Aromataza
Aromataza, također zvana i estrogen-sintetaza ili estrogen-sintaza, je enzim odgovoran za ključni korak u biosintezi estrogena. To je CYP19A1, član superporodice citohrom P450 (EC broj | 1.14.14.1), u kojoj su monooksigenaze – katalizatori mnogih reakcije, uključenih u steroidogenezu. Aromataza je posebno odgovorna za aromatizaciju androgena u estrogene. Enzim aromataza može se naći u mnogim tkivima, uključujući gonade (granulozne ćelije, mozak, masno tkivo, placenta, krvni sudovi, koža i kosti, kao i u tkivima endometrioze, mioma maternice, raka dojke i raka endometrija. Važan je faktor u seksualnom razvoju.
Funkcija uredi
Aromataza je lokalizirana u endoplazmatskom retikulumu, gdje se regulira tkivno specifičnim promotorima koje zauzvrat kontroliraju hormoni, citokini i drugi činitelji. Katalizira posljednje korake biosinteze estrogena iz androgena (konkretno, pretvara androstenedion u estron i testosteron u estradiol). Ovi koraci uključuju tri uzastopne hidroksilacije 19-metilne grupee androgena, nakon čega slijedi istodobno uklanjanje metilne grupe, kao formata i aromatizacija A-prstena.
- Androstenedion + 3O2 + 3NADPH + 3H+ Estron + Format + 4H2O + 3NADP+
- Testosteron + 3O2 + 3NADPH + 3H+ 17β-estradiol + Format + 4H2O + 3NADP+
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Ispoljavanje uredi
Aromataza se izražava u gonadama, posteljici, mozgu, masnom tkivu, kostima i drugim tkivima. Gotovo se ne može otkriti u jetri odraslog čovjeka.[6]
Genomika uredi
Odgovarajući gen eksprimira dvije varijante prijepisa (transkripta).[7] U ljudi, gen CYP19, koji kodira aromatazu, smješten na hromosomu 15, dugi krak: q21.1.[8] Gen ima devet kodirajućih egzona i niz alternativnih nekodirajućih prvih egzona koji reguliraju tkivno specifičnu.[9]
CYP19 prisutan je u rano divergirajućim hordatima, cefalohordatima amfioksusu (floridske Lanceleolata, Branchiostoma floridae ), ali ne i u ranijim divergentnim tunikatima Ciona intestinalis. Dakle, gen aromataze pojavio se rano u evoluciji hordata i čini se da nije prisutan kod nehordata beskičmenjaka (npr. Insekti, mehkušci, bodljošošci, morske spužve, koral i). Međutim, estrogeni mogu se sintetizirati u nekim od ovih organizama, drugim nepoznatim putevima.
Aktivnost uredi
Aktivnost aromataze smanjuje se za prolaktin, antimüllerov hormon i uobičajeni herbicid glifosat.[10] Aktivnost aromataze pojačana je u određenim estrogen-ovisnim lokalnim tkivima uz tkivo dojke, rak endometrija, endometrioze i mioma maternice.
Uloga u određivanju spola uredi
Aromataza je općenito vrlo prisutna tokom diferencijacije jajnika.[11][12] Također je osjetljiva na utjecaje okoline, posebno na temperaturu. U vrsta s određivanjem spola ovisnog o temperaturi, aromataza se izražava u većim količinama na temperaturama koje daju žensko potomstvo.[11] Unatoč činjenici da podaci sugeriraju temperaturnu kontrolu količine aromataze, druge studije su pokazale da aromataza može nadjačati učinke temperature: ako je izložen većem broju aromataze na temperaturi kod mužjaka, organizam će postati ženka i obratno, ako je izložen manjoj količini aromataze na temperaturama koje proizvode ženke, organizam će razviti mužjaka (vidi reverzija spola).[11] U organizmima koji se razvijaju genetičkim određivanjem spola, temperatura ne utiče na ekspresiju i funkciju aromataze, što sugerira da je aromataza ciljna molekula temperature za vrijeme TSD [11]. Razlikuje se od vrste do vrste da li je to protein aromataza koji ima različitu aktivnost na različitim temperaturama ili je količina transkripcije koju prolazi gen aromataze ono što je osjetljivo na temperaturu, ali u oba slučaja, na različitim temperaturama, opaža se različit razvoj.[13]
Uloga u neurozaštiti uredi
U mozgu, aromataza izražava se obično samo u neuronima. Međutim, nakon penetrativne ozljede mozga i miša i zebraste zebe, pokazalo se da je izražena i u astrocitima.[14] Također se pokazalo da smanjuje učestalost apoptoza nakon ozljede mozga u zebrastih zeba.[15] Smatra se da je to posljedica neuroprotektivnog djelovanja estrogena, uključujući estradiol. Istraživanje je pokazalo da su dva proupalna citokina, interleukin-1β (IL-1β) i interleukin-6 (IL-6) odgovorna za indukciju ekspresije aromataze u astrocitima, nakon penetrativne ozljede mozga kod zebrastih zeba.[16]
Poremećaji uredi
Sindrom viška aromataze uredi
