Aldosterone synthase: Difference between revisions

Jump to navigation Jump to search
VisualWikitext
m (Robot: Automated text replacement (-{{WikiDoc Cardiology Network Infobox}} +, -<references /> +{{reflist|2}}, -{{reflist}} +{{reflist|2}}))
 
m (→‎Metabolism: Disambiguated wikilink for 11-Deoxycorticosterone)
Line 1: Line 1:
<!-- The PBB_Controls template provides controls for Protein Box Bot, please see Template:PBB_Controls for details. -->
{{Infobox gene}}
{{PBB_Controls
| update_page = yes
| require_manual_inspection = no
| update_protein_box = yes
| update_summary = yes
| update_citations = yes
}}


<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot. See Template:PBB_Controls to Stop updates. -->
'''Aldosterone synthase''' is a steroid [[hydroxylase]] [[cytochrome P450]] enzyme involved in the biosynthesis of the mineralocorticoid [[aldosterone]]. It is a protein which is only expressed in the [[zona glomerulosa]]<ref name="Bassett">{{cite journal | vauthors = Bassett MH, White PC, Rainey WE | title = The regulation of aldosterone synthase expression | journal = Mol. Cell. Endocrinol. | volume = 217 | issue = 1–2 | pages = 67–74 |date=March 2004 | pmid = 15134803 | doi = 10.1016/j.mce.2003.10.011 }}</ref> of the [[adrenal cortex]] and is primarily regulated by the [[renin-angiotensin system]].<ref name="Peter M">{{cite journal | vauthors = Peter M, Dubuis JM, Sippell WG | title = Disorders of the aldosterone synthase and steroid 11β-hydroxylase deficiencies | journal = Horm. Res. | volume = 51 | issue = 5 | pages = 211–22 | year = 1999 | pmid = 10559665 | doi = 10.1159/000023374 }}</ref> It is the sole enzyme capable of synthesizing aldosterone in humans and plays an important role in [[electrolyte]] balance and [[blood pressure]].<ref name="Structural">{{cite journal | vauthors = Strushkevich N, Gilep AA, Shen L, Arrowsmith CH, Edwards AM, Usanov SA, Park HW | title = Structural insights into aldosterone synthase substrate specificity and targeted inhibition | journal = Molecular Endocrinology | volume = 27 | issue = 2 | pages = 315–324 |date=February 2013 | pmid = 23322723 | doi = 10.1210/me.2012-1287 }}</ref>
{{GNF_Protein_box
| image = 
| image_source = 
| PDB =  
| Name = Cytochrome P450, family 11, subfamily B, polypeptide 2
| HGNCid = 2592
| Symbol = CYP11B2
| AltSymbols =; CPN2; CYP11B; ALDOS; CYP11BL; P-450C18; P450C18; P450aldo
| OMIM = 124080
| ECnumber = 1.14.15.4
| Homologene = 73878
| MGIid = 88583
| GeneAtlas_image1 = PBB_GE_CYP11B2_214630_at_tn.png
| Function = {{GNF_GO|id=GO:0004497 |text = monooxygenase activity}} {{GNF_GO|id=GO:0004507 |text = steroid 11-beta-monooxygenase activity}} {{GNF_GO|id=GO:0005506 |text = iron ion binding}} {{GNF_GO|id=GO:0019825 |text = oxygen binding}} {{GNF_GO|id=GO:0020037 |text = heme binding}} {{GNF_GO|id=GO:0046872 |text = metal ion binding}} {{GNF_GO|id=GO:0047783 |text = corticosterone 18-monooxygenase activity}}
| Component = {{GNF_GO|id=GO:0005739 |text = mitochondrion}} {{GNF_GO|id=GO:0016020 |text = membrane}}
| Process = {{GNF_GO|id=GO:0006118 |text = electron transport}} {{GNF_GO|id=GO:0006629 |text = lipid metabolic process}} {{GNF_GO|id=GO:0006700 |text = C21-steroid hormone biosynthetic process}} {{GNF_GO|id=GO:0006704 |text = glucocorticoid biosynthetic process}} {{GNF_GO|id=GO:0008202 |text = steroid metabolic process}} {{GNF_GO|id=GO:0008217 |text = blood pressure regulation}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 1585
    | Hs_Ensembl = ENSG00000179142
    | Hs_RefseqProtein = NP_000489
    | Hs_RefseqmRNA = NM_000498
    | Hs_GenLoc_db =
    | Hs_GenLoc_chr = 8
    | Hs_GenLoc_start = 143988983
    | Hs_GenLoc_end = 143996261
    | Hs_Uniprot = P19099
    | Mm_EntrezGene = 110115
    | Mm_Ensembl = 
    | Mm_RefseqmRNA = NM_001033229
    | Mm_RefseqProtein = NP_001028401
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 
    | Mm_GenLoc_start = 
    | Mm_GenLoc_end = 
    | Mm_Uniprot = 
  }}
}}
'''Aldosterone synthase''' (or '''18-hydroxylase''') is a [[steroid]] [[hydroxylase]] [[cytochrome P450 oxidase]] [[enzyme]] involved in the generation of [[aldosterone]].


