Aromataza

CYP19A1
Dostupne strukture
PDB	Pretraga ortologa: PDBe RCSB
Spisak PDB ID kodova
	3EQM, 3S79, 3S7S, 4GL5, 4GL7, 4KQ8
Identifikatori
Aliasi	CYP19A1
Vanjski ID-jevi	OMIM: 107910 MGI: 88587 HomoloGene: 30955 GeneCards: CYP19A1
Lokacija gena (čovjek)
Hrom.	Hromosom 15 (čovjek)
Kraj	51,338,601 bp
Lokacija gena (miš)
Hrom.	Hromosom 9 (miš)
Kraj	54,175,394 bp
Obrazac RNK ekspresije
	Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija	• iron ion binding; • oxygen binding; • vezivanje iona metala; • monooxygenase activity; • heme binding; • GO:0050602 oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen; • electron transfer activity; • oxidoreductase activity; • aromatase activity; • oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen; • steroid hydroxylase activity;
Ćelijska komponenta	• endoplasmic reticulum membrane; • Endoplazmatski retikulum; • membrana; • integral component of membrane;
Biološki proces	• estrogen biosynthetic process; • androgen metabolic process; • negative regulation of chronic inflammatory response; • prostate gland growth; • sterol metabolic process; • negative regulation of macrophage chemotaxis; • steroid biosynthetic process; • female gonad development; • female genitalia development; • mammary gland development; • uterus development; • testosterone biosynthetic process; • androgen catabolic process; • positive regulation of estradiol secretion; • Lanac transporta elektrona;
	Izvori:Amigo / QuickGO
Ortolozi
	1588
	13075
	ENSG00000137869
	ENSMUSG00000032274
	P11511
	P28649
NM_000103; NM_001347248; NM_001347249; NM_001347250; NM_001347251;
	NM_001347252; NM_001347253; NM_001347254; NM_001347255; NM_001347256; NM_031226
	NM_007810; NM_001348171; NM_001348172; NM_001348173
NP_000094; NP_001334177; NP_001334178; NP_001334179; NP_001334180;
	NP_001334181; NP_001334182; NP_001334183; NP_001334184; NP_001334185; NP_112503
	NP_001335100; NP_001335101; NP_001335102; NP_031836
	Wikipodaci
Pogledaj/uredi – čovjek	Pogledaj/uredi – miš

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

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⁺

\rightleftharpoons

Estron + Format + 4H₂O + 3NADP⁺

Testosteron + 3O₂ + 3NADPH + 3H⁺

\rightleftharpoons

17β-estradiol + Format + 4H₂O + 3NADP⁺

Opća reakcija za pretvorbu testosterona u estradiol, katalizirana aromatazom. Steroidi se sastoje od četiri spojena prstena (označeni A-D). Aromataza pretvara prsten s oznakom "A" u aromatsko stanje.

Katalitski mehanizam aromataze. Metil grupa je oksidirana, a zatim eliminirana.^[5]

Ispoljavanje

Aromataza se izražava u gonadama, posteljici, mozgu, masnom tkivu, kostima i drugim tkivima. Gotovo se ne može otkriti u jetri odraslog čovjeka.^[6]

Genomika

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

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

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

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

Sindrom viška aromataze

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

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

Inhibicija aromataze može uzrokovati hipoestrogenizam (niska razina estrogena). Utvrđeno je da sljedeći prirodni proizvodi imaju inhibirajući učinak na aromatazu.

Inhibicijsko djelovanje ekstrakta nekih gljiva na aromatazu

Ekstrakti nekih pčečurki (varijeteti „bijelog dugmeta“: Agaricus bisporus), gljiva pokazali su da inhibiraju aromatazu in vitro .^[32]

Farmaceutski inhibitori aromataze

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

Reference

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Vanjski linkovi

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

Portal Biologija

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000137869 - Ensembl, maj 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000032274 - Ensembl, maj 2017

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[urlAromatase_Inhibitors-33] "Aromatase Inhibitors". Breastcancer.org.

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