“Aldosterone synthase”的意思、由来-开放百科全书

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

Metabolism

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^[7] 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.^[8]

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.^[9] 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.^[9] 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.^[9]

Enzymatic inhibition

Inhibition of aldosterone synthase is currently being investigated as a medical treatment for hypertension, heart failure, and renal disorders.^[10] 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.^[10] 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.^[10] 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.^[10]

See also

Additional images

References

1. ^¹²³⁴{{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 }}
2. ^{{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 }}
3. ^{{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 | pmc = 5417327 | doi = 10.1210/me.2012-1287 }}
4. ^{{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 }}
5. ^{{cite web | title = CYP11B2| url = http://ghr.nlm.nih.gov/gene/CYP11B2 | accessdate=17 September 2013}}
6. ^{{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=}}
7. ^{{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 | pmid = 15947886 }}
8. ^{{cite journal | author = National Library of Medicine (US) | title = CYP11B1 | journal = Genetics Home Reference |date=Sep 2013 }}
9. ^¹²{{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 }}
10. ^¹²³{{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 }}