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
[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 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
[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]
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
[uredi | uredi izvor]- ^ a b c GRCh38: Ensembl release 89: ENSG00000179142 - Ensembl, maj 2017
- ^ 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.
- ^ a b c d 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.
- ^ Peter M, Dubuis JM, Sippell WG (1999). "Disorders of the aldosterone synthase and steroid 11beta-hydroxylase deficiencies". Hormone Research. 51 (5): 211–22. doi:10.1159/000023374. PMID 10559665. S2CID 24182379.
- ^ a b c d e f Strushkevich N, Gilep AA, Shen L, Arrowsmith CH, Edwards AM, Usanov SA, Park HW (februar 2013). "Structural insights into aldosterone synthase substrate specificity and targeted inhibition". Molecular Endocrinology. 27 (2): 315–24. doi:10.1210/me.2012-1287. PMC 5417327. PMID 23322723.
- ^ "UniProt, P19099" (jezik: engleski). Pristupljeno 16. 9. 2021.
- ^ Pascoe L, Curnow KM, Slutsker L, Rösler A, White PC (juni 1992). "Mutations in the human CYP11B2 (aldosterone synthase) gene causing corticosterone methyloxidase II deficiency". Proceedings of the National Academy of Sciences of the United States of America. 89 (11): 4996–5000. Bibcode:1992PNAS...89.4996P. doi:10.1073/pnas.89.11.4996. PMC 4921. PMID 1594605.
- ^ Brown RD, Strott CA, Liddle GW (juni 1972). "Site of stimulation of aldosterone biosynthesis by angiotensin and potassium". The Journal of Clinical Investigation. 51 (6): 1413–8. doi:10.1172/JCI106937. PMC 292278. PMID 4336939.
- ^ Mornet E, Dupont J, Vitek A, White PC (decembar 1989). "Characterization of two genes encoding human steroid 11 beta-hydroxylase (P-450(11) beta)". The Journal of Biological Chemistry. 264 (35): 20961–7. doi:10.1016/S0021-9258(19)30030-4. PMID 2592361.
- ^ "CYP11B2". Pristupljeno 17. 9. 2013.
- ^ Williams GH (januar 2005). "Aldosterone biosynthesis, regulation, and classical mechanism of action". Heart Failure Reviews. 10 (1): 7–13. doi:10.1007/s10741-005-2343-3. PMID 15947886. S2CID 19588366.
- ^ "CYP11B1". Genetics Home Reference. U.S. National Library of Medicine. Sep 2013.
- ^ a b c d e f g h van Rooyen D, Gent R, Barnard L, Swart AC (april 2018). "The in vitro metabolism of 11β-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.
- ^ Lenders JW, Williams TA, Reincke M, Gomez-Sanchez CE (januar 2018). "DIAGNOSIS OF ENDOCRINE DISEASE: 18-Oxocortisol and 18-hydroxycortisol: is there clinical utility of these steroids?". European Journal of Endocrinology. 178 (1): R1–R9. doi:10.1530/EJE-17-0563. PMC 5705277. PMID 28904009.
- ^ Freel EM, Shakerdi LA, Friel EC, Wallace AM, Davies E, Fraser R, Connell JM (septembar 2004). "Studies on the origin of circulating 18-hydroxycortisol and 18-oxocortisol in normal human subjects". The Journal of Clinical Endocrinology and Metabolism. 89 (9): 4628–33. doi:10.1210/jc.2004-0379. PMC 1283128. PMID 15356073.
- ^ 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
[uredi | uredi izvor]- Helmberg A (august 1993). "Twin genes and endocrine disease: CYP21 and CYP11B genes". Acta Endocrinologica. 129 (2): 97–108. doi:10.1530/acta.0.1290097. PMID 8372604.
- Slight SH, Joseph J, Ganjam VK, Weber KT (juni 1999). "Extra-adrenal mineralocorticoids and cardiovascular tissue". Journal of Molecular and Cellular Cardiology. 31 (6): 1175–84. doi:10.1006/jmcc.1999.0963. PMID 10371693.
