Affinage

CYP11A1

Cholesterol side-chain cleavage enzyme, mitochondrial · UniProt P05108

Length
521 aa
Mass
60.1 kDa
Annotated
2026-06-09
100 papers in source corpus 39 papers cited in narrative 39 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CYP11A1 (P450scc) catalyzes the rate-limiting, obligatory first step of all steroid hormone biosynthesis—the side-chain cleavage of cholesterol to pregnenolone—and Cyp11a1-null mice completely lack steroidogenesis, die shortly after birth unless rescued by steroid injection, and show feminization of XY males, establishing the enzyme as indispensable (PMID:3011839, PMID:12145347). The enzyme is membrane-associated, contacting the phospholipid bilayer in part through its F-G loop (PMID:14637024), and depends on a Type I electron-transfer chain in which adrenodoxin reductase and adrenodoxin deliver NADPH-derived electrons; CYP11A1 engages adrenodoxin through positively charged proximal-surface residues (K403, K405, R426), and the stability of the adrenodoxin·CYP11A1 complex directly sets catalytic throughput (PMID:12081479, PMID:11459837). Cholesterol delivery to the inner-membrane enzyme is itself rate-limiting and requires sterol transfer machinery and StAR-type proteins (PMID:22217822, PMID:18573681). Beyond cholesterol, reconstituted CYP11A1 hydroxylates alternative sterol substrates—7-dehydrocholesterol, vitamin D3, vitamin D2, and lumisterol—generating bioactive metabolites such as 20-hydroxyvitamin D3, whose antiproliferative and antifibrotic effects act through nuclear receptors VDR and RORγ (PMID:14657394, PMID:15511223, PMID:16817851, PMID:21677063, PMID:25130438, PMID:33107570). Transcription in steroidogenic tissues is driven by cAMP–PKA signaling through SF-1/Ad4BP acting combinatorially with CREB/ATF, Sp1, and NF1-like factors at promoter and upstream enhancer elements, with the HIPK3/JNK/c-Jun module potentiating SF-1 activity (PMID:8247022, PMID:8026494, PMID:7592707, PMID:10383457, PMID:17210646). Post-translationally, CYP11A1 abundance is controlled by LONP1-mediated proteolysis, a mechanism exploited pharmacologically by artemisinins to lower androgen output (PMID:38870290). Loss-of-function CYP11A1 mutations cause classic and nonclassic lipoid congenital adrenal hyperplasia and primary adrenal insufficiency, with genotype severity tracking residual catalytic activity or protein stability (PMID:12161514, PMID:21159840, PMID:23337730, PMID:30620006). The enzyme also exerts non-adrenal functions: its steroidogenic activity in CD8+ and TH2 cells is required for IL-13/TH2 cytokine production (PMID:23630275, PMID:23870673), and pharmacological inhibition (ODM-208) confirms CYP11A1 as the source of residual androgens in castration-resistant prostate cancer (PMID:38320513).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1986 High

    Established that a single enzyme, P450scc, performs cholesterol-to-pregnenolone conversion in human steroidogenesis and that its expression is hormonally controlled, defining the entry point of steroid synthesis.

    Evidence Northern blot and progesterone secretion assays with hCG/FSH dose-response in primary human granulosa cells

    PMID:3011839

    Open questions at the time
    • Did not define the cis-elements or transcription factors mediating cAMP induction
    • No structural basis for catalysis addressed
  2. 1992 Medium

    Resolved how cholesterol reaches the inner-membrane enzyme, showing that substrate delivery rather than catalysis is the kinetically limiting event in steroidogenesis.

    Evidence Cell fractionation, inhibitor studies, and reconstitution of mitochondrial cholesterol transfer with defined factors

    PMID:22217822

    Open questions at the time
    • Partly a review compiling earlier work
    • Relative contributions of SCP2, StAR-type peptides, and GTP not fully quantified
  3. 1994 High

    Mapped the cAMP-responsive transcriptional architecture, identifying SF-1/Ad4BP acting with CREB/ATF, Sp1, and NF1-like factors at distinct proximal and upstream elements to confer cell-specific, hormone-inducible CYP11A1 expression.

    Evidence Promoter deletion, footprinting, EMSA/supershift, and reporter transfection across adrenal (Y1), placental (JEG-3), and Sp-negative SL2 cells, plus PKA-deficient lines

    PMID:10383457 PMID:1333053 PMID:1446636 PMID:2154474 PMID:7592707 PMID:8026494 PMID:8119986 PMID:8247022 PMID:8703023

    Open questions at the time
    • Tissue-specific differences (e.g. placental vs adrenal use of distinct elements) only partially explained
    • In vivo relevance of individual elements not yet tested
  4. 1999 High

    Defined the molecular basis of the redox partnership, showing that specific proximal-surface basic residues mediate electrostatic docking of adrenodoxin and that complex stability dictates catalytic efficiency.

    Evidence Site-directed mutagenesis (K403/K405/R426; adrenodoxin S112W), binding/reduction kinetics, cholesterol conversion assays, and molecular docking

    PMID:11459837 PMID:12081479

    Open questions at the time
    • No high-resolution co-structure of the human complex in the timeline
    • Dynamics of electron transfer during the three sequential oxidations not resolved
  5. 2002 High

    Demonstrated genetically that CYP11A1 is essential and obligatory for all steroidogenesis, and linked human mutations to P450scc-deficiency phenotypes.

    Evidence Cyp11a1 knockout mice with steroid rescue, plus patient mutation analysis recreated in fusion-protein enzyme assays

    PMID:12145347 PMID:12161514

    Open questions at the time
    • Did not establish full genotype-phenotype spectrum for partial-activity alleles
  6. 2003 High

    Revealed that CYP11A1 has a broader substrate range than cholesterol, hydroxylating 7-dehydrocholesterol and vitamin D to novel bioactive metabolites, and clarified its monotopic membrane association.

