CYP11B2
Aldosteron-sintaza, zvana i steroid 18-hidroksilaza, kortikosteron 18-monooksigenaza ili P450C18, je steroidna hidroksilazni enzim citohrom P450 uključen u biosintezu mineralokortikoida aldosterona i drugih steroida. Enzim katalizira sekvencne hidroksilacije steroidne ugaone metilne grupe na C18, nakon početne 11β-hidroksilacije (enzim ima steroidnu 18-hidroksilaznu aktivnost, kao i steroidnu 11 beta-hidroksilaznu aktivnost). Kod ljudi kodiran je genom "'CYP11B2'".
Aldosteron-sintaza je protein koji se eksprimira samo u strukturi zvanoj zona glomerulosa[5] kore nadbubrežne žlijezde i primarno je reguliran sistemom renin -angiotenzinskim sistemom.[6] To je jedini enzim koji u ljudi može sintetizirati aldosteron i ima važnu ulogu u ravnoteži elektrolita i krvnog pritiska.[7]
Aminokiselinska sekvenca
urediDužina polipeptidnog lanca je 503 aminokiseline, а molekulska težina 57.560 Da.[8]
10 | 20 | 30 | 40 | 50 | ||||
---|---|---|---|---|---|---|---|---|
MALRAKAEVC | VAAPWLSLQR | ARALGTRAAR | APRTVLPFEA | MPQHPGNRWL | ||||
RLLQIWREQG | YEHLHLEMHQ | TFQELGPIFR | YNLGGPRMVC | VMLPEDVEKL | ||||
QQVDSLHPCR | MILEPWVAYR | QHRGHKCGVF | LLNGPEWRFN | RLRLNPDVLS | ||||
PKAVQRFLPM | VDAVARDFSQ | ALKKKVLQNA | RGSLTLDVQP | SIFHYTIEAS | ||||
NLALFGERLG | LVGHSPSSAS | LNFLHALEVM | FKSTVQLMFM | PRSLSRWISP | ||||
KVWKEHFEAW | DCIFQYGDNC | IQKIYQELAF | NRPQHYTGIV | AELLLKAELS | ||||
LEAIKANSME | LTAGSVDTTA | FPLLMTLFEL | ARNPDVQQIL | RQESLAAAAS | ||||
ISEHPQKATT | ELPLLRAALK | ETLRLYPVGL | FLERVVSSDL | VLQNYHIPAG | ||||
TLVQVFLYSL | GRNAALFPRP | ERYNPQRWLD | IRGSGRNFHH | VPFGFGMRQC | ||||
LGRRLAEAEM | LLLLHHVLKH | FLVETLTQED | IKMVYSFILR | PGTSPLLTFR | ||||
AIN |
Funkcija
urediAldosteron-sintaza je enzim koji ima steroidnu 18-hidroksilaznu, kao i steroidnu 11 beta-hidroksilaznu aktivnost. Aktivnost 18-hidroksilaze sastoji se u kataliziranju sekvencijalnih hidroksilacija steroidne ugaone metilne grupe na C18.
Dok steroidna 11β-hidroksilaza (kodirana genom CYP11B1 ) katalizira samo hidroksilaciju na poziciji 11 beta (uglavnom 11-deoksikortikosterona i 11-deoksikortizola), aldosteron-sintaza (kodirana genom CYP11B2 ) katalizira sintezu aldosterona iz deoksikortikosterona, u procesu koji sukcesivno zahtijeva hidroksilaciju na pozicijama 11 beta i 18 i oksidaciju na poziciji 18.[9]
Pretpostavlja se da u regulaciji aldosteron-sintaze ima ulogu adrenokortikotropni hormon, vjerovatno stimulacijom sinteze 11-deoksikortikosterona koji je početni supstrat enzimskog djelovanja aldosteron-sintaze.[10]
Genetika
urediAldosteron-sintaza je kodirana na hromosomu 8, sekvenca q22[5] genom CYP11B2.[5] Gen sadrži devet egzona i obuhvata približno 7000 parova baza DNK. CYP11B2 je usko povezan sa CYP11B1. Dva gena pokazuju 93% međusobne homologije i oba su kodirana na istom hromosomu.[11] Istraživanja su pokazala da kalcijeve ioni aktiviraju transkripcijski faktori na CYP11B2 kroz dobro definirane interakcije na 5'-bočnom području CYP11B2.[5]
Aldosteron-sintaza je član natporodice enzima citohroma P450.[12] Proteini citohroma P450 su monooksigenaze koje kataliziraju mnoge reakcije uključene u metabolizam lijekova i sintezu holesterola, steroida i drugih lipida.