- 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.
- Pascoe L, Curnow KM, Slutsker L, Rösler A, White PC (juni 1992). "Mutations in the human CYP11B2 (aldosterone synthase) gene causing corticosterone methyloxidase II deficiency". Proceedings of the National Academy of Sciences of the United States of America. 89 (11): 4996–5000. Bibcode:1992PNAS...89.4996P. doi:10.1073/pnas.89.11.4996. PMC 49215. PMID 1594605.
- Kawamoto T, Mitsuuchi Y, Toda K, Yokoyama Y, Miyahara K, Miura S, et al. (februar 1992). "Role of steroid 11 beta-hydroxylase and steroid 18-hydroxylase in the biosynthesis of glucocorticoids and mineralocorticoids in humans". Proceedings of the National Academy of Sciences of the United States of America. 89 (4): 1458–62. Bibcode:1992PNAS...89.1458K. doi:10.1073/pnas.89.4.1458. PMC 48470. PMID 1741400.
- 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.
- Kawainoto T, Mitsuuchi Y, Ohnishi T, Ichikawa Y, Yokoyama Y, Sumimoto H, et al. (novembar 1990). "Cloning and expression of a cDNA for human cytochrome P-450aldo as related to primary aldosteronism". Biochemical and Biophysical Research Communications. 173 (1): 309–16. doi:10.1016/S0006-291X(05)81058-7. PMID 2256920.
- Mornet E, Dupont J, Vitek A, White PC (decembar 1989). "Characterization of two genes encoding human steroid 11 beta-hydroxylase (P-450(11) beta)". The Journal of Biological Chemistry. 264 (35): 20961–7. doi:10.1016/S0021-9258(19)30030-4. PMID 2592361.
- Martsev SP, Chashchin VL, Akhrem AA (februar 1985). "[Reconstruction and study of a multi-enzyme system by 11 beta-hydroxylase steroids]". Biokhimiia. 50 (2): 243–57. PMID 3872685.
- Shizuta Y, Kawamoto T, Mitsuuchi Y, Miyahara K, Rösler A, Ulick S, Imura H (januar 1995). "Inborn errors of aldosterone biosynthesis in humans". Steroids. 60 (1): 15–21. doi:10.1016/0039-128X(94)00023-6. PMID 7792802. S2CID 23433739.
- Mitsuuchi Y, Kawamoto T, Miyahara K, Ulick S, Morton DH, Naiki Y, et al. (februar 1993). "Congenitally defective aldosterone biosynthesis in humans: inactivation of the P-450C18 gene (CYP11B2) due to nucleotide deletion in CMO I deficient patients". Biochemical and Biophysical Research Communications. 190 (3): 864–9. doi:10.1006/bbrc.1993.1128. PMID 8439335.
- Fardella CE, Rodriguez H, Montero J, Zhang G, Vignolo P, Rojas A, et al. (decembar 1996). "Genetic variation in P450c11AS in Chilean patients with low renin hypertension". The Journal of Clinical Endocrinology and Metabolism. 81 (12): 4347–51. doi:10.1210/jc.81.12.4347. PMID 8954040.
- Nomoto S, Massa G, Mitani F, Ishimura Y, Miyahara K, Toda K, et al. (maj 1997). "CMO I deficiency caused by a point mutation in exon 8 of the human CYP11B2 gene encoding steroid 18-hydroxylase (P450C18)". Biochemical and Biophysical Research Communications. 234 (2): 382–5. doi:10.1006/bbrc.1997.6651. PMID 9177280.
- Taymans SE, Pack S, Pak E, Torpy DJ, Zhuang Z, Stratakis CA (mart 1998). "Human CYP11B2 (aldosterone synthase) maps to chromosome 8q24.3". The Journal of Clinical Endocrinology and Metabolism. 83 (3): 1033–6. doi:10.1210/jc.83.3.1033. PMID 9506770.
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