    Evidence Reconstituted purified-enzyme systems with MS/NMR product identification, plus fluorescent membrane-binding probes on F-G loop residues

    PMID:14637024 PMID:14657394

    Open questions at the time
    • Physiological abundance and in vivo roles of these metabolites not established at this stage
  7. 2008 High

    Extended the alternative-substrate catalogue and characterized sequential hydroxylation kinetics in membranes, identifying vitamin D2 and lumisterol products and StAR-stimulated substrate exchange.

    Evidence Reconstituted membrane-bound kinetics, NMR/LC-MS product identification, tissue (adrenal, pig adrenal, skin mitochondria) validation

    PMID:15511223 PMID:16817851 PMID:18573681 PMID:25130438

    Open questions at the time
    • Quantitative in vivo contribution of CYP11A1 to circulating vitamin D/lumisterol metabolites not measured
  8. 2011 High

    Connected CYP11A1-derived sterol metabolites to downstream signaling, showing the hydroxyvitamin D products are biologically active through VDR and RORγ.

    Evidence Reconstituted enzymatic production with NMR, keratinocyte/fibroblast proliferation and differentiation assays, VDR translocation imaging, and RORγ knockout fibroblasts

    PMID:21677063 PMID:33107570

    Open questions at the time
    • Receptor selectivity among multiple metabolites not fully dissected
    • In vivo significance in human skin physiology not established
  9. 2013 High

    Identified non-adrenal immune functions, establishing that CYP11A1 steroidogenic activity in CD8+ and TH2 cells is required for IL-13/TH2 cytokine production and allergic inflammation.

    Evidence Pharmacological inhibition (aminoglutethimide) plus shRNA knockdown, cytokine quantification, adoptive transfer, and in vivo allergy models

    PMID:23630275 PMID:23870673

    Open questions at the time
    • Identity of the active steroid metabolite mediating cytokine switching beyond pregnenolone not pinpointed
    • Mechanism linking steroid output to cytokine gene regulation unresolved
  10. 2013 High

    Refined the human disease genotype-activity-phenotype relationship and revealed dosage-sensitive reproductive consequences of CYP11A1 levels.

    Evidence Multiple patient missense mutations recreated in fusion-protein enzyme assays with kinetic parameters, plus BAC-transgenic Cyp11a1-overexpressing mice

    PMID:21159840 PMID:23337730 PMID:23555723 PMID:23966322

    Open questions at the time
    • Trophoblast apoptosis mechanism relied on single-method overexpression readout
    • Causal vs correlative role of CYP11A1 upregulation in preeclampsia not resolved
  11. 2019 High

    Established that disease can arise through protein-stability defects, not only catalytic loss, exemplified by the missplicing/turnover phenotype of the common p.E314K variant.

    Evidence Minigene splicing assay, mammalian-cell expression, cycloheximide-chase half-life measurement, and fusion-protein activity assays

    PMID:30299480 PMID:30620006

    Open questions at the time
    • Cellular machinery degrading the destabilized variant not identified at this stage
  12. 2024 High

    Identified a post-translational control axis, showing LONP1-mediated proteolysis sets CYP11A1 abundance and that artemisinins exploit this to lower androgen biosynthesis.

    Evidence Target identification of artemisinins, reciprocal LONP1-CYP11A1 co-IP, degradation assays, LONP1 overexpression, and androgen measurements in PCOS models and patients

    PMID:38870290

    Open questions at the time
    • Whether LONP1 degradation is regulated physiologically to tune steroidogenesis not established
    • Structural basis of LONP1 recognition of CYP11A1 unknown
  13. 2023 High

    Validated CYP11A1 as a therapeutic target, with the inhibitor ODM-208 abolishing residual androgen biosynthesis in castration-resistant prostate cancer.

    Evidence Phase 1/2 clinical trial with pharmacodynamic steroid measurements and PSA response in 92 patients

    PMID:38320513

    Open questions at the time
    • On-target adrenal insufficiency requires steroid replacement
    • Durability of response and resistance mechanisms not addressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved which steroid metabolite mediates CYP11A1's immunomodulatory and tissue-specific functions and how its substrate selection between cholesterol and alternative sterols is regulated in vivo.
  • Effector metabolite in immune cells not identified
  • In vivo balance between classical steroidogenesis and vitamin D/lumisterol hydroxylation unquantified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 5 GO:0016787 hydrolase activity 4 GO:0008289 lipid binding 2
Localization
GO:0005739 mitochondrion 4
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-168256 Immune System 2
Partners
FDX1FDXRLONP1NR5A1