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
== Genetics ==
{{PBB_Summary
Aldosterone synthase is encoded on [[chromosome 8]]q22<ref name="Bassett" /> by the CYP11B2 gene.<ref name="Bassett" /> The gene contains 9 exons and spans roughly 7000 base pairs of DNA.<ref name="Bassett" /> CYP11B2 is closely related with [[CYP11B1]]. The two genes show 93% [[Homology (biology)|homology]] to each other and are both encoded on the same chromosome.<ref name="Mornet">{{cite journal | vauthors = Mornet E, Dupont J, Vitek A, White PC | title = Characterization of two genes encoding human steroid 11-beta-hydroxylase (P-45011-beta) | journal = J Biol Chem | volume = 264 | issue = 15 | pages = 20961–20967 |date=June 1989 | pmid = 2592361 }}</ref> Research has shown that calcium ions act as a [[transcription factor]] for CYP11B2 through well defined interactions at the 5'-flanking region of CYP11B2.<ref name="Bassett" />
| section_title =  
| summary_text = 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. The enzyme has steroid 18-hydroxylase activity to synthesize aldosterone and 18-oxocortisol as well as steroid 11 beta-hydroxylase activity. Mutations in this gene cause corticosterone methyl oxidase deficiency.<ref>{{cite web | title = Entrez Gene: CYP11B2 cytochrome P450, family 11, subfamily B, polypeptide 2| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1585| accessdate = }}</ref>
}}


It converts [[11-deoxycorticosterone]] to [[corticosterone]], to [[18-hydroxycorticosterone]], and finally to [[aldosterone]]:
Aldosterone synthase is a member of the cytochrome P450 superfamily of enzymes.<ref>{{cite web | title = CYP11B2| url = http://ghr.nlm.nih.gov/gene/CYP11B2 | accessdate=17 September 2013}}</ref> The cytochrome P450 proteins are [[monooxygenase]]s that catalyze many reactions involved in drug metabolism and synthesis of [[cholesterol]], [[steroids]], and other [[lipids]].