Brojni istražitelji izvijestili su o prilično rijetkom sindromu prekomjerne aktivnosti aromataze. Kod dječaka stvara ginekomastiju, a kod djevojčica prijevremeni pubertet i gigantomastiju. U oba spola, rano zatvaranje epifize dovodi do niskog rasta. Ovo stanje posljedica je mutacija gena CYP19A1 koji kodira aromatazu.[17] Nasljeđuje se kao autosomno dominantno svojstvo.[18] Pretpostavlja se da su faraon Akhenaten i drugi članovi njegove porodice mogli patiti od ovog poremećaja,[19] ali novije genetičko testiranje sugerira suprotno.[20] To je jedan od uzroka porodičnog prijevremenog puberteta – stanja koje je prvi put opisano 1937.[21]
Sindrom nedostatka aromataze uredi
Ovaj sindrom je posljedica mutacije gena CYP19 i nasljeđuje se kao autosomno recesivno obilježje. Akumulacije androgena tokom trudnoće mogu dovesti do virilizacije ženke pri rođenju (to ne utiče na muškarce). Žene će imati primarnu amenoreju. Osobe oba spola bit će visoke, jer nedostatak estrogena ne dovodi do zatvaranja epifiznih linija.
Inhibicija aromataze uredi
Inhibicija aromataze može uzrokovati hipoestrogenizam (niska razina estrogena). Utvrđeno je da sljedeći prirodni proizvodi imaju inhibirajući učinak na aromatazu.
Ekstrakti nekih pčečurki (varijeteti „bijelog dugmeta“: Agaricus bisporus), gljiva pokazali su da inhibiraju aromatazu in vitro .[32]
Farmaceutski inhibitori aromataze uredi
Inhibitori aromataze, koji zaustavljaju proizvodnju estrogena u postmenopauzi žena postali su korisni u liječenju pacijenata s karcinomom dojke za koje je utvrđeno da su pozitivne za receptor estrogena.[33] Inhibitori koji se sada koriste u kliničkoj primjeni uključuju anastrozol, eksemestan i letrozol. Inhibitori aromataze također se počinju propisivati za muškarce u nadomjesnoj terapiji testosteronom, kao načinom da se razina estrogena ne povisi nakon uvođenja doza testosterona u njihov sistem.
Također pogledajte uredi
Reference uredi
- ^ a b c GRCh38: Ensembl release 89: ENSG00000137869 - Ensembl, maj 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000032274 - Ensembl, maj 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". u Fisher M, Lee JK, Obach RE (ured.). 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 (juni 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.
- ^ Gasnier C, Dumont C, Benachour N, Clair E, Chagnon MC, Séralini GE (august 2009). "Glyphosate-based herbicides are toxic and endocrine disruptors in human cell lines". Toxicology. 262 (3): 184–91. doi:10.1016/j.tox.2009.06.006. PMID 19539684.
- ^ 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. 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 (mart 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.
- ^ 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 (juli 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, Hanaki K, Kanzaki S, Ohyama K, Sano T, Nishigaki T, Yokoya S, Binder G, Horikawa R, Ogata T (juni 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.
- ^ Seshadri KG (maj 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 (jezik: poljski). 12 (1): 53–8. PMID 16704862.
- ^ 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, Yamada K, Aoki N (juli 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 (maj 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. PMID 16611391.
- ^ Le Bail JC, Pouget C, Fagnere C, Basly JP, Chulia AJ, Habrioux G (januar 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 (oktobar 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 (juli 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, Wertz K (juni 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.
- ^ 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, Shrode GE, Belury M, Adams LS, Williams D (decembar 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.
Dopunska literatura uredi
- Attar E, Bulun SE (maj 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 (juni 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, Speed C, Jones M (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, Sebastian S (decembar 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.
- Balthazart J, Baillien M, Ball GF (decembar 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.
- Richards JA, Petrel TA, Brueggemeier RW (februar 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.
