Affinage

CYP11B2

Cytochrome P450 11B2, mitochondrial · UniProt P19099

Round 2 corrected
Length
503 aa
Mass
57.6 kDa
Annotated
2026-04-28
130 papers in source corpus 33 papers cited in narrative 33 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CYP11B2 (aldosterone synthase) is a mitochondrial cytochrome P450 that catalyzes the final three steps of aldosterone biosynthesis—11β-hydroxylation, 18-hydroxylation, and 18-oxidation of deoxycorticosterone—activities that distinguish it from its 93%-identical paralog CYP11B1, which lacks 18-oxidase capacity (PMID:2256920, PMID:23322723). Crystal structures reveal that the unique 18-oxidase activity depends on divergent residues in the I-helix near the oxygen activation site and loops around the H-helix that form an egress channel retaining intermediates, with low processivity controlling aldosterone output (PMID:23322723). Transcription in the adrenal zona glomerulosa is driven by angiotensin II and K⁺ via calcium/CaMKI signaling converging on a CRE-like element (−71/−64) and an SF-1/COUP-TF site, with SF-1 paradoxically repressing CYP11B2 while activating other steroidogenic genes (PMID:9139807, PMID:12193581, PMID:11932209). Loss-of-function mutations cause corticosterone methyloxidase deficiency (types I and II), while chimeric CYP11B1/CYP11B2 genes arising from unequal crossing-over cause glucocorticoid-remediable aldosteronism (PMID:1594605, PMID:1303253).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1989 High

    Identification of CYP11B2 as a second 11β-hydroxylase gene with divergent promoter architecture established that aldosterone biosynthesis could be genetically separable from cortisol production.

    Evidence Genomic cloning and sequencing of the human CYP11B locus revealed two nine-exon genes sharing 93% protein identity but with divergent 5′-flanking regions.

    PMID:2592361

    Open questions at the time
    • CYP11B2 transcripts were not detectable in normal adrenal at time of cloning
    • enzymatic activity not yet assigned to the CYP11B2 product
  2. 1990 High

    Functional reconstitution answered whether CYP11B2 encodes a distinct enzyme: its product catalyzes the complete conversion of deoxycorticosterone to aldosterone, while CYP11B1 cannot, establishing CYP11B2 as aldosterone synthase.

    Evidence cDNA expression in COS-7 and COS-1 cells with steroid product analysis demonstrated 11β-hydroxylase, 18-hydroxylase, and 18-oxidase activities for CYP11B2 but only 11β-hydroxylase for CYP11B1.

    PMID:1741400 PMID:1775135 PMID:2256920

    Open questions at the time
    • structural basis for 18-oxidase specificity not determined
    • electron transfer partners not defined
  3. 1992 High

    Genetic studies resolved the molecular basis of two Mendelian disorders: loss-of-function CYP11B2 mutations (R181W, V386A) cause corticosterone methyloxidase II deficiency, while chimeric CYP11B1/CYP11B2 genes from unequal crossing-over cause glucocorticoid-remediable aldosteronism, mapping disease-critical 18-oxidase determinants to the 3′ coding region.

    Evidence Patient sequencing, exon-swap constructs expressed in cultured cells, and Southern blot/PCR of chimeric genes across 12 kindreds.

    PMID:1303253 PMID:1346492 PMID:1518866 PMID:1594605

    Open questions at the time
    • genotype-phenotype discordance (CMO-I vs CMO-II) not fully explained by in vitro activity
    • additional unidentified mutations or modifiers suggested by some pedigrees
  4. 1997 High

    Promoter dissection identified the cis-regulatory logic of CYP11B2: a CRE-like element at −71/−64 binding CREB/ATF factors and an SF-1/COUP-TF element at −129/−114 are both required for basal activity and agonist (angiotensin II, K⁺, cAMP) induction.

    Evidence Deletion/mutation reporter constructs, DNase I footprinting, and EMSA with H295R adrenocortical cell nuclear extracts.

    PMID:9139807 PMID:9584833

    Open questions at the time
    • identity of trans-acting factors mediating agonist-specific responses not fully resolved
    • role of distal enhancers (e.g., Alu elements) not yet explored
  5. 2002 High

    The calcium/calmodulin-dependent kinase CaMKI was identified as the specific kinase transducing calcium signals to CYP11B2 transcription via the CRE element, while SF-1 was shown to paradoxically repress CYP11B2—making it unique among steroidogenic genes.

