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 11
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
[uredi | uredi izvor]Dužina 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 |
C: Cistein
D: Aspartat
E: Glutamat
F: Fenilalanin
G: Glicin
H: Histidin
I: Izoleucin
K: Lizin
L: Leucin
M: Metionin
N: Asparagin
P: Prolin
Q: Glutamin
R: Arginin
S: Serin
T: Treonin
V: Valin
- W: Triptofan
Y: Tirozin
Funkcija
[uredi | uredi izvor]Aldosteron-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 11
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]
![](https://upload.wikimedia.org/wikipedia/commons/thumb/3/36/Renin-angiotensin-aldosterone_system.svg/700px-Renin-angiotensin-aldosterone_system.svg.png)
Genetika
[uredi | uredi izvor]Aldosteron-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
[uredi | uredi izvor]![](https://upload.wikimedia.org/wikipedia/commons/thumb/7/71/ALDOSTERONESynthesis.svg/400px-ALDOSTERONESynthesis.svg.png)
Aldosteron-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
[uredi | uredi izvor]Aldosteron-sintaza pokazuje različitu katalitsku aktivnost tokom metabolizma svojih supstrata.[7] Slijede neki supstrati, grupiraniprema katalitskoj aktivnosti enzima:
Nedostatak metil-oksidaze
[uredi | uredi izvor]Nedostatak 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
[uredi | uredi izvor]Inhibicija 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
[uredi | uredi izvor]Reference
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- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000075604 - 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.
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- ^ "CYP11B2". Pristupljeno 17. 9. 2013.
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β -hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway". The Journal of Steroid Biochemistry and Molecular Biology. 178: 203–212. doi:10.1016/j.jsbmb.2017.12.014. PMID 29277707. S2CID 3700135. - ^ Bassett MH, White PC, Rainey WE (mart 2004). "The regulation of aldosterone synthase expression". Molecular and Cellular Endocrinology. 217 (1–2): 67–74. doi:10.1016/j.mce.2003.10.011. PMID 15134803. S2CID 43133280.
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- ^ Lisboa BP, Gustafsson JA (juni 1969). "Biosynthesis of 18-hydroxytestosterone in the human foetal liver". European Journal of Biochemistry. 9 (3): 402–5. doi:10.1111/j.1432-1033.1969.tb00622.x. PMID 4307594.
- ^ Nakamura Y, Yamazaki Y, Tezuka Y, Satoh F, Sasano H (novembar 2016). "Expression of CYP11B2 in Aldosterone-Producing Adrenocortical Adenoma: Regulatory Mechanisms and Clinical Significance". The Tohoku Journal of Experimental Medicine. 240 (3): 183–190. doi:10.1620/tjem.240.183. PMID 27853054.
- ^ a b c Peter M, Fawaz L, Drop SL, Visser HK, Sippell WG (novembar 1997). "Hereditary defect in biosynthesis of aldosterone: aldosterone synthase deficiency 1964-1997". The Journal of Clinical Endocrinology and Metabolism. 82 (11): 3525–8. doi:10.1210/jc.82.11.3525. PMID 9360501.
- ^ a b c d Azizi M, Amar L, Menard J (januar 2013). "Aldosterone synthase inhibition in humans". Nephrology, Dialysis, Transplantation. 28 (1): 36–43. doi:10.1093/ndt/gfs388. PMID 23045428.
Dopunska literatura
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- Stowasser M, Gunasekera TG, Gordon RD (decembar 2001). "Familial varieties of primary aldosteronism". Clinical and Experimental Pharmacology & Physiology. 28 (12): 1087–90. doi:10.1046/j.1440-1681.2001.03574.x. PMID 11903322. S2CID 23091842.
- Padmanabhan N, Padmanabhan S, Connell JM (decembar 2000). "Genetic basis of cardiovascular disease--the renin-angiotensin-aldosterone system as a paradigm". Journal of the Renin-Angiotensin-Aldosterone System. 1 (4): 316–24. doi:10.3317/jraas.2000.060. PMID 11967817.
- Lifton RP, Dluhy RG, Powers M, Rich GM, Gutkin M, Fallo F, et al. (septembar 1992). "Hereditary hypertension caused by chimaeric gene duplications and ectopic expression of aldosterone synthase". Nature Genetics. 2 (1): 66–74. doi:10.1038/ng0992-66. PMID 1303253. S2CID 975796.
- Mitsuuchi Y, Kawamoto T, Naiki Y, Miyahara K, Toda K, Kuribayashi I, et al. (januar 1992). "Congenitally defective aldosterone biosynthesis in humans: the involvement of point mutations of the P-450C18 gene (CYP11B2) in CMO II deficient patients". Biochemical and Biophysical Research Communications. 182 (2): 974–9. doi:10.1016/0006-291X(92)91827-D. PMID 1346492.
- Pascoe L, Curnow KM, Slutsker L, Connell JM, Speiser PW, New MI, White PC (septembar 1992). "Glucocorticoid-suppressible hyperaldosteronism results from hybrid genes created by unequal crossovers between CYP11B1 and CYP11B2". Proceedings of the National Academy of Sciences of the United States of America. 89 (17): 8327–31. Bibcode:1992PNAS...89.8327P. doi:10.1073/pnas.89.17.8327. PMC 49911. PMID 1518866.
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- Curnow KM, Tusie-Luna MT, Pascoe L, Natarajan R, Gu JL, Nadler JL, White PC (oktobar 1991). "The product of the CYP11B2 gene is required for aldosterone biosynthesis in the human adrenal cortex". Molecular Endocrinology. 5 (10): 1513–22. doi:10.1210/mend-5-10-1513. PMID 1775135.
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Vanjski linkovi
[uredi | uredi izvor]- 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