- Balthazart J, Baillien M, Ball GF (maj 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. PMID 12053085.
- Carreau S, Bourguiba S, Lambard S, Galeraud-Denis I, Genissel C, Levallet J (juli 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.
- 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.
- 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, Sgarbi I (2003). "[Estrogen resistance and aromatase deficiency in humans]". Journal de la Société de Biologie. 196 (3): 245–8. doi:10.1051/jbio/2002196030245. PMID 12462077.
- Kragie L (august 2002). "Aromatase in primate pregnancy: a review". Endocrine Research. 28 (3): 121–8. doi:10.1081/ERC-120015041. PMID 12489562.
- Simpson ER (juli 2000). "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, Sasano H, Yilmaz B, Sebastian S (februar 2004). "Organization of the human aromatase p450 (CYP19) gene". Seminars in Reproductive Medicine. 22 (1): 5–9. doi:10.1055/s-2004-823022. PMID 15083376.
- Simpson ER (februar 2004). "Aromatase: biologic relevance of tissue-specific expression". Seminars in Reproductive Medicine. 22 (1): 11–23. doi:10.1055/s-2004-823023. PMID 15083377.
- Bulun SE, Fang Z, Imir G, Gurates B, Tamura M, Yilmaz B, Langoi D, Amin S, Yang S, Deb S (februar 2004). "Aromatase and endometriosis". Seminars in Reproductive Medicine. 22 (1): 45–50. doi:10.1055/s-2004-823026. PMID 15083380.
- Shozu M, Murakami K, Inoue M (februar 2004). "Aromatase and leiomyoma of the uterus". Seminars in Reproductive Medicine. 22 (1): 51–60. doi:10.1055/s-2004-823027. PMID 15083381.
- Chen S, Ye J, Kijima I, Kinoshita Y, Zhou D (maj 2005). "Positive and negative transcriptional regulation of aromatase expression in human breast cancer tissue". The Journal of Steroid Biochemistry and Molecular Biology. 95 (1–5): 17–23. doi:10.1016/j.jsbmb.2005.04.002. PMID 15955695.
- Lambard S, Silandre D, Delalande C, Denis-Galeraud I, Bourguiba S, Carreau S (maj 2005). "Aromatase in testis: expression and role in male reproduction". The Journal of Steroid Biochemistry and Molecular Biology. 95 (1–5): 63–9. doi:10.1016/j.jsbmb.2005.04.020. PMID 16019206.
- Bulun SE, Imir G, Utsunomiya H, Thung S, Gurates B, Tamura M, Lin Z (maj 2005). "Aromatase in endometriosis and uterine leiomyomata". The Journal of Steroid Biochemistry and Molecular Biology. 95 (1–5): 57–62. doi:10.1016/j.jsbmb.2005.04.012. PMID 16024248.
- Lambard S, Carreau S (oktobar 2005). "Aromatase and oestrogens in human male germ cells". International Journal of Andrology. 28 (5): 254–9. doi:10.1111/j.1365-2605.2005.00546.x. PMID 16128984.
- Ellem SJ, Risbridger GP (mart 2006). "Aromatase and prostate cancer". Minerva Endocrinologica. 31 (1): 1–12. PMID 16498360.
- Brueggemeier RW, Díaz-Cruz ES (mart 2006). "Relationship between aromatase and cyclooxygenases in breast cancer: potential for new therapeutic approaches". Minerva Endocrinologica. 31 (1): 13–26. PMID 16498361.
- Jongen VH, Hollema H, Van Der Zee AG, Heineman MJ (mart 2006). "Aromatase in the context of breast and endometrial cancer. A review". Minerva Endocrinologica. 31 (1): 47–60. PMID 16498363.
- Hiltunen M, Iivonen S, Soininen H (mart 2006). "Aromatase enzyme and Alzheimer's disease". Minerva Endocrinologica. 31 (1): 61–73. PMID 16498364.
Vanjski linkovi uredi
- n:U.S. study of gay sheep may shed light on sexuality|", via WikiNews, 15 August 2005.
- https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&lastVirtModeType=default&lastVirtModeExtraState=&virtModeType=default&virtMode=0&nonVirtPosition=&position=chr15%3A51208057%2D51338596&hgsid=996683881_ajzaeDmb6Of0b3q4jGdjdV5amC0V
- https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_type=knownGene&hgg_gene=CYP19A1
- P11511
Šablon:Steroidne hidroksilaze Šablon:Citohrom Šablon:Oksigenaze