    Evidence Constitutively active CaMK isoform transfections with CYP11B2 reporter and CRE mutations in H295R cells; SF-1 co-transfection assays comparing CYP11B2 with CYP11B1/CYP11A1/CYP17 reporters.

    PMID:11932209 PMID:12193581

    Open questions at the time
    • downstream transcription factor phosphorylated by CaMKI not identified
    • mechanism of SF-1 repression unknown
  6. 2002 High

    Site-directed mutagenesis of specific residues (I112, D147, V381, I384) mapped substrate access and individual catalytic steps (11β-hydroxylation, 18-hydroxylation, 18-oxidation) to discrete structural features, advancing understanding of how CYP11B2 differs from CYP11B1 at the atomic level.

    Evidence Mutant CYP11B2 and CYP11B1 proteins expressed in E. coli with in vitro steroid hydroxylation assays and homology modeling.

    PMID:11856349 PMID:9874258

    Open questions at the time
    • no experimental 3D structure available at this time
    • electron transfer coupling not structurally characterized
  7. 2013 High

    Crystal structures of CYP11B2 with substrate (deoxycorticosterone) and inhibitor (fadrozole) revealed the structural basis of 18-oxidase specificity: divergent I-helix residues near the O₂ activation site and H-helix egress-channel loops retain reaction intermediates, while low processivity limits aldosterone output.

    Evidence X-ray crystallography at atomic resolution combined with biochemical substrate conversion assays.

    PMID:23322723

    Open questions at the time
    • no structure of CYP11B2 bound to 18-hydroxycorticosterone intermediate
    • dynamic conformational changes during catalytic cycle not captured
  8. 2014 Medium

    Post-transcriptional regulation of CYP11B2 was established: miR-10b and later miR-193a-3p directly target the CYP11B2 3′-UTR, adding a layer of negative regulation beyond transcriptional control.

    Evidence Luciferase reporter assays with wild-type and mutant 3′-UTR constructs, miRNA overexpression/knockdown, and functional rescue in H295R cells.

    PMID:24768260 PMID:29665181

    Open questions at the time
    • physiological contexts triggering miR-10b or miR-193a-3p regulation of aldosterone in vivo not established
    • relative contribution of miRNA versus transcriptional regulation to aldosterone output unknown
  9. 2021 Medium

    Chemical biology identified a covalent inhibition mechanism exploiting Cys450 and Ala320 unique to CYP11B2: atractylenolide-I is epoxidized and covalently modifies Cys450, disrupting heme interaction and selectively inactivating aldosterone synthase without affecting CYP11B1.

    Evidence Activity-based protein profiling, molecular docking, mutagenesis, and cell-based aldosterone/cortisol assays with in vivo hyperaldosteronism model.

    PMID:35127376

    Open questions at the time
    • co-crystal structure of covalent adduct not obtained
    • pharmacokinetics and selectivity in humans unknown
  10. 2023 Medium

    Epigenetic regulation was defined: CYP11B2 promoter DNA methylation recruits MeCP2 and reduces CREB1/NGFIB binding, while physiological stimuli (low salt, angiotensin II, K⁺) induce promoter hypomethylation, linking environmental signals to epigenetic derepression.

    Evidence DNA methylation arrays, bisulfite sequencing, EMSA, and reporter assays in adrenal tissue and cell lines.

    PMID:36982850

    Open questions at the time
    • identity of demethylase(s) mediating stimulus-dependent hypomethylation unknown
    • relative importance of methylation versus transcription factor availability in vivo not quantified

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural dynamics of CYP11B2 during the multi-step catalytic cycle—particularly how intermediates (corticosterone, 18-hydroxycorticosterone) are retained or released, and how electron transfer from adrenodoxin is coupled to each oxidation step—remain incompletely resolved at the structural level.
  • no structures of intermediate-bound states
  • cryo-EM or time-resolved crystallography of catalytic cycle not performed
  • in vivo regulation of CYP11B2 processivity not characterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 8 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005739 mitochondrion 2
Pathway
R-HSA-1430728 Metabolism 4 R-HSA-162582 Signal Transduction 3
Partners
ATF2CAMK1CREB1CYP11B1MECP2SF1