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1986 P450scc (CYP11A1) is the single enzyme mediating conversion of cholesterol to pregnenolone (20,22-desmolase activity) in human steroidogenesis; its mRNA accumulation in granulosa cells is stimulated in a dose-dependent, cAMP-mediated manner by hCG and FSH, indicating gonadotropin-specific transcriptional regulation. Northern blot hybridization with 32P-labeled P450scc cDNA; progesterone secretion assay; hormone dose-response in primary human granulosa cell cultures The Journal of Clinical Endocrinology and Metabolism High 3011839
1990 The bovine CYP11A1 promoter contains a cAMP-responsive region between -186 and -101 bp that functions independently of canonical CRE sequences; sequences between -183 and -83 bp drive both basal and cAMP-enhanced transcription when fused to a heterologous promoter in adrenocortical cells. Deletion mutagenesis of the 5'-flanking region linked to a reporter gene; transient transfection into mouse Y1 adrenal tumor cells and primary bovine adrenocortical cells; primer extension for transcription start site mapping The Journal of Biological Chemistry High 2154474
1992 A G-rich sequence element at -118 to -100 bp in the bovine CYP11A promoter binds an Sp1-related protein and overlaps with a putative adrenal-specific protein binding site; deletion of this minimal cAMP-responsive sequence abolishes cAMP-dependent reporter gene transcription in Y1 cells. DNase I footprinting, electrophoretic mobility shift assay (EMSA), competition analysis, reporter gene transfection into Y1 adrenocortical cells Molecular Endocrinology High 1333053
1992 Transfer of cholesterol to the inner mitochondrial membrane–bound CYP11A1 is the rate-limiting step in steroid synthesis; cholesterol supply involves cytoskeletal elements and sterol carrier protein-2 (SCP2) for outer membrane delivery, and steroidogenesis activator peptide plus GTP facilitate inner-to-outer membrane cholesterol transfer. Cell fractionation, inhibitor studies, reconstitution of mitochondrial cholesterol transfer with defined factors, digitonin solubilization of outer mitochondrial membranes The Journal of Steroid Biochemistry and Molecular Biology Medium 22217822
1992 cAMP-dependent regulation of CYP11A1 mRNA in JEG-3 cytotrophoblast cells is principally transcriptional (as shown by RNA polymerase run-on assays), whereas adrenodoxin mRNA regulation is posttranscriptional and not mediated by the AUUUA sequences in its 3'-UTR. Chimeric vector transfection with swapped 3'-UTRs; RNA polymerase run-on assay; actinomycin-D mRNA stability assay; cycloheximide treatment Endocrinology High 1446636
1993 The steroidogenic cell-specific transcription factor Ad4BP (SF-1) activates the CYP11A1 (CYP11A) gene through an Ad4 cis-element in both adrenal and Leydig cells; activation is potentiated by the cAMP pathway via protein kinase A and is absent in nonsteroidogenic cells lacking Ad4BP. Reporter gene constructs with combinations of Ad1/Ad4 cis-elements; transient transfection into Y1, I-10, and PC-12 cells; cotransfection of Ad4BP expression vector; immunoblot for Ad4BP Molecular Endocrinology High 8247022
1993 CYP11A1 fusion proteins with adrenodoxin reductase and adrenodoxin (P450scc-AdRed-Adx triple fusion) achieve substantially higher pregnenolone production than triple transfection of individual components, demonstrating that physical linkage of the Type I electron transfer chain components enhances catalytic efficiency. Construction of fusion protein expression vectors by PCR/cassette assembly; transfection into COS-1 cells; pregnenolone secretion assay using 22R-hydroxycholesterol substrate DNA and Cell Biology High 8517924
1994 The human CYP11A1 gene contains a proximal cAMP-responsive sequence (P-CRS) active in both adrenal Y1 and placental JEG-3 cells, and an upstream CRS (U-CRS, -1621 to -1503) plus an enhancer (-1931 to -1822) that function only in Y1 cells; U-CRS-mediated cAMP response requires protein kinase A, whereas P-CRS does not. Deletion analysis with reporter gene constructs; transient transfection into Y1 and JEG-3 cells; protein kinase A-deficient cell line; DNase I footprinting; gel mobility shift and antibody supershift The Journal of Biological Chemistry High 8119986
1994 CREB/ATF proteins and Ad4BP (SF-1) bind to closely arranged CRE-like and Ad4 sequences in the upstream CYP11A1 regulatory region and act synergistically to confer cAMP-responsive, steroidogenic cell-specific expression. DNase I footprinting with bovine adrenal nuclear extracts; point mutation analysis; reporter gene transfection European Journal of Biochemistry High 8026494
1994 An upstream element (AdE) in the human CYP11A1 gene containing two protein binding regions (AdE1 and AdE2) that bind NF1- and Sp1-like proteins enhances CYP11A1 expression specifically in steroidogenic cells; AdE1 and AdE2 act combinatorially for full activity. EMSA, footprinting, competition, antibody supershift; mutagenesis of binding sites; reporter gene transfection into steroidogenic and nonsteroidogenic cell lines The Journal of Biological Chemistry High 8703023
1995 Two Sp1-binding sites at -111/-100 bp and -70/-50 bp in the bovine CYP11A promoter are necessary for both basal and cAMP-dependent transcription; mutations eliminating Sp1 binding at -111/-100 markedly reduce cAMP-induced transcription via the protein kinase A pathway. EMSA with purified Sp1; anti-Sp1 antibody supershift; mutation analysis; reporter gene transfection into Y1 adrenal cells The Journal of Biological Chemistry High 7592707
1998 Human CYP11A1 expressed in E. coli retains catalytic activity comparable to placenta-purified enzyme; mutation of Ile-462 to Leu decreases kcat with cholesterol and increases Km for 22R-hydroxycholesterol but not for 20α-hydroxycholesterol, indicating that Ile-462 resides near the side-chain binding site. Recombinant expression in E. coli; enzyme purification; kinetic assays (Km, Vmax, kcat) with cholesterol and hydroxycholesterol substrates; site-directed mutagenesis Archives of Biochemistry and Biophysics High 9578606
1999 Sp1 alone is sufficient to confer cAMP-dependent transcriptional activation of CYP11A1 through the -118/-100 element; Sp3 does not repress Sp1-dependent activation at this promoter, unlike other GC-rich promoters. Drosophila SL2 cells lacking endogenous Sp factors; cotransfection of Sp1, Sp3, Sp4 expression vectors with CYP11A reporter; cotransfection of PKA catalytic subunit; mutation of -118/-100 element The Journal of Biological Chemistry High 10383457
