CYP11B1
Steroid 11β-monooksigenaza | |
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Identifikatori | |
Simbol | ? |
CAS broj |
Steroid 11β-hidroksilaza, znana i kao steroid 11β-monooksigenaza, je enzim steroid-hidrokslaza u zona glomerulosa i zona fasciculata u kori nadbubrežne žlijezde. Službeno je imenovana kao mitohondrijski citohrom P450 11B1, protein koji je kod ljudi kodiran genom CYP11B1.[5][6] Enzim je uključen u biosintezu nadbubrežnih kortikosteroida[7] katalizirajući dodavanja hidroksilne grupe tokom reakcija oksidacije.
Aminokiselinska sekvenca
[uredi | uredi izvor]Dužina polipeptidnog lanca je 503 aminokiseline, а molekulska težina 57.573 Da.[8]
10 | 20 | 30 | 40 | 50 | ||||
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MALRAKAEVC | MAVPWLSLQR | AQALGTRAAR | VPRTVLPFEA | MPRRPGNRWL | ||||
RLLQIWREQG | YEDLHLEVHQ | TFQELGPIFR | YDLGGAGMVC | VMLPEDVEKL | ||||
QQVDSLHPHR | MSLEPWVAYR | QHRGHKCGVF | LLNGPEWRFN | RLRLNPEVLS | ||||
PNAVQRFLPM | VDAVARDFSQ | ALKKKVLQNA | RGSLTLDVQP | SIFHYTIEAS | ||||
NLALFGERLG | LVGHSPSSAS | LNFLHALEVM | FKSTVQLMFM | PRSLSRWTSP | ||||
KVWKEHFEAW | DCIFQYGDNC | IQKIYQELAF | SRPQQYTSIV | AELLLNAELS | ||||
PDAIKANSME | LTAGSVDTTV | FPLLMTLFEL | ARNPNVQQAL | RQESLAAAAS | ||||
ISEHPQKATT | ELPLLRAALK | ETLRLYPVGL | FLERVASSDL | VLQNYHIPAG | ||||
TLVRVFLYSL | GRNPALFPRP | ERYNPQRWLD | IRGSGRNFYH | VPFGFGMRQC | ||||
LGRRLAEAEM | LLLLHHVLKH | LQVETLTQED | IKMVYSFILR | PSMFPLLTFR | ||||
AIN |
Gen
[uredi | uredi izvor]Gen CYP11B1 kodira 11β -hidroksilazu – člana nadporodice enzima citohromi P450. Proteini citohroma P450 su monooksigenaze, koje kataliziraju mnoge reakcije uključene u metabolizam lijekova i sintezu holesterola, steroida i drugih lipida. Proizvod ovog gena CYP11B1 je protein 11β-hidroksilaza. Ovaj protein nalazi se u unutrašnjoj membrani mitohondrija i uključen je u pretvorbu različitih steroida u kori nadbubrežne žlijezde. Za ovaj gen zabilježene su varijante transkripta koje kodiraju različite izoforme[6]
Gen CYP11B1 se reverzibilno inhibira etomidatom[9][10] i metiraponom.
Funkcija
[uredi | uredi izvor]11β-hidroksilaza je steroidogeni enzim, tj. enzim uključen u metabolizam steroida.
Ljudi imaju dva izoenzima sa 11β-hidroksilaznom aktivnošću: CYP11B1 i CYP11B2.