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1989 CYP11B2 was identified as a second human steroid 11β-hydroxylase gene (alongside CYP11B1), each containing nine exons. The CYP11B2-encoded protein shares 93% amino acid identity with CYP11B1, but the 5'-flanking regions of the two genes diverge considerably, and CYP11B2 transcripts were not detected in normal adrenal mRNA at the time of initial characterization. Genomic cloning, sequencing, exon-intron mapping, and comparative analysis of CYP11B1 and CYP11B2 genes The Journal of biological chemistry High 2592361
1990 The CYP11B2-encoded protein (P-450aldo) was shown by cDNA expression in COS-7 cells to preferentially catalyze the full conversion of 11-deoxycorticosterone to aldosterone via corticosterone and 18-hydroxycorticosterone, whereas the closely related P-450(11)β (CYP11B1 product) substantially fails to catalyze aldosterone formation, establishing CYP11B2 as the aldosterone synthase. cDNA cloning from adrenal tumor, expression in COS-7 cells, steroid product analysis Biochemical and biophysical research communications High 2256920
1991 Expression of CYP11B2 cDNA in COS-1 cells demonstrated that its protein product can 11β-hydroxylate, 18-hydroxylate, and 18-oxidize corticosteroids, synthesizing aldosterone from deoxycorticosterone, whereas CYP11B1 product only 11β-hydroxylates. CYP11B2 mRNA is induced in adrenal zona glomerulosa cells by angiotensin II, confirming CYP11B2 is required for aldosterone biosynthesis. PCR-based expression analysis, cDNA cloning, transient transfection of COS-1 cells, steroid product measurement Molecular endocrinology (Baltimore, Md.) High 1775135
1992 CYP11B2 encodes both steroid 11β-hydroxylase and 18-hydroxylase (P-450C18/aldosterone synthase) activities. Expression in COS-7 cells confirmed that CYP11B2 product catalyzes synthesis of aldosterone and 18-oxocortisol, whereas CYP11B1 product exclusively exhibits 11β-hydroxylase activity. Promoter deletion analysis showed the two genes are regulated by distinct transcriptional mechanisms. Genomic cloning, cDNA expression in COS-7 cells, CAT reporter gene assays with deletion mutants of promoter regions in Y-1 adrenal tumor cells Proceedings of the National Academy of Sciences of the United States of America High 1741400
1992 Glucocorticoid-suppressible hyperaldosteronism (GSH) is caused by unequal meiotic crossing-over between CYP11B1 and CYP11B2, generating a hybrid gene with CYP11B1 5'-regulatory/coding sequences and CYP11B2 3'-coding sequences. Cells transfected with hybrid cDNAs containing up to three CYP11B1 exons synthesized aldosterone at near-normal levels, but hybrids with five or more CYP11B1 exons could not produce detectable aldosterone, mapping the aldosterone synthase functional determinants to the 3' coding region of CYP11B2. Southern blot, PCR detection of hybrid genes in patients, transient transfection of hybrid cDNAs in cultured cells with steroid product measurement Proceedings of the National Academy of Sciences of the United States of America High 1518866
1992 Glucocorticoid-remediable aldosteronism in 12 kindreds is caused by chimeric gene duplications fusing CYP11B1 regulatory sequences to CYP11B2 coding sequences via unequal crossing-over at introns 2–4, placing aldosterone synthase under ACTH/glucocorticoid-suppressible regulation. Sites of crossing-over range from intron 2 to intron 4. Southern blot and PCR analysis of chimeric gene structure in affected kindreds Nature genetics High 1303253
1992 Two point mutations in CYP11B2 — R181W (exon 3) and V386A (exon 7) — were identified as the molecular basis of corticosterone methyloxidase II (CMO-II) deficiency. When expressed in cultured cells, R181W abolished 18-oxidase activity and reduced 18-hydroxylase activity while preserving 11β-hydroxylase activity; V386A caused a smaller reduction in 18-hydroxycorticosterone production. These mutations map the 18-oxidase and 18-hydroxylase functions to specific CYP11B2 residues. Mutation identification by sequencing, site-directed mutagenesis of CYP11B2 cDNA, expression in cultured cells with steroid product assay Proceedings of the National Academy of Sciences of the United States of America High 1594605