1999 Positively charged residues K403, K405, and R426 on the proximal surface of bovine P450scc (CYP11A1) are required for electrostatic interaction with adrenodoxin; R426Q mutation completely abolishes adrenodoxin binding while retaining CO-binding and chemical reducibility. Site-directed mutagenesis of 13 P450scc variants; adrenodoxin binding assay; reduction kinetics; enzymatic activity measurement; molecular modeling and docking Biochemistry High 12081479
2001 Adrenodoxin mutants with C-terminal truncation and introduction of a tryptophan residue (S112W) form more stable complexes with CYP11A1, show faster reduction rates, and achieve ~100-fold increased efficiency in cholesterol-to-pregnenolone conversion, demonstrating that adrenodoxin–CYP11A1 complex stability directly determines catalytic throughput. Site-directed mutagenesis of adrenodoxin; kinetic measurement of CYP11A1·CO complex formation; cholesterol conversion assay The Journal of Biological Chemistry High 11459837
2002 Cyp11a1 null mice completely lack steroid synthesis, die shortly after birth (rescued by steroid injection), develop ectopic Cyp21 expression in the testis due to absence of glucocorticoid feedback, and exhibit feminization of XY males—establishing CYP11A1 as essential for the first and obligatory step of all steroid hormone biosynthesis. Targeted gene disruption (neo insertion into exon 1); steroid measurements; hormonal rescue experiments; histological analysis of adrenals/gonads; RT-PCR for ectopic gene expression Molecular Endocrinology High 12145347
2002 A compound heterozygous CYP11A1 mutation (R353W + A189V/splicing) causes partial P450scc deficiency in humans; R353W markedly reduces enzymatic activity, demonstrating that Arg353 is a crucial residue for catalytic function. Sequencing of CYP11A1; site-directed mutagenesis to recreate mutations in F2 fusion protein; pregnenolone production assay in transfected COS-1 cells The Journal of Clinical Endocrinology and Metabolism High 12161514
2003 Purified CYP11A1 (P450scc) reconstituted with adrenodoxin and adrenodoxin reductase hydroxylates vitamin D3 to produce 20-hydroxyvitamin D3 and 20,22-dihydroxyvitamin D3 as major products, and converts 7-dehydrocholesterol to 7-dehydropregnenolone—identifying a vitamin D hydroxylation pathway distinct from classical 1α/25-hydroxylation. In vitro reconstituted system with purified CYP11A1, adrenodoxin, adrenodoxin reductase; NADPH-dependent metabolism assay; product identification by MS and comparison with standards Proceedings of the National Academy of Sciences of the United States of America High 14657394
2003 The F-G loop region (residues V212 and L219) of CYP11A1 becomes localized to a hydrophobic environment upon membrane binding, as shown by fluorescent probe blue-shift, indicating that CYP11A1 has a monotopic association with the phospholipid membrane mediated at least in part through the F-G loop. Hydrophobicity profiling; A'-helix deletion mutagenesis; cysteine-scanning mutagenesis (L24C, V212C, L219C) with NBD fluorescent labeling; fluorescence blue-shift assay with phospholipid vesicles; tryptophan quenching by acrylamide Biochimica et Biophysica Acta High 14637024
2004 P450scc enzyme and its electron transfer partners (adrenodoxin, adrenodoxin reductase, MLN64) are expressed and functionally active in skin mitochondria; purified P450scc and placental/adrenal mitochondria convert 7-dehydrocholesterol to 7-dehydropregnenolone with kinetics similar to cholesterol conversion. RT-PCR and immunoblot for P450scc system components in skin cells; functional assay of 7-DHC conversion in isolated skin mitochondria; product identity confirmed by NMR, MS, and comparison with synthetic standard European Journal of Biochemistry High 15511223
2006 CYP11A1 metabolizes vitamin D2 in a reconstituted system to produce 20-hydroxyvitamin D2 and 17,20-dihydroxyvitamin D2; adrenal mitochondria also metabolize vitamin D2 with this pathway inhibited by the CYP11A1 inhibitor aminoglutethimide, confirming CYP11A1 as responsible. Reconstituted P450scc system; NMR structure determination of products; adrenal mitochondria metabolism with pharmacological inhibitor control; keratinocyte DNA synthesis assay The FEBS Journal High 16817851
2007 HIPK3 and c-Jun are required for basal and cAMP-stimulated CYP11A1 expression; cAMP stimulation leads to HIPK3-mediated phosphorylation of JNK and c-Jun, and these phosphorylation events enhance SF-1 transcriptional activity for CYP11A1. Cotransfection/overexpression of HIPK3 and c-Jun; siRNA knockdown; luciferase reporter assay; phosphorylation detection; SF-1 activity assays in adrenal/gonadal cells Molecular and Cellular Biology High 17210646
2008 CYP11A1 hydroxylates vitamin D3 sequentially in phospholipid vesicles producing 20(OH)D3 then 20,23(OH)2D3 then 17,20,23(OH)3D3; the Km for vitamin D3 in vesicles is 3.3 mol/mol phospholipid, with StAR protein stimulating vitamin D3 exchange between vesicles. Reconstituted membrane-bound P450scc kinetics; gel filtration of vesicles; sequential product identification; N-62 StAR protein addition assay The International Journal of Biochemistry & Cell Biology High 18573681
2010 Mutation of the proximal SF-1-binding site in the Cyp11a1 promoter in vivo causes downregulation of CYP11A1 in the adrenal and testis but not in the ovary and placenta, resulting in attenuated corticosterone circadian rhythms and blunted stress response. Transgenic mouse with mutated SF-1-binding site driving reporter gene; endogenous gene expression analysis; corticosterone measurements under stress Molecular and Cellular Endocrinology High 21195129
2010 A novel CYP11A1 missense mutation A269V retains 11% of wild-type P450scc activity and causes nonclassic lipoid congenital adrenal hyperplasia when compound heterozygous with a frameshift mutation, establishing a direct genotype-activity-phenotype relationship. Sequencing; site-directed mutagenesis recreating mutations in F2 fusion protein; pregnenolone production assay (Vmax/Km) in transfected COS-1 cells The Journal of Clinical Endocrinology and Metabolism High 21159840
2011 CYP11A1 produces 22-hydroxyvitamin D3 and 20,22-dihydroxyvitamin D3 as additional products of vitamin D3 metabolism; these 22-hydroxy derivatives are biologically active on keratinocytes via the vitamin D receptor (VDR), stimulating VDR translocation to the nucleus and inhibiting proliferation. Reconstituted P450scc reaction; NMR structure determination; purified 22(OH)D3 as substrate for further P450scc action; keratinocyte proliferation/differentiation assays; VDR translocation immunofluorescence Drug Metabolism and Disposition High 21677063