== Function ==
Aldosterone, when present, binds to intracellular mineralocorticoid receptors which can then bind to DNA and influence transcription of genes encoding serum and glucocorticoid induced kinase, [[SGK]]. Serum and glucocorticoid induced kinase (SGK) can phosphorylate a uniquitin ligase ([[NEDD4]]) which inactivates its ability to remove and degrade sodium channels from apical membranes.<ref name="White">{{cite journal | author = White PC | title = Aldosterone synthase deficiency and related disorders | journal = Mol. Cell. Endocrinol. | volume = 217 | issue = 1–2 | pages = 81–7 |date=March 2004 | pmid = 15134805 | doi = 10.1016/j.mce.2003.10.013 }}</ref> Aldosterone activity is primarily regulated by the [[renin-angiotensin system]] and shows a diurnal rhythm of secretion.<ref name="Peter M" /> [[Adrenocorticotropic hormone]] is also assumed to play a role in the regulation of aldosterone synthase likely through stimulating the synthesis of [[11-deoxycorticosterone]] which is the initial substrate of the enzymatic action in aldosterone synthase.<ref>{{cite journal |vauthors =Brown RD, Strott CA, Liddle GW |title=Site of stimulation of aldosterone biosynthesis by angiotensin and potassium |journal=J Clin Invest |volume=51 |issue=6 |pages=1413–8 |date=June 1972 |pmid=4336939 |pmc=292278 |doi=10.1172/JCI106937 |url=}}</ref>
[[Image:Renin-angiotensin-aldosterone system.png|thumb|center|700px|Renin-angiotensin system schematic showing aldosterone activity on the right]]
Aldosterone can be inhibited by antialdosteronic drugs such as [[spironolactone]] and [[eplerenone]]. In the chance that aldosterone activity is too high to be metabolically beneficial salt and fluid build up can occur which may stiffen the heart muscle increasing the risk of cardiovascular malfunction.<ref name="Martinez">{{cite journal | author = Martinez FA | title =  Aldosterone inhibition and cardiovascular protection: more important than it once appeared | journal = Cardiovascular drugs and therapy | volume = 24 | issue = 4 | pages = 345–350 |date=Aug 2010 | pmid = 20676926 | doi = 10.1007/s10557-010-6256-6 }}</ref>
== Metabolism ==
[[Image:ALDOSTERONESynthesis.svg|thumb|400px|Biosynthetic pathway of aldosterone starting with progesterone]]
Aldosterone synthase converts [[11-deoxycorticosterone]] to [[corticosterone]], to [[18-hydroxycorticosterone]], and finally to [[aldosterone]]:
<gallery>
<gallery>
  Image:Deoxycorticosterone.svg|11-[[Deoxycorticosterone]]
  Image:11-Deoxycorticosterone.svg|[[11-deoxycorticosterone]]
  Image:Corticosterone.svg|[[Corticosterone]]
  Image:Corticosterone-2D-skeletal.svg|[[Corticosterone]]
  Image:18-hydroxycorticosterone.PNG|[[18-hydroxycorticosterone]]
  Image:18-hydroxycorticosterone.PNG|[[18-hydroxycorticosterone]]
  Image:Aldosterone.svg|[[Aldosterone]]
  Image:Aldosterone-2D-skeletal.svg|[[Aldosterone]]
</gallery>
</gallery>
In human metabolism the biosynthesis of aldosterone largely depends on the metabolism of [[cholesterol]]. [[Cholesterol]] is metabolized in what is known as the early pathway of aldosterone synthesis<ref name="Williams">{{cite journal | author = Williams GH | title = Aldosterone Biosynthesis, Regulation, and Classical Mechanism of Action | journal = Heart failure reviews | volume = 10 | issue = 1 | pages = 7–13 |date=January 2005 | doi = 10.1007/s10741-005-2343-3 }}</ref> and is hydroxylated becoming  (20R,22R)-dihydroxycholesterol which is then metabolized as a direct precursor to [[pregnenolone]]. [[Pregnenolone]] can then followed one of two pathways which involve the metabolism of [[progesterone]] or the [[testosterone]] and [[estradiol]] biosynthesis. Aldosterone is synthesized by following the metabolism of [[progesterone]].
In the potential case where aldosterone synthase is not metabolically active the body accumulates [[11-deoxycorticosterone]]. This increases salt retention leading to increased [[hypertension]].<ref name="USMED">{{cite journal | author = National Library of Medicine (US) | title = CYP11B1 | journal = Genetics Home Reference |date=Sep 2013 }}</ref>
== Methyl oxidase deficiency ==
Lack of metabolically active aldosterone synthase leads to corticosterone methyl oxidase deficiency type I and II. The deficiency is characterized clinically by salt-wasting, failure to thrive, and growth retardation.<ref name="Defective">{{cite journal | vauthors = Peter M, Fawaz L, Drop SL, Visser HK, Sippell WG | title = Hereditary defect in biosynthesis of aldosterone: aldosterone synthase deficiency 1964-1997 | journal = J. Clin. Endocrinol. Metab. | volume = 82 | issue = 11 | pages = 3525–8 |date=November 1997 | pmid = 9360501 | doi = 10.1210/jc.82.11.3525 }}</ref> The in-active proteins are caused by the autosomal recessive inheritance of defective CYP11B2 genes in which genetic mutations destroy the enzymatic activity of aldosterone synthase.<ref name="Defective" /> Deficient aldosterone synthase activity results in impaired biosynthesis of [[aldosterone]] while [[corticosterone]] in the [[zona glomerulosa]] is excessively produced in both corticosterone methyl oxidase deficiency type I and II. The corticosterone methyl oxidase deficiencies both share this effect however type I causes an overall deficiency of 18-hydroxycorticosterone while type II overproduces it.<ref name="Defective" />
== Enzymatic inhibition ==
Inhibition of aldosterone synthase is currently being investigated as a medical treatment for [[hypertension]], [[heart failure]], and [[renal disorder]]s.<ref name="Inhibition">{{cite journal | vauthors = Azizi M, Amar L, Menard J | title = Aldosterone synthase inhibition in humans | journal = Nephrol. Dial. Transplant | volume = 28 | issue = 1 | pages = 36–43 |date=October 2013 | pmid = 23045428 | doi =  10.1093/ndt/gfs388 }}</ref> Deactivation of enzymatic activity reduces aldosterone concentrations in plasma and tissues which decreases [[mineralocorticoid receptor]]-dependent and independent effects in cardiac vascular and renal target organs.<ref name="Inhibition" /> Inhibition has shown to decrease plasma and urinary aldosterone concentrations by 70 - 80%, rapid [[hypokalaemia]] correction, moderate decrease of blood pressure, and an increase plasma [[renin]] activity in patients who are on a low-sodium diet.<ref name="Inhibition" /> Ongoing medical research is focusing on the synthesis of second-generation aldosterone synthase inhibitors to create an ideally selective inhibitor as the current, orally delivered, LCl699 has shown to be non-specific to aldosterone synthase.<ref name="Inhibition" />
==See also==
* [[Steroidogenic enzyme]]
* [[Hypoaldosteronism]]
* [[Glucocorticoid remediable aldosteronism]]


It is found in the [[zona glomerulosa]].
== Additional images ==
[[File:Steroidogenesis.svg|thumb|500px|[[Steroidogenesis]], showing aldosterone synthase at right.]]