1992 Point mutations R181W and V386A in CYP11B2 (P-450C18) were confirmed in CMO-II deficiency patients by PCR-restriction analysis, with patients homozygous for both mutations and unaffected parents heterozygous, consistent with autosomal recessive inheritance. PCR-restriction enzyme analysis of CYP11B2 mutations in patients and family members Biochemical and biophysical research communications High 1346492
1991 Rat cytochrome P-450aldo (CYP11B2 ortholog) and P-450(11)β genes share similar intron-exon organization but have divergent 5'-flanking regions. A putative cAMP-responsive element (TGACGTGA) is present in the P-450aldo gene but altered in P-450(11)β, suggesting differential transcriptional regulation. S1 nuclease assay identified a single transcription initiation site for P-450aldo. Genomic cloning, sequencing, S1 nuclease protection assay Biochemical and biophysical research communications Medium 1953771
1995 A mutation T318M in CYP11B2 was identified in a patient with CMO-II deficiency. When this mutation (along with parental allele mutations R181W, delta C372, and V386A) was expressed in cDNA vectors, neither allele contributed measurable aldosterone synthase activity, yet the clinical phenotype was CMO-II (not CMO-I), suggesting that factors beyond CYP11B2 enzymatic activity modulate the severity of the deficiency phenotype. Direct DNA sequencing, cDNA expression in cultured cells with steroid assay American journal of human genetics Medium 7485152
1996 A gene conversion in exons 3-4 of CYP11B2 (introducing D141E, K151N, I246T changes) was identified in CMO-II deficiency patients, but functional expression in COS-1, MA-10, and JEG-3 cells showed that these triple mutations retain normal 18-oxidase activity, demonstrating the gene conversion per se does not cause CMO-II deficiency and pointing to unidentified mutations elsewhere. Sequencing of CYP11B2, site-directed mutagenesis, expression in COS-1, MA-10, and JEG-3 cells, steroid product assay The Journal of clinical endocrinology and metabolism High 8550772
1996 Calcium signaling via L-type calcium channel activation and ionomycin treatment increases human CYP11B2 reporter gene expression in H295R adrenocortical cells but not in Y-1 cells, demonstrating that calcium-signaling pathways regulate CYP11B2 transcription, and that H295R is the appropriate model for this study. Transient transfection of luciferase reporter constructs containing CYP11B2 5'-flanking DNA in H295R and Y-1 adrenocortical cell lines Endocrine research Medium 8969900
1997 Angiotensin II, K+, and cAMP signaling pathways regulate human CYP11B2 transcription through two distinct cis-elements: a CRE-like element at -71/-64 (TGACGTGA) that binds CREB proteins, and an SF-1/COUP-TF binding element at -129/-114. Both elements are required for full basal activity and maximal induction, as shown by deletion, mutation, DNase I footprinting, and EMSA analyses. Transient transfection of deletion/mutation reporter constructs in H295R cells, DNase I footprinting, EMSA with nuclear extracts Molecular endocrinology (Baltimore, Md.) High 9139807
1997 Angiotensin II and KCl stimulate CYP11B2 promoter activity in NCI-H295 cells via common cis-elements. A cis-element at -143/-161 is required for high-level promoter activity upon stimulation. Calcium channel blockade abolishes KCl stimulation, while protein kinase C inhibition (bisindolylmaleimide) enhances promoter activity, indicating PKC negatively regulates CYP11B2 transcription, and the PKA pathway positively regulates it. Transient transfection of hamster CYP11B2 deletion/mutation reporter constructs in NCI-H295 cells, pharmacological inhibitors of calcium channels and PKC Journal of molecular endocrinology Medium 9584833