2013 CYP11A1 overexpression in trophoblastic cells reduces proliferation and induces apoptosis via activation of caspase-3; in preeclampsia placenta, CYP11A1 is significantly upregulated at both mRNA and protein levels. CYP11A1 overexpression in HTR8/SVneo trophoblastic cells; TUNEL staining for apoptosis; caspase-3 activation assay; RT-PCR and Western blot in patient tissue PLoS ONE Medium 23555723
2013 Cyp11a1 enzymatic activity in CD8+ T cells is required for IL-4-induced conversion from IFN-γ to IL-13 production; inhibition with aminoglutethimide or shRNA knockdown prevents this phenotypic conversion without affecting T-bet or GATA3 expression. Aminoglutethimide pharmacological inhibition; shRNA knockdown of Cyp11a1; cytokine measurement by ELISA/RT-PCR; adoptive transfer into CD8-deficient recipients; airway hyperresponsiveness measurement Proceedings of the National Academy of Sciences of the United States of America High 23630275
2013 Cyp11a1 inhibition (aminoglutethimide) prevents peanut-induced allergic diarrhea and intestinal inflammation; shRNA silencing in polarized TH2 CD4+ T cells reduces pregnenolone and IL-13, establishing that Cyp11a1 steroidogenic activity is required for TH2 cytokine production. In vivo aminoglutethimide treatment in peanut sensitization/challenge model; shRNA silencing in polarized T cells; pregnenolone ELISA; IL-13/IL-17A mRNA and protein quantification The Journal of Allergy and Clinical Immunology High 23870673
2013 Overexpression of Cyp11a1 in transgenic mice disrupts normal corpus luteum development, causes progesterone insufficiency during early pregnancy (delayed steroidogenic gene activation, elongated mitochondria, lipid accumulation), and leads to impaired implantation, anomalous placentation, and delayed parturition. BAC transgenic mice with extra Cyp11a1 copies; progesterone ELISA; luteal cell morphology (mitochondrial imaging); gene expression analysis; P4 supplementation rescue Biology of Reproduction High 23966322
2013 Seven CYP11A1 missense mutations causing P450scc deficiency were characterized; mutations including Phe215Ser retain only 2.5% and Val415Glu/c.835delA lack detectable enzymatic activity, while Ala269Val retains 12%—directly correlating residue identity with catalytic competence. CYP11A1 sequencing; site-directed mutagenesis recreating mutations in F2 fusion protein; pregnenolone production assay in transfected COS-1 cells with apparent kinetic parameters The Journal of Clinical Endocrinology and Metabolism High 23337730
2014 CYP11A1 metabolizes lumisterol 3 (L3) to produce 24-hydroxy-L3, 22-hydroxy-L3, and 20,22-dihydroxy-L3 as major products, plus pregnalumisterol from side-chain cleavage; this metabolism was confirmed in pig adrenal fragments by LC/MS, establishing a new CYP11A1 substrate pathway. Reconstituted bovine and human CYP11A1 incubation with L3; NMR structure determination of products; pig adrenal fragment assay; LC/MS product detection The International Journal of Biochemistry & Cell Biology High 25130438
2014 Artemisinins directly target LONP1, enhance the LONP1–CYP11A1 physical interaction, and facilitate LONP1-catalyzed proteolytic degradation of CYP11A1 protein, thereby reducing androgen biosynthesis; LONP1 overexpression alone replicates the androgen-lowering effect. Target identification of artemisinins binding LONP1; co-immunoprecipitation of LONP1-CYP11A1 complex; CYP11A1 protein degradation assay; LONP1 overexpression; androgen measurements in rodent PCOS models and human patients Science High 38870290
2016 CYP11A1 in steroidogenic cell mitochondria affects mitochondrial morphology; steroidogenic cells exhibit tubular-vesicular cristae (distinct from lamellar cristae in non-steroidogenic cells), and the presence of steroidogenic enzymes in the inner mitochondrial membrane is linked to this morphological feature and degree of cell differentiation. Electron microscopy of steroidogenic vs. non-steroidogenic mitochondria; correlation with Cyp11a1 transgenic mouse studies showing elongated mitochondria upon overexpression Molecular and Cellular Endocrinology Medium 27815210
2018 The common CYP11A1 variant p.E314K (rs6161, predicted benign) causes missplicing, produces a nonfunctional protein in mammalian cells, and is a major cause of primary adrenal insufficiency when compound heterozygous with other CYP11A1 variants. Next-generation sequencing; in silico splicing prediction; in vitro minigene splicing assay; E. coli enzyme activity assay (showed no loss-of-function); mammalian cell transfection to demonstrate nonfunctional protein; cycloheximide chase not mentioned but splicing assay central Journal of the Endocrine Society High 30620006
2019 CYP11A1 variant p.E314K causes ~50% decreased protein half-life (increased turnover by cycloheximide chase assay) and retains 60% of wild-type enzymatic activity, establishing that this variant causes primary adrenal insufficiency primarily through impaired protein stability rather than catalytic loss. HEK293T transfection; cycloheximide chase assay for protein stability; pregnenolone production assay from p.E314K-F2 fusion protein in COS-1 cells The Journal of Clinical Endocrinology and Metabolism High 30299480
2022 Human glial cells produce pregnenolone via a mitochondrial CYP450 enzyme other than CYP11A1; pregnenolone synthesis in glial cells is not inhibited by CYP11A1 inhibitors (aminoglutethimide, ketoconazole) and is not altered by overexpression of CYP11A1 isoform b, but is inhibited by ferredoxin reductase knockdown—indicating a different mitochondrial P450. Mass spectrometry and ELISA for pregnenolone; pharmacological inhibition (aminoglutethimide, ketoconazole); CYP11A1 isoform b overexpression; siRNA knockdown of NADPH-cytochrome P450 reductase and ferredoxin reductase; ROS modulation The Journal of Biological Chemistry High 35688208
2021 Antiproliferative and antifibrotic activities of CYP11A1-derived vitamin D3 hydroxyderivatives (20(OH)D3, 20,23(OH)2D3, 1,20(OH)2D3, 1,20,23(OH)3D3) in skin fibroblasts are dependent on functional RORγ; these effects are reversed or abolished in RORγ knockout fibroblasts. Wild-type, heterozygous, and RORγ knockout murine fibroblasts; proliferation assay; TGF-β1-induced collagen synthesis assay; RNA-seq transcriptome analysis Endocrinology High 33107570
2023 ODM-208, a novel CYP11A1 inhibitor, potently suppresses steroid hormone biosynthesis (testosterone to undetectable levels in 87% of patients within one week) in metastatic castration-resistant prostate cancer patients, confirming that CYP11A1 catalytic activity is the primary source of residual androgen biosynthesis in this disease setting. Phase 1/2 clinical trial; pharmacodynamic measurement of circulating testosterone and other steroids; PSA response measurement; adrenal insufficiency as on-target toxicity NEJM Evidence High 38320513