==Additional images==
== References ==
[[Image:Steroidogenesis.gif|thumb|center|500px|[[Steroidogenesis]], showing aldosterone synthase at right.]]
{{Reflist}}
<gallery>
Image:Corticosteroid-biosynthetic-pathway-rat.png|Corticosteroid biosynthetic pathway in rat
</gallery>


==References==
== Further reading ==
{{reflist|2}}
==Further reading==
{{refbegin | 2}}
{{refbegin | 2}}
{{PBB_Further_reading
*{{cite journal  | author=Helmberg A |title=Twin genes and endocrine disease: CYP21 and CYP11B genes |journal=Acta Endocrinol. |volume=129 |issue= 2 |pages= 97–108 |year= 1993 |pmid= 8372604 |doi=  10.1530/acta.0.1290097}}
| citations =
*{{cite journal  | vauthors=Slight SH, Joseph J, Ganjam VK, Weber KT |title=Extra-adrenal mineralocorticoids and cardiovascular tissue |journal=J. Mol. Cell. Cardiol. |volume=31 |issue= 6 |pages= 1175–84 |year= 1999 |pmid= 10371693 |doi= 10.1006/jmcc.1999.0963 }}
*{{cite journal  | author=Helmberg A |title=Twin genes and endocrine disease: CYP21 and CYP11B genes. |journal=Acta Endocrinol. |volume=129 |issue= 2 |pages= 97-108 |year= 1993 |pmid= 8372604 |doi=  }}
*{{cite journal  | vauthors=Stowasser M, Gunasekera TG, Gordon RD |title=Familial varieties of primary aldosteronism |journal=Clin. Exp. Pharmacol. Physiol. |volume=28 |issue= 12 |pages= 1087–90 |year= 2002 |pmid= 11903322 |doi=10.1046/j.1440-1681.2001.03574.x }}
*{{cite journal  | author=Slight SH, Joseph J, Ganjam VK, Weber KT |title=Extra-adrenal mineralocorticoids and cardiovascular tissue. |journal=J. Mol. Cell. Cardiol. |volume=31 |issue= 6 |pages= 1175-84 |year= 1999 |pmid= 10371693 |doi= 10.1006/jmcc.1999.0963 }}
*{{cite journal  | vauthors=Padmanabhan N, Padmanabhan S, Connell JM |title=Genetic basis of cardiovascular disease--the renin-angiotensin-aldosterone system as a paradigm |journal=Journal of the renin-angiotensin-aldosterone system : JRAAS |volume=1 |issue= 4 |pages= 316–24 |year= 2002 |pmid= 11967817 |doi= 10.3317/jraas.2000.060 }}
*{{cite journal  | author=Stowasser M, Gunasekera TG, Gordon RD |title=Familial varieties of primary aldosteronism. |journal=Clin. Exp. Pharmacol. Physiol. |volume=28 |issue= 12 |pages= 1087-90 |year= 2002 |pmid= 11903322 |doi=  }}
*{{cite journal  | vauthors=Lifton RP, Dluhy RG, Powers M, Rich GM, Gutkin M, Fallo F, ((Gill JR Jr)), Feld L, Ganguly A, Laidlaw JC |title=Hereditary hypertension caused by chimaeric gene duplications and ectopic expression of aldosterone synthase |journal=Nat. Genet. |volume=2 |issue= 1 |pages= 66–74 |year= 1993 |pmid= 1303253 |doi= 10.1038/ng0992-66 |display-authors=etal}}
*{{cite journal  | author=Padmanabhan N, Padmanabhan S, Connell JM |title=Genetic basis of cardiovascular disease--the renin-angiotensin-aldosterone system as a paradigm. |journal=Journal of the renin-angiotensin-aldosterone system : JRAAS |volume=1 |issue= 4 |pages= 316-24 |year= 2002 |pmid= 11967817 |doi= 10.3317/jraas.2000.060 }}
*{{cite journal  | vauthors=Mitsuuchi Y, Kawamoto T, Naiki Y, Miyahara K, Toda K, Kuribayashi I, Orii T, Yasuda K, Miura K, Nakao K |title=Congenitally defective aldosterone biosynthesis in humans: the involvement of point mutations of the P-450C18 gene (CYP11B2) in CMO II deficient patients |journal=Biochem. Biophys. Res. Commun. |volume=182 |issue= 2 |pages= 974–9 |year= 1992 |pmid= 1346492 |doi=10.1016/0006-291X(92)91827-D |display-authors=etal}}
*{{cite journal  | author=Lifton RP, Dluhy RG, Powers M, ''et al.'' |title=Hereditary hypertension caused by chimaeric gene duplications and ectopic expression of aldosterone synthase. |journal=Nat. Genet. |volume=2 |issue= 1 |pages= 66-74 |year= 1993 |pmid= 1303253 |doi= 10.1038/ng0992-66 }}
*{{cite journal  | vauthors=Pascoe L, Curnow KM, Slutsker L, Connell JM, Speiser PW, New MI, White PC |title=Glucocorticoid-suppressible hyperaldosteronism results from hybrid genes created by unequal crossovers between CYP11B1 and CYP11B2 |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=89 |issue= 17 |pages= 8327–31 |year= 1992 |pmid= 1518866 |doi=10.1073/pnas.89.17.8327  | pmc=49911 }}