1998 Two mutations E198D and V386A in CYP11B2 together cause aldosterone synthase deficiency type I in two twins. When expressed individually, these and R173K have modest effects; together, they cause decreased 11β-hydroxylase activity, large decrease of 18-hydroxylase, and absent 18-oxidase activity, demonstrating that combined mutations can produce a more severe phenotype than either alone. Sequencing of CYP11B2, transfection assays of mutant cDNA combinations in cultured cells with steroid product measurement The Journal of clinical endocrinology and metabolism High 9814506
1998 Rat CYP11B2 and the mutant DR-CYP11B1 (from Dahl salt-resistant rats) were expressed in Escherichia coli. The V381L and I384L double mutation in CYP11B1 accounts for its low 18-hydroxylase activity. V443M is responsible for decreased 19-hydroxylase activity. These results functionally assign 18-hydroxylase and 19-hydroxylase activities to specific residues in the CYP11B sequence. Site-directed mutagenesis, expression of rat CYP11B1 and CYP11B2 in E. coli, in vitro steroid hydroxylation assays European journal of biochemistry High 9874258
2000 The CRE/Ad1 cis-element is required for basal expression and agonist-stimulated transcription of both CYP11B1 and CYP11B2, but mutation of the CRE in CYP11B2 abolishes basal expression yet retains agonist (angiotensin II, cAMP) response, suggesting additional cis-elements mediate hormonal regulation of CYP11B2. EMSA demonstrated binding of CREB, ATF-1, and ATF-2 to the CRE elements, with ATF-2 forming the complex most similar to that seen in H295R nuclear extracts. Transient transfection of CYP11B1 and CYP11B2 reporter constructs with CRE mutations in H295R cells, EMSA with in vitro transcription factor proteins and nuclear extracts Endocrine research High 11196473
2002 Steroidogenic factor-1 (SF-1) paradoxically inhibits CYP11B2 reporter activity while stimulating CYP11B1, CYP11A1, and CYP17 reporters, making CYP11B2 the first steroid hydroxylase not positively regulated by SF-1. The -344C/T polymorphism in the Ad4 (SF-1 binding) element of CYP11B2 influences SF-1 binding in EMSA (C allele binds more strongly), but does not alter agonist-stimulated reporter expression in H295R cells. Transient co-transfection of reporter constructs with SF-1 expression vectors in H295R and Y-1 cells, EMSA with SF-1 and -344C/T allele probes Journal of molecular endocrinology High 11932209
2002 Calmodulin-dependent kinase I (CaMKI) is the primary calcium-dependent kinase regulating CYP11B2 transcription. Constitutively active CaMKI stimulated CYP11B2 reporter expression in H295R cells via the cAMP regulatory element at -71/-64, while CaMKII had no effect and CaMKIV had a small effect. CaMKI expression was confirmed in adrenal cortex and H295R cells by immunohistochemistry and Western/Northern blot. Transient transfection of CaMK expression vectors and CYP11B2 reporter constructs in H295R cells, pharmacological inhibitors (KN93, calmidazolium), mutational analysis of promoter, immunohistochemistry, Western and Northern blot Endocrinology High 12193581
2002 The amino acid substitutions I112P and D147E in human CYP11B2 increase 11β-hydroxylation activity (up to 6-fold when combined), while I112P enhances 18-hydroxylase activity by 70%. The 18-oxidase activity is slightly reduced by most mutations except D147E. Residue I112 in the putative substrate access channel and D147 on the protein surface influence substrate recognition and conversion in CYP11B2. Site-directed mutagenesis of CYP11B2 residues, expression of mutant proteins in E. coli, in vitro steroid hydroxylation assays, computer homology modeling European journal of biochemistry High 11856349
