Aldosterone synthase

Aldosterone synthase

Cytochrome P450, family 11, subfamily B, polypeptide 2
PDB rendering completed using PISA software. Human aldosterone synthase in complex with 11-deoxycorticosterone
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols  ; ALDOS; CPN2; CYP11B; CYP11BL; CYPXIB2; P-450C18; P450C18; P450aldo
External IDs IUPHAR: ChEMBL: GeneCards:
EC number
RNA expression pattern
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)
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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]

Contents

  • Genetics 1
  • Function 2
  • Metabolism 3
  • Methyl oxidase deficiency 4
  • Enzymatic inhibition 5
  • See also 6
  • Additional images 7
  • References 8
  • Further reading 9
  • External links 10

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 encodes 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

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

Category:Cytochrome P450

External links

  • Helmberg A (1993). "Twin genes and endocrine disease: CYP21 and CYP11B genes". Acta Endocrinol. 129 (2): 97–108.  
  • Slight SH, Joseph J, Ganjam VK, Weber KT (1999). "Extra-adrenal mineralocorticoids and cardiovascular tissue". J. Mol. Cell. Cardiol. 31 (6): 1175–84.  
  • Stowasser M, Gunasekera TG, Gordon RD (2002). "Familial varieties of primary aldosteronism". Clin. Exp. Pharmacol. Physiol. 28 (12): 1087–90.  
  • Padmanabhan N, Padmanabhan S, Connell JM (2002). "Genetic basis of cardiovascular disease--the renin-angiotensin-aldosterone system as a paradigm". Journal of the renin-angiotensin-aldosterone system : JRAAS 1 (4): 316–24.  
  • Lifton RP, Dluhy RG, Powers M, Rich GM, Gutkin M, Fallo F, Gill JR Jr, Feld L, Ganguly A, Laidlaw JC; et al. (1993). "Hereditary hypertension caused by chimaeric gene duplications and ectopic expression of aldosterone synthase". Nat. Genet. 2 (1): 66–74.  
  • Mitsuuchi Y, Kawamoto T, Naiki Y, Miyahara K, Toda K, Kuribayashi I, Orii T, Yasuda K, Miura K, Nakao K; et al. (1992). "Congenitally defective aldosterone biosynthesis in humans: the involvement of point mutations of the P-450C18 gene (CYP11B2) in CMO II deficient patients". Biochem. Biophys. Res. Commun. 182 (2): 974–9.  
  • Pascoe L, Curnow KM, Slutsker L, Connell JM, Speiser PW, New MI, White PC (1992). "Glucocorticoid-suppressible hyperaldosteronism results from hybrid genes created by unequal crossovers between CYP11B1 and CYP11B2". Proc. Natl. Acad. Sci. U.S.A. 89 (17): 8327–31.  
  • Pascoe L, Curnow KM, Slutsker L, Rösler A, White PC (1992). "Mutations in the human CYP11B2 (aldosterone synthase) gene causing corticosterone methyloxidase II deficiency". Proc. Natl. Acad. Sci. U.S.A. 89 (11): 4996–5000.  
  • Kawamoto T, Mitsuuchi Y, Toda K, Yokoyama Y, Miyahara K, Miura S, Ohnishi T, Ichikawa Y, Nakao K, Imura H; et al. (1992). "Role of steroid 11 beta-hydroxylase and steroid 18-hydroxylase in the biosynthesis of glucocorticoids and mineralocorticoids in humans". Proc. Natl. Acad. Sci. U.S.A. 89 (4): 1458–62.  
  • Curnow KM, Tusie-Luna MT, Pascoe L, Natarajan R, Gu JL, Nadler JL, White PC (1992). "The product of the CYP11B2 gene is required for aldosterone biosynthesis in the human adrenal cortex". Mol. Endocrinol. 5 (10): 1513–22.  
  • Kawainoto T, Mitsuuchi Y, Ohnishi T, Ichikawa Y, Yokoyama Y, Sumimoto H, Toda K, Miyahara K, Kuribayashi I, Nakao K; et al. (1991). "Cloning and expression of a cDNA for human cytochrome P-450aldo as related to primary aldosteronism". Biochem. Biophys. Res. Commun. 173 (1): 309–16.  
  • Mornet E, Dupont J, Vitek A, White PC (1990). "Characterization of two genes encoding human steroid 11 beta-hydroxylase (P-450(11) beta)". J. Biol. Chem. 264 (35): 20961–7.  
  • Martsev SP, Chashchin VL, Akhrem AA (1985). "[Reconstruction and study of a multi-enzyme system by 11 beta-hydroxylase steroids]". Biokhimiia 50 (2): 243–57.  
  • Shizuta Y, Kawamoto T, Mitsuuchi Y, Miyahara K, Rösler A, Ulick S, Imura H (1995). "Inborn errors of aldosterone biosynthesis in humans". Steroids 60 (1): 15–21.  
  • Mitsuuchi Y, Kawamoto T, Miyahara K, Ulick S, Morton DH, Naiki Y, Kuribayashi I, Toda K, Hara T, Orii T; et al. (1993). "Congenitally defective aldosterone biosynthesis in humans: inactivation of the P-450C18 gene (CYP11B2) due to nucleotide deletion in CMO I deficient patients". Biochem. Biophys. Res. Commun. 190 (3): 864–9.  
  • Fardella CE, Rodriguez H, Montero J, Zhang G, Vignolo P, Rojas A, Villarroel L, Miller WL (1997). "Genetic variation in P450c11AS in Chilean patients with low renin hypertension". J. Clin. Endocrinol. Metab. 81 (12): 4347–51.  
  • 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 (1997). "CMO I deficiency caused by a point mutation in exon 8 of the human CYP11B2 gene encoding steroid 18-hydroxylase (P450C18)". Biochem. Biophys. Res. Commun. 234 (2): 382–5.  
  • Taymans SE, Pack S, Pak E, Torpy DJ, Zhuang Z, Stratakis CA (1998). "Human CYP11B2 (aldosterone synthase) maps to chromosome 8q24.3". J. Clin. Endocrinol. Metab. 83 (3): 1033–6.  