*{{cite journal  | author=Mitsuuchi Y, Kawamoto T, Naiki Y, ''et al.'' |title=Congenitally defective aldosterone biosynthesis in humans: the involvement of point mutations of the P-450C18 gene (CYP11B2) in CMO II deficient patients. |journal=Biochem. Biophys. Res. Commun. |volume=182 |issue= 2 |pages= 974-9 |year= 1992 |pmid= 1346492 |doi=  }}
*{{cite journal  | vauthors=Pascoe L, Curnow KM, Slutsker L, Rösler A, White PC |title=Mutations in the human CYP11B2 (aldosterone synthase) gene causing corticosterone methyloxidase II deficiency |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=89 |issue= 11 |pages= 4996–5000 |year= 1992 |pmid= 1594605 |doi=10.1073/pnas.89.11.4996  | pmc=49215 }}
*{{cite journal  | author=Pascoe L, Curnow KM, Slutsker L, ''et al.'' |title=Glucocorticoid-suppressible hyperaldosteronism results from hybrid genes created by unequal crossovers between CYP11B1 and CYP11B2. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=89 |issue= 17 |pages= 8327-31 |year= 1992 |pmid= 1518866 |doi=  }}
*{{cite journal  | vauthors=Kawamoto T, Mitsuuchi Y, Toda K, Yokoyama Y, Miyahara K, Miura S, Ohnishi T, Ichikawa Y, Nakao K, Imura H |title=Role of steroid 11 beta-hydroxylase and steroid 18-hydroxylase in the biosynthesis of glucocorticoids and mineralocorticoids in humans |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=89 |issue= 4 |pages= 1458–62 |year= 1992 |pmid= 1741400 |doi=10.1073/pnas.89.4.1458 | pmc=48470  |display-authors=etal}}
*{{cite journal  | author=Pascoe L, Curnow KM, Slutsker L, ''et al.'' |title=Mutations in the human CYP11B2 (aldosterone synthase) gene causing corticosterone methyloxidase II deficiency. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=89 |issue= 11 |pages= 4996-5000 |year= 1992 |pmid= 1594605 |doi=  }}
*{{cite journal  | vauthors=Curnow KM, Tusie-Luna MT, Pascoe L, Natarajan R, Gu JL, Nadler JL, White PC |title=The product of the CYP11B2 gene is required for aldosterone biosynthesis in the human adrenal cortex |journal=Mol. Endocrinol. |volume=5 |issue= 10 |pages= 1513–22 |year= 1992 |pmid= 1775135 |doi=10.1210/mend-5-10-1513 }}
*{{cite journal  | author=Kawamoto T, Mitsuuchi Y, Toda K, ''et al.'' |title=Role of steroid 11 beta-hydroxylase and steroid 18-hydroxylase in the biosynthesis of glucocorticoids and mineralocorticoids in humans. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=89 |issue= 4 |pages= 1458-62 |year= 1992 |pmid= 1741400 |doi=  }}
*{{cite journal  | vauthors=Kawainoto T, Mitsuuchi Y, Ohnishi T, Ichikawa Y, Yokoyama Y, Sumimoto H, Toda K, Miyahara K, Kuribayashi I, Nakao K |title=Cloning and expression of a cDNA for human cytochrome P-450aldo as related to primary aldosteronism |journal=Biochem. Biophys. Res. Commun. |volume=173 |issue= 1 |pages= 309–16 |year= 1991 |pmid= 2256920 |doi=10.1016/S0006-291X(05)81058-7 |display-authors=etal}}
*{{cite journal  | author=Curnow KM, Tusie-Luna MT, Pascoe L, ''et al.'' |title=The product of the CYP11B2 gene is required for aldosterone biosynthesis in the human adrenal cortex. |journal=Mol. Endocrinol. |volume=5 |issue= 10 |pages= 1513-22 |year= 1992 |pmid= 1775135 |doi=  }}
*{{cite journal  | vauthors=Mornet E, Dupont J, Vitek A, White PC |title=Characterization of two genes encoding human steroid 11 beta-hydroxylase (P-450(11) beta) |journal=J. Biol. Chem. |volume=264 |issue= 35 |pages= 20961–7 |year= 1990 |pmid= 2592361 |doi=  }}
*{{cite journal  | author=Kawainoto T, Mitsuuchi Y, Ohnishi T, ''et al.'' |title=Cloning and expression of a cDNA for human cytochrome P-450aldo as related to primary aldosteronism. |journal=Biochem. Biophys. Res. Commun. |volume=173 |issue= 1 |pages= 309-16 |year= 1991 |pmid= 2256920 |doi=  }}
*{{cite journal  | vauthors=Martsev SP, Chashchin VL, Akhrem AA | author3-link=:be:Афанасій Андрэевіч Ахрэм |title=[Reconstruction and study of a multi-enzyme system by 11 beta-hydroxylase steroids] |journal=Biokhimiia |volume=50 |issue= 2 |pages= 243–57 |year= 1985 |pmid= 3872685 |doi=  }}