2002 Human CYP11B2 was functionally expressed in fission yeast (Schizosaccharomyces pombe), where its mitochondrial targeting signal is functional (confirmed by Western blot, fluorescence, and electron microscopy). A novel fission yeast ferredoxin-domain protein, etp1, can replace adrenodoxin in electron transfer to CYP11B2, enabling steroid hydroxylation in a reconstituted assay. CYP11B2 in intact yeast cells converts 11-deoxycorticosterone to corticosterone, 18-hydroxycorticosterone, and aldosterone. Heterologous expression in S. pombe, Western blot, fluorescence and electron microscopy for localization, in vivo and reconstituted in vitro steroid hydroxylation assays with recombinant etp1 Biochemistry High 11841224
2006 PCB126 upregulates CYP11B2 mRNA in H295R human adrenocortical cells not through aryl hydrocarbon receptor (AhR)-mediated transcriptional activation, but by increasing posttranscriptional mRNA stability, as demonstrated by AhR antagonist experiments (which failed to block induction) and RNA degradation assays. An internal region of CYP11B1 mRNA (nucleotides 881-1285) was identified as important for PCB126-mediated transcript stabilization. AhR antagonist (3',4'-DMF) treatment, RNA degradation assays, promoter analyses, RT-PCR in H295R cells Endocrinology Medium 16396990
2001 A deletion hybrid CYP11B gene (CYP11B2 promoter + exons 1-6 fused to CYP11B1 exons 7-9 plus an I339T intracodon mutation) was characterized in a patient with 11β-hydroxylase deficiency/congenital adrenal hyperplasia. Expression of the corresponding cDNA in COS-1 cells showed relatively unimpaired 11β-hydroxylase and aldosterone synthase activities, demonstrating that the 11β-hydroxylase deficiency results from absence of CYP11B1 zona fasciculata expression rather than enzymatic incapacity. Gene structure determination, cDNA expression in COS-1 cells, steroid product assay The Journal of clinical endocrinology and metabolism Medium 11443188
2011 CYP11B2 promoter activity is regulated by Alu retrotransposable elements (functioning as enhancers) and conserved proximal cis-elements including Ad5 (bound by ERRα during basal expression) and SF-1 sites. Mutation of the Ad5 site reduces promoter activity to minimal levels. CYP11B1-specific L1 element (CYP11B1-L1.2) inserted between Alu and the conserved region blocks Alu enhancement in CYP11B1 but not CYP11B2, explaining part of the differential regulation of the two paralogs. Reporter gene assays with deletion/mutation constructs, EMSA, sequence analysis, transposable element functional dissection in adrenocortical cell lines Steroids Medium 22079243
2013 Crystal structures of human aldosterone synthase (CYP11B2) in complex with substrate deoxycorticosterone and inhibitor fadrozole were solved. The structures reveal a hydrophobic active site with features for corticosteroid recognition. Divergent residues conferring 18-oxidase activity (unique to CYP11B2 vs. CYP11B1) are located in the I-helix (near O2 activation) and loops around the H-helix (affecting an egress channel required for retaining intermediates). Fadrozole binds in R-configuration using part of the active site cavity. Low processivity (high release of intermediates) is identified as a mechanism of controlled aldosterone production. X-ray crystallography of CYP11B2 with substrate and inhibitor, biochemical substrate conversion assays Molecular endocrinology (Baltimore, Md.) High 23322723
2010 Five novel CYP11B2 mutations causing aldosterone synthase deficiency type I (W260X, G206WfsX51, L496SfsX169, S315R, R374W) were identified. Expression of S315R and R374W in COS-1 cells showed complete absence of CYP11B2 activity for conversion of 11-deoxycorticosterone to aldosterone. 3D modeling indicated these mutations disrupt hydrogen bond networks in the enzyme. Sequencing, expression of mutant CYP11B2 in COS-1 cells, steroid product assay, 3D structural modeling Molecular genetics and metabolism High 20494601
2008 A novel CYP11B2 mutation S308P (T925C in exon 5) was identified in siblings with hyperreninemic hypoaldosteronism. Functional characterization in vitro showed complete loss of enzyme activity. Structural modeling placed S308 within the alpha-helix I near the heme-binding active site. However, in vivo dexamethasone treatment further reduced aldosterone levels, suggesting some residual mineralocorticoid biosynthesis occurs through alternative pathways or residual mutant activity. Sequencing, in vitro functional expression of S308P mutant, structural modeling, dexamethasone suppression test in vivo The Journal of clinical endocrinology and metabolism High 19116236