Metabolizam
urediAldosteron-sintaza pretvara 11-deoksikortikosteron u kortikosteron, u 18-hidroksikortikosteron i na kraju u aldosteron
U ljudskom metabolizmu, biosinteza aldosterona uveliko ovisi o metabolizmu holesterola. Holesterol se metabolizira u onome što je poznato kao rani put sinteze aldosterona[13] i hidroksilira se u (20R, 22R)-dihidroksiholesterol, koji se zatim metabolizira kao direktni prekursor pregnenolona. Pregnenolon tada može slijediti jedan od dva puta koji uključuju metabolizam progesterona ili biosintezu testosterona i estradiola. Aldosteron se sintetizira prateći metabolizam progesterona.
U potencijalnom slučaju, kada aldosteron-sintaza nije metabolički aktivna, u tijelu se akumulira 11-deoksikortikosteron. Ovo povećava zadržavanje soli što dovodi do povećane hipertenzije.[14]
Podloge
urediAldosteron-sintaza pokazuje različitu katalitsku aktivnost tokom metabolizma svojih supstrata.[7] Slijede neki supstrati, grupiraniprema katalitskoj aktivnosti enzima:
Nedostatak metil-oksidaze
urediNedostatak metabolički aktivne aldosteron-sintaze dovodi do nedostatka kortikosteron metil-oksidaze tipa I i II. Klinički se nedostatak karakterizira trošenjem soli, neuspjehom u napredovanju i usporavanjem rasta.[21] Neaktivni proteini uzrokovani su autosomno recesivnim nasljeđivanjem defektnih gena CYP11B2 u kojima mutacije uništavaju enzimsku aktivnost aldosteron-sintaze.[21] Nedostatak aktivnosti aldosteron-sintaze dovodi do poremećaja biosinteze aldosterona, dok se kortikosteron prekomjerno proizvodi u zona glomerulosa u oba nedostatka kortikosteron metil-oksidaze tipa I i II. I nedostatak kortikosteron metil-oksidaze ima ovaj učinak, aki tip I uzrokuje ukupni nedostatak 18-hidroksikortikosterona, dok ga tip II pretjerano proizvodi.[21]
Enzimska inhibicija
urediInhibicija aldosteron-sintaze još se istražuje kao medicinski tretman za hipertenziju, srčanu insuficijenciju i bubrežni poremećaj.[22] Deaktivacija enzimske aktivnosti smanjuje koncentraciju aldosterona u plazmi i tkivu, što smanjuje mineralokortikoidni receptor-ovisne i neovisne učinke na srčane vaskularne i bubrežne ciljne organe.[22] Pokazalo se da inhibicija smanjuje koncentracije plazmatskog i mokraćnog aldosterona za 70 - 80%, brzu korekciju hipoglikemije, umjereno smanjenje krvnog pritiska i povećanje aktivnosti renina u plazmi kod pacijenata koji su na dijeti s niskim udjelom natrija.[22] Tekuća medicinska istraživanja usredotočena su na sintezu inhibitora aldosteron-sintaze druge generacije, kako bi se stvorio idealno selektivan inhibitor jer se trenutni, oralno isporučljivi, LCl699 pokazao nespecifičnim za aldosteron-sintazu.[22]
Također pogledajte
urediReference
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- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000075604 - Ensembl, maj 2017
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- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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Vanjski linkovi
uredi- Aldosterone synthase na US National Library of Medicine Medical Subject Headings (MeSH)
- Lokacija ljudskog genoma CPN2 i stranica sa detaljima o genu CPN2 u UCSC Genome Browseru.
- Lokacija ljudskog genoma CYP11B2 i stranica sa detaljima o genu CYP11B2 u UCSC Genome Browseru.
Šablon:Oksigenaze Šablon:Steroidne hidroksilaze Šablon:Cytochrome P450