*{{cite journal  | author=Mornet E, Dupont J, Vitek A, White PC |title=Characterization of two genes encoding human steroid 11 beta-hydroxylase (P-450(11) beta). |journal=J. Biol. Chem. |volume=264 |issue= 35 |pages= 20961-7 |year= 1990 |pmid= 2592361 |doi=  }}
*{{cite journal  | vauthors=Shizuta Y, Kawamoto T, Mitsuuchi Y, Miyahara K, Rösler A, Ulick S, Imura H |title=Inborn errors of aldosterone biosynthesis in humans |journal=Steroids |volume=60 |issue= 1 |pages= 15–21 |year= 1995 |pmid= 7792802 |doi=10.1016/0039-128X(94)00023-6 }}
*{{cite journal  | author=Martsev SP, Chashchin VL, Akhrem AA |title=[Reconstruction and study of a multi-enzyme system by 11 beta-hydroxylase steroids] |journal=Biokhimiia |volume=50 |issue= 2 |pages= 243-57 |year= 1985 |pmid= 3872685 |doi=  }}
*{{cite journal  | vauthors=Mitsuuchi Y, Kawamoto T, Miyahara K, Ulick S, Morton DH, Naiki Y, Kuribayashi I, Toda K, Hara T, Orii T |title=Congenitally defective aldosterone biosynthesis in humans: inactivation of the P-450C18 gene (CYP11B2) due to nucleotide deletion in CMO I deficient patients |journal=Biochem. Biophys. Res. Commun. |volume=190 |issue= 3 |pages= 864–9 |year= 1993 |pmid= 8439335 |doi=10.1006/bbrc.1993.1128  |display-authors=etal}}
*{{cite journal  | author=Shizuta Y, Kawamoto T, Mitsuuchi Y, ''et al.'' |title=Inborn errors of aldosterone biosynthesis in humans. |journal=Steroids |volume=60 |issue= 1 |pages= 15-21 |year= 1995 |pmid= 7792802 |doi=  }}
*{{cite journal  | vauthors=Fardella CE, Rodriguez H, Montero J, Zhang G, Vignolo P, Rojas A, Villarroel L, Miller WL |title=Genetic variation in P450c11AS in Chilean patients with low renin hypertension |journal=J. Clin. Endocrinol. Metab. |volume=81 |issue= 12 |pages= 4347–51 |year= 1997 |pmid= 8954040 |doi=10.1210/jc.81.12.4347  }}
*{{cite journal  | author=Mitsuuchi Y, Kawamoto T, Miyahara K, ''et al.'' |title=Congenitally defective aldosterone biosynthesis in humans: inactivation of the P-450C18 gene (CYP11B2) due to nucleotide deletion in CMO I deficient patients. |journal=Biochem. Biophys. Res. Commun. |volume=190 |issue= 3 |pages= 864-9 |year= 1993 |pmid= 8439335 |doi= }}
*{{cite journal  | vauthors=Nomoto S, Massa G, Mitani F, Ishimura Y, Miyahara K, Toda K, Nagano I, Yamashiro T, Ogoshi S, Fukata J, Onishi S, Hashimoto K, Doi Y, Imura H, Shizuta Y |title=CMO I deficiency caused by a point mutation in exon 8 of the human CYP11B2 gene encoding steroid 18-hydroxylase (P450C18) |journal=Biochem. Biophys. Res. Commun. |volume=234 |issue= 2 |pages= 382–5 |year= 1997 |pmid= 9177280 |doi=10.1006/bbrc.1997.6651  }}
*{{cite journal  | author=Fardella CE, Rodriguez H, Montero J, ''et al.'' |title=Genetic variation in P450c11AS in Chilean patients with low renin hypertension. |journal=J. Clin. Endocrinol. Metab. |volume=81 |issue= 12 |pages= 4347-51 |year= 1997 |pmid= 8954040 |doi= }}
*{{cite journal  | vauthors=Taymans SE, Pack S, Pak E, Torpy DJ, Zhuang Z, Stratakis CA |title=Human CYP11B2 (aldosterone synthase) maps to chromosome 8q24.3 |journal=J. Clin. Endocrinol. Metab. |volume=83 |issue= 3 |pages= 1033–6 |year= 1998 |pmid= 9506770 |doi=10.1210/jc.83.3.1033  }}
*{{cite journal  | author=Nomoto S, Massa G, Mitani F, ''et al.'' |title=CMO I deficiency caused by a point mutation in exon 8 of the human CYP11B2 gene encoding steroid 18-hydroxylase (P450C18). |journal=Biochem. Biophys. Res. Commun. |volume=234 |issue= 2 |pages= 382-5 |year= 1997 |pmid= 9177280 |doi= }}
*{{cite journal  | author=Peter M, Fawaz L, Drop SL, ''et al.'' |title=Hereditary defect in biosynthesis of aldosterone: aldosterone synthase deficiency 1964-1997. |journal=J. Clin. Endocrinol. Metab. |volume=82 |issue= 11 |pages= 3525-8 |year= 1997 |pmid= 9360501 |doi= }}
*{{cite journal  | author=Taymans SE, Pack S, Pak E, ''et al.'' |title=Human CYP11B2 (aldosterone synthase) maps to chromosome 8q24.3. |journal=J. Clin. Endocrinol. Metab. |volume=83 |issue= 3 |pages= 1033-6 |year= 1998 |pmid= 9506770 |doi= }}
}}
{{refend}}
{{refend}}