2011 HDL2 stimulates aldosterone synthesis in H295R human adrenocortical cells by increasing CYP11B2 mRNA expression up to 19-fold. This effect is mediated through a calcium signaling cascade (abolished by calcium channel blockers and calmodulin kinase inhibitors) and is not additive with angiotensin II or K+ stimulation. H295R cell treatment with HDL subfractions, CYP11B2 mRNA quantification, aldosterone measurement, pharmacological inhibitors of calcium signaling Endocrinology Medium 21239432
2014 miR-10b, induced by hypoxia and HIF-1α in H295R adrenocortical cells, negatively regulates CYP11B2 (and CYP11B1) mRNA through their 3'-UTRs. Luciferase assays with 3'-UTR constructs, combined with miRNA overexpression and knockdown, established CYP11B2 as a direct post-transcriptional target of miR-10b. miRNA arrays, luciferase reporter assays with CYP11B2 3'-UTR in H295R cells, miRNA overexpression and knockdown, HIF-1α overexpression Marine pollution bulletin Medium 24768260
2015 Torasemide (but not furosemide) inhibits human CYP11B2 enzymatic activity by 75% in transfected lung fibroblasts (V79MZ cells), independently of mineralocorticoid receptor. In mice with cardiac Rac1 overexpression, torasemide prevented atrial fibrosis and atrial fibrillation correlated with suppression of CTGF, LOX, and miR-21; the selective CYP11B2 inhibitor SL242 mimicked torasemide effects, establishing CYP11B2 activity as a contributor to atrial fibrosis. CYP11B2 activity assay in transfected cells, cardiac fibroblast assays, in vivo mouse model with torasemide/furosemide treatment, gene expression and histology Journal of molecular and cellular cardiology Medium 26047574
2018 miR-193a-3p directly targets the 3'-UTR of CYP11B2 in H295R adrenocortical cells, as validated by luciferase reporter assay and site-directed mutation of the binding site. Overexpression of miR-193a-3p reduces CYP11B2 mRNA and protein, decreases aldosterone secretion, inhibits proliferation, and promotes apoptosis. Restoration of CYP11B2 rescues these effects, establishing CYP11B2 as a functional target of miR-193a-3p in aldosterone-producing adenoma. Luciferase reporter assays with wild-type and mutant CYP11B2 3'-UTR, miRNA mimic transfection in H295R cells, qRT-PCR, Western blot, aldosterone ELISA, flow cytometry International journal of experimental pathology Medium 29665181
2021 Atractylenolide-I (AT-I) selectively inhibits CYP11B2 through a covalent mechanism: the C8/C9 double bond of AT-I is epoxidized and then undergoes nucleophilic addition with Cys450 of CYP11B2 (enabled by the presence of Ala320 in CYP11B2, absent in CYP11B1). This covalent binding disrupts the interaction between heme and CYP11B2, inactivating the enzyme and suppressing aldosterone synthesis without affecting CYP11B1-mediated cortisol production. Chemical biology/activity-based protein profiling, molecular docking, mutagenesis, cell-based aldosterone/cortisol measurement, in vivo hyperaldosteronism model Acta pharmaceutica Sinica. B Medium 35127376
2023 DNA methylation negatively controls CYP11B2 expression; hypomethylation of the CYP11B2 promoter is seen in aldosterone-producing adenomas. Methylation of recognition sites for CREB1 and NGFIB (nerve growth factor-induced clone B) reduces their DNA-binding activity. Methyl-CpG-binding protein 2 (MeCP2) directly cooperates with methylated CpG dinucleotides of the CYP11B2 promoter. Low-salt diet, angiotensin II, and K+ stimulation increase CYP11B2 mRNA and induce promoter DNA hypomethylation. DNA methylation array, bisulfite sequencing, reporter assays, EMSA, adrenal tissue analysis International journal of molecular sciences Medium 36982850