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1986 Hormonal regulation of P450scc (20,22-desmolase) and P450c17 (17 alpha-hydroxylase/17,20-lyase) in cultured human granulosa cells. The Journal of clinical endocrinology and metabolism 277 3011839
2014 Novel activities of CYP11A1 and their potential physiological significance. The Journal of steroid biochemistry and molecular biology 252 25448732
2009 Transcriptional regulation of steroidogenic genes: STARD1, CYP11A1 and HSD3B. Experimental biology and medicine (Maywood, N.J.) 215 19491374
2004 A novel pathway for sequential transformation of 7-dehydrocholesterol and expression of the P450scc system in mammalian skin. European journal of biochemistry 211 15511223
1993 Activation of CYP11A and CYP11B gene promoters by the steroidogenic cell-specific transcription factor, Ad4BP. Molecular endocrinology (Baltimore, Md.) 211 8247022
1997 Association of the steroid synthesis gene CYP11a with polycystic ovary syndrome and hyperandrogenism. Human molecular genetics 201 9147642
1996 ACTH receptor, CYP11A1, CYP17 and CYP21A2 genes are expressed in skin. The Journal of clinical endocrinology and metabolism 186 8675607
1992 Regulation of cholesterol movement to mitochondrial cytochrome P450scc in steroid hormone synthesis. The Journal of steroid biochemistry and molecular biology 150 22217822
2003 A pathway for the metabolism of vitamin D3: unique hydroxylated metabolites formed during catalysis with cytochrome P450scc (CYP11A1). Proceedings of the National Academy of Sciences of the United States of America 142 14657394
2013 The role of CYP11A1 in the production of vitamin D metabolites and their role in the regulation of epidermal functions. The Journal of steroid biochemistry and molecular biology 136 24176765
1993 Construction and function of fusion enzymes of the human cytochrome P450scc system. DNA and cell biology 133 8517924
1995 Expression of the steroidogenic enzyme P450scc in the central and peripheral nervous systems during rodent embryogenesis. Endocrinology 128 7750493
2002 Steroid deficiency syndromes in mice with targeted disruption of Cyp11a1. Molecular endocrinology (Baltimore, Md.) 118 12145347
1990 Characterization of the promoter/regulatory region of the bovine CYP11A (P-450scc) gene. Basal and cAMP-dependent expression. The Journal of biological chemistry 115 2154474
2024 Artemisinins ameliorate polycystic ovarian syndrome by mediating LONP1-CYP11A1 interaction. Science (New York, N.Y.) 101 38870290
2006 An alternative pathway of vitamin D metabolism. Cytochrome P450scc (CYP11A1)-mediated conversion to 20-hydroxyvitamin D2 and 17,20-dihydroxyvitamin D2. The FEBS journal 88 16817851
2022 A Review on CYP11A1, CYP17A1, and CYP19A1 Polymorphism Studies: Candidate Susceptibility Genes for Polycystic Ovary Syndrome (PCOS) and Infertility. Genes 85 35205347
2021 The significance of CYP11A1 expression in skin physiology and pathology. Molecular and cellular endocrinology 80 33716049
2011 Production of 22-hydroxy metabolites of vitamin d3 by cytochrome p450scc (CYP11A1) and analysis of their biological activities on skin cells. Drug metabolism and disposition: the biological fate of chemicals 78 21677063
2002 Compound heterozygous mutations in the cholesterol side-chain cleavage enzyme gene (CYP11A) cause congenital adrenal insufficiency in humans. The Journal of clinical endocrinology and metabolism 78 12161514
2010 Regulation of steroid production: analysis of Cyp11a1 promoter. Molecular and cellular endocrinology 77 21195129
1995 Two Sp1-binding sites mediate cAMP-induced transcription of the bovine CYP11A gene through the protein kinase A signaling pathway. The Journal of biological chemistry 77 7592707
2006 Expression of aromatase, estrogen receptor alpha and beta, androgen receptor, and cytochrome P-450scc in the human early prepubertal testis. Pediatric research 76 17065579
2010 Partial defect in the cholesterol side-chain cleavage enzyme P450scc (CYP11A1) resembling nonclassic congenital lipoid adrenal hyperplasia. The Journal of clinical endocrinology and metabolism 74 21159840
2000 The expression of the sex steroid-synthesizing enzymes CYP11A1, 3beta-HSD, CYP17, and CYP19 in gonads and adrenals of adult and developing zebra finches. General and comparative endocrinology 74 10936034
2004 Large-scale analysis of the relationship between CYP11A promoter variation, polycystic ovarian syndrome, and serum testosterone. The Journal of clinical endocrinology and metabolism 71 15126571
1992 3',5'-cyclic adenosine monophosphate-dependent transcription of the CYP11A (cholesterol side chain cleavage cytochrome P450) gene involves a DNA response element containing a putative binding site for transcription factor Sp1. Molecular endocrinology (Baltimore, Md.) 71 1333053
2024 Biological Effects of CYP11A1-Derived Vitamin D and Lumisterol Metabolites in the Skin. The Journal of investigative dermatology 69 39001720
2004 Function of Cyp11a1 in animal models. Molecular and cellular endocrinology 68 15026180
1999 Role of Sp1 in cAMP-dependent transcriptional regulation of the bovine CYP11A gene. The Journal of biological chemistry 68 10383457
2012 Gonadal transactivation of STARD1, CYP11A1 and HSD3B. Frontiers in bioscience (Landmark edition) 66 22201776
2016 Function of CYP11A1 in the mitochondria. Molecular and cellular endocrinology 63 27815210
1998 Induction of Ad4BP/SF-1, steroidogenic acute regulatory protein, and cytochrome P450scc enzyme system expression in newly established human granulosa cell lines. Endocrinology 62 9794480
2003 The F-G loop region of cytochrome P450scc (CYP11A1) interacts with the phospholipid membrane. Biochimica et biophysica acta 61 14637024
