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.

CYP11B1
Identifikatori
AliasiCYP11B1
Vanjski ID-jeviOMIM: 610613 MGI: 88584 HomoloGene: 128035 GeneCards: CYP11B1
EC broj1.14.15.4
Lokacija gena (čovjek)
Hromosom 8 (čovjek)
Hrom.Hromosom 8 (čovjek)[1]
Hromosom 8 (čovjek)
Genomska lokacija za CYP11B1
Genomska lokacija za CYP11B1
Bend8q24.3Početak142,872,356 bp[1]
Kraj142,879,846 bp[1]
Lokacija gena (miš)
Hromosom 15 (miš)
Hrom.Hromosom 15 (miš)[2]
Hromosom 15 (miš)
Genomska lokacija za CYP11B1
Genomska lokacija za CYP11B1
Bend15 D3|15 34.29 cMPočetak74,722,859 bp[2]
Kraj74,728,167 bp[2]
Obrazac RNK ekspresije
Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija iron ion binding
corticosterone 18-monooxygenase activity
vezivanje iona metala
monooxygenase activity
GO:0050602 oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen
oxidoreductase activity
steroid 11-beta-monooxygenase activity
heme binding
Ćelijska komponenta membrana
mitochondrial membranes
mitohondrija
mitochondrial inner membrane
Biološki proces glucose homeostasis
lipid metabolism
aldosterone biosynthetic process
cortisol biosynthetic process
regulation of blood pressure
C21-steroid hormone biosynthetic process
cellular response to hormone stimulus
glucocorticoid biosynthetic process
GO:0046730, GO:0046737, GO:0046738, GO:0046736 Imuni odgovor
sterol metabolic process
cellular response to potassium ion
steroid biosynthetic process
steroid metabolic process
cholesterol metabolic process
cellular response to peptide hormone stimulus
cortisol metabolic process
Izvori:Amigo / QuickGO
Ortolozi
VrsteČovjekMiš
Entrez
Ensembl
UniProt
RefSeq (mRNK)

NM_000497
NM_001026213

NM_009991

RefSeq (bjelančevina)

NP_000488
NP_001021384

NP_034121

Lokacija (UCSC)Chr 8: 142.87 – 142.88 MbChr 15: 74.72 – 74.73 Mb
PubMed pretraga[3][4]
Wikipodaci
Pogledaj/uredi – čovjekPogledaj/uredi – miš
Steroid 11β-monooksigenaza
Identifikatori
Simbol?
CAS broj9029-66-7

Aminokiselinska sekvenca

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Dužina polipeptidnog lanca je 503 aminokiseline, а molekulska težina 57.573 Da.[8]

1020304050
MALRAKAEVCMAVPWLSLQRAQALGTRAARVPRTVLPFEAMPRRPGNRWL
RLLQIWREQGYEDLHLEVHQTFQELGPIFRYDLGGAGMVCVMLPEDVEKL
QQVDSLHPHRMSLEPWVAYRQHRGHKCGVFLLNGPEWRFNRLRLNPEVLS
PNAVQRFLPMVDAVARDFSQALKKKVLQNARGSLTLDVQPSIFHYTIEAS
NLALFGERLGLVGHSPSSASLNFLHALEVMFKSTVQLMFMPRSLSRWTSP
KVWKEHFEAWDCIFQYGDNCIQKIYQELAFSRPQQYTSIVAELLLNAELS
PDAIKANSMELTAGSVDTTVFPLLMTLFELARNPNVQQALRQESLAAAAS
ISEHPQKATTELPLLRAALKETLRLYPVGLFLERVASSDLVLQNYHIPAG
TLVRVFLYSLGRNPALFPRPERYNPQRWLDIRGSGRNFYHVPFGFGMRQC
LGRRLAEAEMLLLLHHVLKHLQVETLTQEDIKMVYSFILRPSMFPLLTFR
AIN

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

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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

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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

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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

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Ekspresiju enzima u adrenokorteksnim ćelijama regulira trofni hormon kortikotropin (ACTH).[28]

Klinički značaj

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Mutacija odgovarajućeg gena povezana je s poremećajem zvanim kongenitalna adrenalna hiperplazija zbog nedostatka 11β-hidroksilaze.

Također pogledajte

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Dodatne slike

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Steroidogeneza, sa 11-beta-hidroksilazom, okomito na desnoj strani.

Reference

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  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000022589 - Ensembl, maj 2017
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  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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  6. ^ a b "Entrez Gene: CYP11B1 cytochrome P450, family 11, subfamily B, polypeptide 1". National Center for Biotechnology Information. Pristupljeno 30. 11. 2020. 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.
  7. ^ Zöllner A, Kagawa N, Waterman MR, Nonaka Y, Takio K, Shiro Y, et al. (februar 2008). "Purification and functional characterization of human 11beta hydroxylase expressed in Escherichia coli". The FEBS Journal. 275 (4): 799–810. doi:10.1111/j.1742-4658.2008.06253.x. PMID 18215163. S2CID 45997341.
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  15. ^ a b c d e 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.
  16. ^ Mello, Penachioni, Amaral, Castro (oktobar 2004). "11beta-hydroxylase deficiency". Arquivos Brasileiros de Endocrinologia e Metabologia (jezik: portugalski). 48 (5): 713–23. doi:10.1590/s0004-27302004000500018. PMID 15761543.
  17. ^ Bulsari K, Falhammar H (januar 2017). "Clinical perspectives in congenital adrenal hyperplasia due to 11β-hydroxylase deficiency". Endocrine. 55 (1): 19–36. doi:10.1007/s12020-016-1189-x. PMID 27928728. S2CID 11153844.
  18. ^ a b Turcu AF, Rege J, Chomic R, Liu J, Nishimoto HK, Else T, et al. (juni 2015). "Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency". The Journal of Clinical Endocrinology and Metabolism. 100 (6): 2283–90. doi:10.1210/jc.2015-1023. PMC 4454804. PMID 25850025.
  19. ^ Storbeck KH, Mostaghel EA (2019). "Canonical and Noncanonical Androgen Metabolism and Activity". Advances in Experimental Medicine and Biology. 1210: 239–277. doi:10.1007/978-3-030-32656-2_11. PMID 31900912. 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
  20. ^ 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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  24. ^ 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.
  25. ^ 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.
  26. ^ 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.
  27. ^ 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.
  28. ^ 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

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Šablon:Oksigenaze Šablon:Steroid hidroksilaze