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
1999 Characterization of single-nucleotide polymorphisms in coding regions of human genes. Nature genetics 1381 10391209
2004 Overview of steroidogenic enzymes in the pathway from cholesterol to active steroid hormones. Endocrine reviews 1274 15583024
2000 DNA cloning using in vitro site-specific recombination. Genome research 815 11076863
1999 Patterns of single-nucleotide polymorphisms in candidate genes for blood-pressure homeostasis. Nature genetics 769 10391210
2004 Comparison of cytochrome P450 (CYP) genes from the mouse and human genomes, including nomenclature recommendations for genes, pseudogenes and alternative-splice variants. Pharmacogenetics 729 15128046
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
1989 Characterization of two genes encoding human steroid 11 beta-hydroxylase (P-450(11) beta). The Journal of biological chemistry 436 2592361
2017 Synergistic drug combinations for cancer identified in a CRISPR screen for pairwise genetic interactions. Nature biotechnology 378 28319085
1991 The product of the CYP11B2 gene is required for aldosterone biosynthesis in the human adrenal cortex. Molecular endocrinology (Baltimore, Md.) 315 1775135
1992 Hereditary hypertension caused by chimaeric gene duplications and ectopic expression of aldosterone synthase. Nature genetics 273 1303253
2013 Development of monoclonal antibodies against human CYP11B1 and CYP11B2. Molecular and cellular endocrinology 245 24325867
2021 Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context. Cell metabolism 239 34800366
1992 Role of steroid 11 beta-hydroxylase and steroid 18-hydroxylase in the biosynthesis of glucocorticoids and mineralocorticoids in humans. Proceedings of the National Academy of Sciences of the United States of America 213 1741400
1992 Glucocorticoid-suppressible hyperaldosteronism results from hybrid genes created by unequal crossovers between CYP11B1 and CYP11B2. Proceedings of the National Academy of Sciences of the United States of America 207 1518866
2001 Effects of three candidate genes on prevalence and incidence of hypertension in a Caucasian population. Journal of hypertension 185 11518842
1995 Haplotype analysis of CYP11B2. Endocrine research 168 7588407
1997 Angiotensin II and potassium regulate human CYP11B2 transcription through common cis-elements. Molecular endocrinology (Baltimore, Md.) 165 9139807
2009 Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip. American journal of human genetics 164 19913121
1992 Mutations in the human CYP11B2 (aldosterone synthase) gene causing corticosterone methyloxidase II deficiency. Proceedings of the National Academy of Sciences of the United States of America 150 1594605
1990 Cloning and expression of a cDNA for human cytochrome P-450aldo as related to primary aldosteronism. Biochemical and biophysical research communications 150 2256920
2001 Molecular basis of salt sensitivity in human hypertension. Evaluation of renin-angiotensin-aldosterone system gene polymorphisms. Hypertension (Dallas, Tex. : 1979) 149 11711524
2017 Age-Related Autonomous Aldosteronism. Circulation 148 28566337
2000 Steroidogenic enzyme gene expression in the human heart. The Journal of clinical endocrinology and metabolism 144 10902803
2002 Differential regulation of aldosterone synthase and 11beta-hydroxylase transcription by steroidogenic factor-1. Journal of molecular endocrinology 126 11932209
2006 Association of DNA repair and steroid metabolism gene polymorphisms with clinical late toxicity in patients treated with conformal radiotherapy for prostate cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 119 16638864
1999 Genetic polymorphism of CYP11B2 gene and hypertension in Japanese. Hypertension (Dallas, Tex. : 1979) 114 9931115
2013 Structural insights into aldosterone synthase substrate specificity and targeted inhibition. Molecular endocrinology (Baltimore, Md.) 108 23322723
2013 Histopathological diagnosis of primary aldosteronism using CYP11B2 immunohistochemistry. The Journal of clinical endocrinology and metabolism 107 23443813
2004 Predictive models for breast cancer susceptibility from multiple single nucleotide polymorphisms. Clinical cancer research : an official journal of the American Association for Cancer Research 102 15102677
2001 Genetic polymorphisms of the renin-angiotensin-aldosterone system in end-stage renal disease. Kidney international 101 11422735
2001 Angiotensin II type 1 receptor-153A/G and 1166A/C gene polymorphisms and increase in aortic stiffness with age in hypertensive subjects. Journal of hypertension 97 11288810
2002 Calmodulin-dependent kinase I regulates adrenal cell expression of aldosterone synthase. Endocrinology 96 12193581
2014 Adrenal CYP11B1/2 expression in primary aldosteronism: immunohistochemical analysis using novel monoclonal antibodies. Molecular and cellular endocrinology 90 24837548
2016 Preclinical and Early Clinical Profile of a Highly Selective and Potent Oral Inhibitor of Aldosterone Synthase (CYP11B2). Hypertension (Dallas, Tex. : 1979) 87 27872236
2002 Variation at the aldosterone synthase (CYP11B2) locus contributes to hypertension in subjects with a raised aldosterone-to-renin ratio. The Journal of clinical endocrinology and metabolism 87 12213905
2002 Functional expression of human mitochondrial CYP11B2 in fission yeast and identification of a new internal electron transfer protein, etp1. Biochemistry 82 11841224
2000 Lys(173)Arg and -344T/C variants of CYP11B2 in Japanese patients with low-renin hypertension. Hypertension (Dallas, Tex. : 1979) 81 10720581
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