Affinage

CYP17A1

Steroid 17-alpha-hydroxylase/17,20 lyase · UniProt P05093

Length
508 aa
Mass
57.4 kDa
Annotated
2026-06-09
100 papers in source corpus 28 papers cited in narrative 28 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CYP17A1 (P450c17) is the pivotal branch-point enzyme of steroidogenesis, a single cytochrome P450 that performs two distinct reactions—steroid 17α-hydroxylation and 17,20-lyase (acyl-carbon C–C bond) cleavage—within one active site, thereby controlling the partition between glucocorticoid and sex-steroid synthesis (PMID:9892022, PMID:15169901, PMID:30202919). The two activities are mechanistically separable: active-site and surface mutations dissociate them, with R347H and R358Q selectively abolishing 17,20-lyase activity by disrupting redox-partner interactions rather than substrate binding, and the active-site residue E305 controlling substrate orientation between the Δ5 (DHEA) and Δ4 (androstenedione) lyase reactions (PMID:9892022, PMID:14504283, PMID:11549685). Efficient lyase catalysis depends on allosteric stimulation by cytochrome b5, whose acidic residues Glu-48/Glu-49 (and Glu-42) form electrostatic contacts with the cationic CYP17A1 surface residues Arg-347, Arg-358, and Arg-449 to promote electron transfer and acyl-carbon cleavage without affecting hydroxylase activity (PMID:15555906, PMID:25315771, PMID:26587646). Lyase output is further tuned post-translationally: serine phosphorylation downstream of the ROCK/Rho pathway selectively raises 17,20-lyase activity, PP2A (which co-immunoprecipitates with P450c17 and is antagonized by SET) dephosphorylates the enzyme to suppress it, and oxidative stress activates p38α (MAPK14) to selectively boost lyase-driven DHEA production (PMID:12444089, PMID:18187541, PMID:30682387). CYP17A1 transcription is governed by multiple inputs including SF-1 (regulated by the inhibitory lipid ligand sphingosine), cAMP/PKA via MKP-1, SET, MAMLD1, TSPYL factors, ZNF217, and promoter CpG methylation that silences the gene tissue-specifically (PMID:12444089, PMID:12506119, PMID:16887917, PMID:11749720, PMID:19403566, PMID:21559465, PMID:35668995, PMID:29027195). Genetic ablation establishes its physiological centrality: deletion is embryonically lethal in mice before gastrulation, and loss across mice, zebrafish, and tilapia causes sex-steroid deficiency, sex reversal, infertility, and disrupted gonadotropin feedback resembling human 46,XY disorders of sex development (PMID:15169901, PMID:30202919, PMID:34581801, PMID:32472014).

Mechanistic history

Synthesis pass · year-by-year structured walk · 28 steps
  1. 1991 Medium

    Established that P450c17 mediates sequential steroid conversions in a reconstituted pathway and that lyase activity toward the Δ4 substrate is species-dependent and intrinsically low for bovine enzyme.

    Evidence Yeast co-expression of bovine P450c17, P450c21, and reductase with radiolabeled progesterone

    PMID:1844874

    Open questions at the time
    • Species-specific (bovine) and does not address human substrate preference
    • Mechanism of low Δ4-lyase activity not defined
  2. 1994 Medium

    First mapped the active-site architecture by homology modeling and mutagenesis, showing the model captures gross geometry but not the atomic determinants of substrate-specific orientation.

    Evidence Homology modeling on P450cam plus site-directed mutagenesis with TLC activity assays in COS-1 cells

    PMID:8015556

    Open questions at the time
    • No crystal structure
    • Could not predict how a single active site discriminates hydroxylase vs lyase substrate orientation
  3. 1997 Medium

    Showed that kinase-mediated phosphorylation alters CYP17 substrate binding and turnover, linking phosphorylation to regulation of steroidogenic output.