==External links==
== External links ==
* {{MeshName|Aldosterone+synthase}}
* {{MeshName|Aldosterone+synthase}}
* {{UCSC gene info|CPN2}}
* {{UCSC gene info|CYP11B2}}


{{oxidoreductase-stub}}
{{Oxygenases}}
{{Oxygenases}}
{{Steroid hydroxylases}}
{{Steroid hydroxylases}}
{{Cytochrome P450}}
{{Cytochrome P450}}
[[Category:Cytochrome P450]]
{{Mitochondrial enzymes}}
 
[[:Category:Cytochrome P450]]
 
[[Category:Enzymes of known structure]]

Revision as of 19:12, 22 November 2017

VALUE_ERROR (nil)
Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

n/a

n/a

Ensembl

n/a

n/a

UniProt

n/a

n/a

RefSeq (mRNA)

n/a

n/a

RefSeq (protein)

n/a

n/a

Location (UCSC)n/an/a
PubMed searchn/an/a
Wikidata
View/Edit Human

Aldosterone synthase is a steroid hydroxylase cytochrome P450 enzyme involved in the biosynthesis of the mineralocorticoid aldosterone. It is a protein which is only expressed in the zona glomerulosa[1] of the adrenal cortex and is primarily regulated by the renin-angiotensin system.[2] It is the sole enzyme capable of synthesizing aldosterone in humans and plays an important role in electrolyte balance and blood pressure.[3]

Genetics

Aldosterone synthase is encoded on chromosome 8q22[1] by the CYP11B2 gene.[1] The gene contains 9 exons and spans roughly 7000 base pairs of DNA.[1] CYP11B2 is closely related with CYP11B1. The two genes show 93% homology to each other and are both encoded on the same chromosome.[4] Research has shown that calcium ions act as a transcription factor for CYP11B2 through well defined interactions at the 5'-flanking region of CYP11B2.[1]

Aldosterone synthase is a member of the cytochrome P450 superfamily of enzymes.[5] The cytochrome P450 proteins are monooxygenases that catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids, and other lipids.

Function

Aldosterone, when present, binds to intracellular mineralocorticoid receptors which can then bind to DNA and influence transcription of genes encoding serum and glucocorticoid induced kinase, SGK. Serum and glucocorticoid induced kinase (SGK) can phosphorylate a uniquitin ligase (NEDD4) which inactivates its ability to remove and degrade sodium channels from apical membranes.[6] Aldosterone activity is primarily regulated by the renin-angiotensin system and shows a diurnal rhythm of secretion.[2] Adrenocorticotropic hormone is also assumed to play a role in the regulation of aldosterone synthase likely through stimulating the synthesis of 11-deoxycorticosterone which is the initial substrate of the enzymatic action in aldosterone synthase.[7]

Renin-angiotensin system schematic showing aldosterone activity on the right

Aldosterone can be inhibited by antialdosteronic drugs such as spironolactone and eplerenone. In the chance that aldosterone activity is too high to be metabolically beneficial salt and fluid build up can occur which may stiffen the heart muscle increasing the risk of cardiovascular malfunction.[8]

Metabolism

File:ALDOSTERONESynthesis.svg
Biosynthetic pathway of aldosterone starting with progesterone

Aldosterone synthase converts 11-deoxycorticosterone to corticosterone, to 18-hydroxycorticosterone, and finally to aldosterone:

In human metabolism the biosynthesis of aldosterone largely depends on the metabolism of cholesterol. Cholesterol is metabolized in what is known as the early pathway of aldosterone synthesis[9] and is hydroxylated becoming (20R,22R)-dihydroxycholesterol which is then metabolized as a direct precursor to pregnenolone. Pregnenolone can then followed one of two pathways which involve the metabolism of progesterone or the testosterone and estradiol biosynthesis. Aldosterone is synthesized by following the metabolism of progesterone.

