Thung S, Gurates B, Tamura M, et al. (Май 2005 г.). «Ароматаза при эндометриозе и лейомиомате матки». Журнал стероидной биохимии и молекулярной биологии . 95 (1–5): 57–62. doi : 10.1016/j.jsbmb.2005.04.012 . PMID 16024248 . S2CID 37228186 .
- Lambard S, Carreau S (октябрь 2005 г.). «Ароматаза и эстрогены у мужчин мужского зародышевых клеток» . Международный журнал андрологии . 28 (5): 254–9. doi : 10.1111/j.1365-2605.2005.00546.x . PMID 16128984 .
- Эллем С.Дж., Рисбриджер Г.П. (март 2006 г.). «Ароматаза и рак простаты». Minerva Endocrinologica . 31 (1): 1–12. PMID 16498360 .
- Brueggemeier RW, Díaz-Cruz ES (март 2006 г.). «Связь между ароматазой и циклооксигеназами при раке молочной железы: потенциал для новых терапевтических подходов». Minerva Endocrinologica . 31 (1): 13–26. PMID 16498361 .
- Jongen VH, Hollema H, Van der Zee AG, Heineman MJ (март 2006 г.). «Ароматаза в контексте рака молочной железы и эндометрия. Обзор». Minerva Endocrinologica . 31 (1): 47–60. PMID 16498363 .
- Hiltunen M, Iivonen S, Soininen H (март 2006 г.). «Ароматазный фермент и болезнь Альцгеймера». Minerva Endocrinologica . 31 (1): 61-73. PMID 16498364 .
Внешние ссылки
[ редактировать ]- «Изучение гей -овцы в США может пролить свет на сексуальность» , через Wikinews , 15 августа 2005 года.
- человека CYP19A1 Расположение генома CYP19A1 и страница гена в браузере генома UCSC .
- Обзор всей структурной информации, доступной в PDB для Uniprot : P11511 (ароматаза) в PDBE-KB .