1991 Cytochrome P450 side-chain cleavage (P450scc) in the hen ovary. II. P450scc messenger RNA, immunoreactive protein, and enzyme activity in developing granulosa cells. Biology of reproduction 58 1666853
1997 Expression of adrenocorticotrophic hormone receptor mRNA in human adrenocortical neoplasms: correlation with P450scc expression. Clinical endocrinology 57 9231058
2005 Ah Receptor-mediated impairment of interrenal steroidogenesis involves StAR protein and P450scc gene attenuation in rainbow trout. Toxicological sciences : an official journal of the Society of Toxicology 56 15635147
1994 Contribution of Ad4BP, a steroidogenic cell-specific transcription factor, to regulation of the human CYP11A and bovine CYP11B genes through their distal promoters. Journal of biochemistry 55 7798178
2002 Probing the interaction of bovine cytochrome P450scc (CYP11A1) with adrenodoxin: evaluating site-directed mutations by molecular modeling. Biochemistry 54 12081479
1999 An additional electrostatic interaction between adrenodoxin and P450c27 (CYP27A1) results in tighter binding than between adrenodoxin and p450scc (CYP11A1). The Journal of biological chemistry 53 9890963
2014 CYP11A1 in skin: an alternative route to photoprotection by vitamin D compounds. The Journal of steroid biochemistry and molecular biology 52 25448743
2011 Testosterone, not 5α-dihydrotestosterone, stimulates LRH-1 leading to FSH-independent expression of Cyp19 and P450scc in granulosa cells. Molecular endocrinology (Baltimore, Md.) 52 21273442
2002 Expression of zebrafish cyp11a1 as a maternal transcript and in yolk syncytial layer. Gene expression patterns : GEP 52 12617804
2001 Role of the pentanucleotide (tttta)(n) polymorphism in the promoter of the CYP11a gene in the pathogenesis of hirsutism. Fertility and sterility 51 11287037
1998 Expression of catalytically active human cytochrome p450scc in Escherichia coli and mutagenesis of isoleucine-462. Archives of biochemistry and biophysics 51 9578606
1999 Sex- and age-specific differences in human brain CYP11A1 mRNA expression. Journal of neuroendocrinology 49 10583724
1994 Actions of two different cAMP-responsive sequences and an enhancer of the human CYP11A1 (P450scc) gene in adrenal Y1 and placental JEG-3 cells. The Journal of biological chemistry 47 8119986
2004 Testicular cytochrome P450scc and LHR as possible targets of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the mouse. Molecular and cellular endocrinology 46 15223135
2007 Cyclic AMP stimulates SF-1-dependent CYP11A1 expression through homeodomain-interacting protein kinase 3-mediated Jun N-terminal kinase and c-Jun phosphorylation. Molecular and cellular biology 44 17210646
1994 Regulatory mechanisms of cAMP-dependent and cell-specific expression of human steroidogenic cytochrome P450scc (CYP11A1) gene. European journal of biochemistry 44 8026494
2008 Kinetics of vitamin D3 metabolism by cytochrome P450scc (CYP11A1) in phospholipid vesicles and cyclodextrin. The international journal of biochemistry & cell biology 43 18573681
2003 Transcriptional regulation of CYP11A1. Journal of biomedical science 43 14576461
1991 Expression and regulation of adrenodoxin and P450scc mRNA in rodent tissues. DNA and cell biology 43 1863358
2020 CYP11A1-derived vitamin D3 products protect against UVB-induced inflammation and promote keratinocytes differentiation. Free radical biology & medicine 42 32447000
2007 Transcriptional regulation of human CYP11A1 in gonads and adrenals. Journal of biomedical science 42 17594537
2013 Varied clinical presentations of seven patients with mutations in CYP11A1 encoding the cholesterol side-chain cleavage enzyme, P450scc. The Journal of clinical endocrinology and metabolism 41 23337730
2013 Abnormal apoptosis of trophoblastic cells is related to the up-regulation of CYP11A gene in placenta of preeclampsia patients. PloS one 41 23555723
2013 Misregulated progesterone secretion and impaired pregnancy in Cyp11a1 transgenic mice. Biology of reproduction 41 23966322
2009 Neurosteroids and epileptogenesis in the pilocarpine model: evidence for a relationship between P450scc induction and length of the latent period. Epilepsia 41 19125849
1997 Transcriptional regulation of the CYP11A1 and ferredoxin genes. Steroids 40 9029712
2013 Steroidogenic enzyme Cyp11a1 regulates Type 2 CD8+ T cell skewing in allergic lung disease. Proceedings of the National Academy of Sciences of the United States of America 39 23630275
2012 Increased expression of P450scc and CYP17 in development of endogenous hyperandrogenism in a rat model of PCOS. Endocrine 39 22798247
2006 Vitamin K deficiency reduces testosterone production in the testis through down-regulation of the Cyp11a a cholesterol side chain cleavage enzyme in rats. Biochimica et biophysica acta 38 16844298
2001 The interaction of bovine adrenodoxin with CYP11A1 (cytochrome P450scc) and CYP11B1 (cytochrome P45011beta ). Acceleration of reduction and substrate conversion by site-directed mutagenesis of adrenodoxin. The Journal of biological chemistry 38 11459837
2014 Lumisterol is metabolized by CYP11A1: discovery of a new pathway. The international journal of biochemistry & cell biology 37 25130438
2023 Targeted Inhibition of CYP11A1 in Castration-Resistant Prostate Cancer. NEJM evidence 34 38320513
2022 The neurosteroid pregnenolone is synthesized by a mitochondrial P450 enzyme other than CYP11A1 in human glial cells. The Journal of biological chemistry 34 35688208
2013 The steroidogenic enzyme Cyp11a1 is essential for development of peanut-induced intestinal anaphylaxis. The Journal of allergy and clinical immunology 34 23870673