Further reading

  1. ^ a b c d e Bassett MH, White PC, Rainey WE (March 2004). "The regulation of aldosterone synthase expression". Mol. Cell. Endocrinol. 217 (1–2): 67–74.  
  2. ^ a b Peter M, Dubuis JM, Sippell WG (1999). "Disorders of the aldosterone synthase and steroid 11β-hydroxylase deficiencies". Horm. Res. 51 (5): 211–22.  
  3. ^ Strushkevich N, Gilep AA, Shen Limin, 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.  
  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.  
  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.  
  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.  
  8. ^ Martinez FA (Aug 2010). "Aldosterone inhibition and cardiovascular protection: more important than it once appeared". Cardiovascular drugs and therapy 24 (4): 345–350.  
  9. ^ Williams GH (January 2005). "Aldosterone Biosynthesis, Regulation, and Classical Mechanism of Action". Heart failure reviews 10 (1): 7–13.  
  10. ^ National Library of Medicine (US) (Sep 2013). "CYP11B1". Genetics Home Reference. 
  11. ^ a b c 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.  
  12. ^ a b c d Azizi M, Amar L, Menard J (October 2013). "Aldosterone synthase inhibition in humans". Nephrol. Dial. Transplant 28 (1): 36–43.  

References

Steroidogenesis, showing aldosterone synthase at right.

Additional images

See also

[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] activity in patients who are on a low-sodium diet.renin correction, moderate decrease of blood pressure, and an increase plasma hypokalaemia Inhibition has shown to decrease plasma and urinary aldosterone concentrations by 70 - 80%, rapid [12]