CYP11B1 (11β-hidroksilaza) eksprimiran je na visokim nivoima i reguliran je preko ACTH, dok je CYP11B2 (aldosteron-sintaza) obično ispoljena na niskim razinama i reguliran je angiotenzinom II. Osim aktivnosti 11β-hidroksilaze, oba izozima imaju i aktivnost 18-hidroksilaza.[11] Izozim CYP11B1 ima snažnu aktivnost 11β-hidroksilaze, ali je aktivnost 18-hidroksilaze samo jedna desetina CYP11B2.[12] Slaba aktivnost CYP11B1 18-hidroksilaze objašnjava zašto nadbubrežna žlijezda s potisnutom ekspresijom CYP11B2 nastavlja sintetizirati 18-hidroksikortikosteron.[13]
Slijedi neki steroidi, grupirani prema katalitskoj aktivnosti izoenzima CYP11B1:
Osim toga, 11β-hidroksilaza može biti uključena i u metabolizam 17α-hidroksiprogesterona u 21-deoksikortizol,[18] posebno u slučajevima nedostatka hidroksilaze 21.[25]
Metabolizam kortizola i kortikosterona
[uredi | uredi izvor]11β-hidroksilaza ima jaku [14] katalitsku aktivnost tokom konverzije 11-deoksikortizola u kortizol i 11-deoksikortikosterona u kortikosteron, katalizom hidroksilacije ugljikove vodikove veze na položaju 11-beta. Obratiti pažnju na dodatni "–OH" na poziciji 11 (blizu centra, na prstenu "C"):
Mehanizam djelovanja
[uredi | uredi izvor]Kao mitohondrijski P450 sistem, P450c11 ovisi o dva proteina za prijenos elektrona, adrenodoksin reduktazi i adrenodoksinu koji prenose dva elektrona iz NADPH u P450 za svaku reakciju monooksigenaze koju katalizira enzim. U većini aspekata ovaj proces prijenosa elektrona izgleda sličan onom u P450scc-sistemu koji katalizira cijepanje bočnog lanca holesterola.[26] Slično kao kod P450scc, proces prijenosa elektrona propušta, što dovodi do stvaranja superoksida. Brzina curenja elektrona tokom metabolizma ovisi o funkcionalnim skupinama supstrata steroida.[27]
Regulacija
[uredi | uredi izvor]Ekspresiju enzima u adrenokorteksnim ćelijama regulira trofni hormon kortikotropin (ACTH).[28]
Klinički značaj
[uredi | uredi izvor]Mutacija odgovarajućeg gena povezana je s poremećajem zvanim kongenitalna adrenalna hiperplazija zbog nedostatka 11β-hidroksilaze.
Također pogledajte
[uredi | uredi izvor]Dodatne slike
[uredi | uredi izvor]![](http://178.128.105.246/content-http-upload.wikimedia.org/wikipedia/commons/thumb/1/13/Steroidogenesis.svg/500px-Steroidogenesis.svg.png)
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Biosintetski put kortikosteroida u biopsiji pacova
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Numeracija steroida
Reference
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This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the mitochondrial inner membrane and is involved in the conversion of progesterone to cortisol in the adrenal cortex. Mutations in this gene cause congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency. Transcript variants encoding different isoforms have been noted for this gene.
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CYP11B1 and 2 have also been shown to 11β-hydroxylate T, yielding 11β-hydroxytestosterone (11OHT), though the levels produced by the adrenal are low due to the limited availability of adrenal derived T
- ^ Stárka L, Dušková M, Vítků J (septembar 2020). "11-Keto-testosterone and other androgens of adrenal origin". Physiological Research. 69 (Suppl 2): S187–S192. doi:10.33549/physiolres.934516. PMID 33094617.
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- ^ Miller WL (2019). "Congenital Adrenal Hyperplasia: Time to Replace 17OHP with 21-Deoxycortisol". Hormone Research in Paediatrics. 91 (6): 416–420. doi:10.1159/000501396. PMID 31450227. S2CID 201733086.
- ^ Hanukoglu I, Privalle CT, Jefcoate CR (maj 1981). "Mechanisms of ionic activation of adrenal mitochondrial cytochromes P-450scc and P-45011 beta" (PDF). J. Biol. Chem. 256 (9): 4329–35. PMID 6783659.
- ^ Rapoport R, Sklan D, Hanukoglu I (mart 1995). "Electron leakage from the adrenal cortex mitochondrial P450scc and P450c11 systems: NADPH and steroid dependence". Arch. Biochem. Biophys. 317 (2): 412–6. doi:10.1006/abbi.1995.1182. PMID 7893157.
- ^ Hanukoglu I, Feuchtwanger R, Hanukoglu A (novembar 1990). "Mechanism of corticotropin and cAMP induction of mitochondrial cytochrome P450 system enzymes in adrenal cortex cells" (PDF). J. Biol. Chem. 265 (33): 20602–8. PMID 2173715.
Dopunska literatura
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Vanjski linkovi
[uredi | uredi izvor]- Steroid 11-beta-hydroxylase na US National Library of Medicine Medical Subject Headings (MeSH)
Šablon:Oksigenaze Šablon:Steroid hidroksilaze