2009 Zebrafish cyp11a1 and hsd3b genes: structure, expression and steroidogenic development during embryogenesis. Molecular and cellular endocrinology 34 19682541
2009 DNA methylation is not involved in preovulatory down-regulation of CYP11A1, HSD3B1, and CYP19A1 in bovine follicles but may have a role in permanent silencing of CYP19A1 in large granulosa lutein cells. Biology of reproduction 33 19794152
1992 Regulation of human cytochrome P450scc and adrenodoxin messenger ribonucleic acids in JEG-3 cytotrophoblast cells. Endocrinology 33 1446636
2007 Regulation of Kruppel-like factor 4, 9, and 13 genes and the steroidogenic genes LDLR, StAR, and CYP11A in ovarian granulosa cells. American journal of physiology. Endocrinology and metabolism 32 18056793
2006 A microsatellite polymorphism (tttta)n in the promoter of the CYP11a gene in Chinese women with polycystic ovary syndrome. Fertility and sterility 32 16764871
1991 Cytochrome P450 side-chain cleavage (P450scc) in the hen ovary. I. Regulation of P450scc messenger RNA levels and steroidogenesis in theca cells of developing follicles. Biology of reproduction 32 1666852
1993 Differential regulation of the CYP11A1 (P450scc) and ferredoxin genes in adrenal and placental cells. DNA and cell biology 31 8216855
2022 CYP11A1‑derived vitamin D hydroxyderivatives as candidates for therapy of basal and squamous cell carcinomas. International journal of oncology 30 35775377
2014 Targeting of GFP-Cre to the mouse Cyp11a1 locus both drives cre recombinase expression in steroidogenic cells and permits generation of Cyp11a1 knock out mice. PloS one 30 24404170
2007 Alteration of brain and interrenal StAR protein, P450scc, and Cyp11beta mRNA levels in atlantic salmon after nominal waterborne exposure to the synthetic pharmaceutical estrogen ethynylestradiol. Journal of toxicology and environmental health. Part A 30 17365614
1999 Expression of cytochrome P450scc mRNA in the hippocampus of patients with temporal lobe epilepsy. Neuroreport 30 10549824
2012 Association between polymorphisms of the CYP11A1 gene and polycystic ovary syndrome in Chinese women. Molecular biology reports 29 22699877
2000 Localization of p450scc and 5alpha-reductase type-2 in the cerebellum of fetal and newborn sheep. Brain research. Developmental brain research 29 11020552
2004 Population-based case-control study of CYP11A gene polymorphism and breast cancer risk. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 28 15159300
1993 Dexamethasone inhibits corticotropin-induced accumulation of CYP11A and CYP17 messenger RNAs in bovine adrenocortical cells. Molecular endocrinology (Baltimore, Md.) 28 8385739
2018 Predicted Benign and Synonymous Variants in CYP11A1 Cause Primary Adrenal Insufficiency Through Missplicing. Journal of the Endocrine Society 27 30620006
1999 Conformational dynamics and molecular interaction reactions of recombinant cytochrome p450scc (CYP11A1) detected by fluorescence energy transfer. Biochimica et biophysica acta 27 10556557
2016 Effects of fluoride and aluminum on expressions of StAR and P450scc of related steroidogenesis in guinea pigs' testis. Chemosphere 26 26774298
2007 Steroidogenic acute regulatory (StAR) protein and cholesterol side-chain cleavage (P450scc) as molecular and cellular targets for 17alpha-ethynylestradiol in salmon previtellogenic oocytes. Chemical research in toxicology 26 18001058
2004 Expression of cytochrome P450scc mRNA and protein in the rat kidney from birth to adulthood. The Journal of steroid biochemistry and molecular biology 26 15026086
1996 Characterization of the upstream sequence of the human CYP11A1 gene for cell type-specific expression. The Journal of biological chemistry 26 8703023
2014 CYP11A1 microsatellite (tttta)n polymorphism in PCOS women from South India. Journal of assisted reproduction and genetics 25 24793009
2005 Adrenodoxin (Adx) and CYP11A1 (P450scc) induce apoptosis by the generation of reactive oxygen species in mitochondria. Biological chemistry 25 15927889
1993 Regulation of expression of the CYP11A (P450scc) gene in bovine ovarian luteal cells by forskolin and phorbol esters. The Journal of biological chemistry 25 8394339
2019 The Footprints of Oxidative Stress and Mitochondrial Impairment in Arsenic Trioxide-Induced Testosterone Release Suppression in Pubertal and Mature F1-Male Balb/c Mice via the Downregulation of 3β-HSD, 17β-HSD, and CYP11a Expression. Biological trace element research 24 31313246
2023 Retinoic acid enhances ovarian steroidogenesis by regulating granulosa cell proliferation and MESP2/STAR/CYP11A1 pathway. Journal of advanced research 23 37315842
2021 Antifibrogenic Activities of CYP11A1-derived Vitamin D3-hydroxyderivatives Are Dependent on RORγ. Endocrinology 23 33107570
2019 Characterization of the CYP11A1 Nonsynonymous Variant p.E314K in Children Presenting With Adrenal Insufficiency. The Journal of clinical endocrinology and metabolism 23 30299480
2015 DNA methylation screening of primary prostate tumors identifies SRD5A2 and CYP11A1 as candidate markers for assessing risk of biochemical recurrence. The Prostate 23 26332453
2022 Novel CYP11A1-Derived Vitamin D and Lumisterol Biometabolites for the Management of COVID-19. Nutrients 22 36432468
2021 Neurosteroidogenic enzymes: CYP11A1 in the central nervous system. Frontiers in neuroendocrinology 22 34015388
2010 Atomic Force Microscopy Study of Protein-Protein Interactions in the Cytochrome CYP11A1 (P450scc)-Containing Steroid Hydroxylase System. Nanoscale research letters 22 27502676

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