In the potential case where aldosterone synthase is not metabolically active the body accumulates 11-deoxycorticosterone. This increases salt retention leading to increased hypertension.[10]

Methyl oxidase deficiency

Lack of metabolically active aldosterone synthase leads to corticosterone methyl oxidase deficiency type I and II. The deficiency is characterized clinically by salt-wasting, failure to thrive, and growth retardation.[11] The in-active proteins are caused by the autosomal recessive inheritance of defective CYP11B2 genes in which genetic mutations destroy the enzymatic activity of aldosterone synthase.[11] Deficient aldosterone synthase activity results in impaired biosynthesis of aldosterone while corticosterone in the zona glomerulosa is excessively produced in both corticosterone methyl oxidase deficiency type I and II. The corticosterone methyl oxidase deficiencies both share this effect however type I causes an overall deficiency of 18-hydroxycorticosterone while type II overproduces it.[11]

Enzymatic inhibition

Inhibition of aldosterone synthase is currently being investigated as a medical treatment for hypertension, heart failure, and renal disorders.[12] Deactivation of enzymatic activity reduces aldosterone concentrations in plasma and tissues which decreases mineralocorticoid receptor-dependent and independent effects in cardiac vascular and renal target organs.[12] Inhibition has shown to decrease plasma and urinary aldosterone concentrations by 70 - 80%, rapid hypokalaemia correction, moderate decrease of blood pressure, and an increase plasma renin activity in patients who are on a low-sodium diet.[12] Ongoing medical research is focusing on the synthesis of second-generation aldosterone synthase inhibitors to create an ideally selective inhibitor as the current, orally delivered, LCl699 has shown to be non-specific to aldosterone synthase.[12]

See also

Additional images

Error creating thumbnail: File missing
Steroidogenesis, showing aldosterone synthase at right.

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 Bassett MH, White PC, Rainey WE (March 2004). "The regulation of aldosterone synthase expression". Mol. Cell. Endocrinol. 217 (1–2): 67–74. doi:10.1016/j.mce.2003.10.011. PMID 15134803.
  2. ↑ 2.0 2.1 Peter M, Dubuis JM, Sippell WG (1999). "Disorders of the aldosterone synthase and steroid 11β-hydroxylase deficiencies". Horm. Res. 51 (5): 211–22. doi:10.1159/000023374. PMID 10559665.
  3. ↑ Strushkevich N, Gilep AA, Shen L, Arrowsmith CH, Edwards AM, Usanov SA, Park HW (February 2013). "Structural insights into aldosterone synthase substrate specificity and targeted inhibition". Molecular Endocrinology. 27 (2): 315–324. doi:10.1210/me.2012-1287. PMID 23322723.
  4. ↑ Mornet E, Dupont J, Vitek A, White PC (June 1989). "Characterization of two genes encoding human steroid 11-beta-hydroxylase (P-45011-beta)". J Biol Chem. 264 (15): 20961–20967. PMID 2592361.
  5. ↑ "CYP11B2". Retrieved 17 September 2013.
  6. ↑ White PC (March 2004). "Aldosterone synthase deficiency and related disorders". Mol. Cell. Endocrinol. 217 (1–2): 81–7. doi:10.1016/j.mce.2003.10.013. PMID 15134805.
  7. ↑ Brown RD, Strott CA, Liddle GW (June 1972). "Site of stimulation of aldosterone biosynthesis by angiotensin and potassium". J Clin Invest. 51 (6): 1413–8. doi:10.1172/JCI106937. PMC 292278. PMID 4336939.
  8. ↑ Martinez FA (Aug 2010). "Aldosterone inhibition and cardiovascular protection: more important than it once appeared". Cardiovascular drugs and therapy. 24 (4): 345–350. doi:10.1007/s10557-010-6256-6. PMID 20676926.
  9. ↑ Williams GH (January 2005). "Aldosterone Biosynthesis, Regulation, and Classical Mechanism of Action". Heart failure reviews. 10 (1): 7–13. doi:10.1007/s10741-005-2343-3.
  10. ↑ National Library of Medicine (US) (Sep 2013). "CYP11B1". Genetics Home Reference.
  11. ↑ 11.0 11.1 11.2 Peter M, Fawaz L, Drop SL, Visser HK, Sippell WG (November 1997). "Hereditary defect in biosynthesis of aldosterone: aldosterone synthase deficiency 1964-1997". J. Clin. Endocrinol. Metab. 82 (11): 3525–8. doi:10.1210/jc.82.11.3525. PMID 9360501.
  12. ↑ 12.0 12.1 12.2 12.3 Azizi M, Amar L, Menard J (October 2013). "Aldosterone synthase inhibition in humans". Nephrol. Dial. Transplant. 28 (1): 36–43. doi:10.1093/ndt/gfs388. PMID 23045428.

Further reading

External links

Category:Cytochrome P450

Retrieved from "https://www.wikidoc.org/index.php?title=Aldosterone_synthase&oldid=1422096"