    Evidence Difference spectroscopy and inhibitor treatment of rat testicular microsomes

    PMID:9070288

    Open questions at the time
    • No phosphorylation site identified
    • Did not separate effects on hydroxylase vs lyase activity
  4. 1999 High

    Resolved that selective 17,20-lyase deficiency arises from disrupted redox-partner interactions rather than active-site changes, identifying Arg-347 as part of the b5 interaction surface.

    Evidence R347H/R358Q mutagenesis with yeast/COS kinetics, competitive inhibition, and b5 rescue

    PMID:9892022

    Open questions at the time
    • Structural geometry of the b5/OR contact not yet defined
    • Did not establish how phosphorylation intersects with these contacts
  5. 2001 High

    Clarified that a reported lyase-deficiency mutation (F417C) is actually complete loss of function, narrowing the bona fide selective-lyase-deficiency mutations to R347H and R358Q.

    Evidence Heterologous expression in yeast and COS-7 with difference spectroscopy

    PMID:11549685

    Open questions at the time
    • Does not extend the catalogue of selective lyase mutations beyond two residues
  6. 2001 Medium

    Identified SET as a developmentally timed transcriptional activator that may initiate P450c17 expression in gonadal tissue.

    Evidence EMSA, reporter assays in MA-10 Leydig cells, and Xenopus oocyte injection

    PMID:11749720

    Open questions at the time
    • Shown for rat promoter; human relevance not established here
    • Relationship to SET's PP2A-inhibitory role not connected in same study
  7. 2002 High

    Defined PP2A as a physical, post-translational repressor of 17,20-lyase activity counteracted by SET, establishing phosphorylation-state control of androgen output.

    Evidence Co-IP, phosphatase inhibitors, and siRNA in NCI-H295A adrenal cells

    PMID:12444089

    Open questions at the time
    • Phosphorylated residue(s) on P450c17 not identified
    • Effector kinase upstream not defined
  8. 2002 Medium

    Connected cAMP/PKA signaling to CYP17 transcription via MKP-1 control of SF-1 phosphorylation, with ERK1/2 acting oppositely.

    Evidence In vitro PKA kinase assay, 32P labeling, antisense knockdown, and reporters in H295R cells

    PMID:12506119

    Open questions at the time
    • Direct SF-1 phosphosite regulation not mapped
    • Single cell-line context
  9. 2002 Medium

    Demonstrated extra-gonadal/extra-adrenal CYP17 activity in adipose tissue and identified a splice variant, broadening the enzyme's tissue distribution.

    Evidence RT-PCR and TLC conversion of [14C]-progesterone in adipose homogenates

    PMID:11834432

    Open questions at the time
    • Physiological significance of adipose CYP17 activity unclear
    • Function of the 156 bp deletion variant untested
  10. 2003 High

    Showed that the active-site residue E305 differentially governs substrate orientation, explaining how a single site can favor one lyase reaction over the other.

    Evidence E305G mutagenesis with kcat/Km kinetics in HEK-293 and yeast plus TLC product analysis

    PMID:14504283

    Open questions at the time
    • No atomic structure of substrate-bound enzyme
    • Δ4 vs Δ5 selectivity mechanism only partially defined
  11. 2004 High

    Established that three cationic surface arginines are specifically required for b5-dependent acyl-carbon cleavage, independent of hydroxylase activity.

    Evidence Systematic non-cationic and Lys-conservative mutagenesis with b5 stimulation assays

    PMID:15555906

    Open questions at the time
    • Did not yet define the reciprocal b5 contact residues
    • Electronic vs structural basis of stimulation unresolved
  12. 2004 High

    Demonstrated that P450c17 is essential before gastrulation, revealing a developmental requirement not explained by known steroid products.

    Evidence Knockout mouse with embryo enzyme assays and failed hormone supplementation rescue

    PMID:15169901

    Open questions at the time
    • Identity of the essential early-embryo product unknown
    • Mechanism of pre-gastrulation lethality uncharacterized
  13. 2006 Medium

    Identified sphingosine as an inhibitory SF-1 lipid ligand whose cAMP-regulated exchange controls CYP17 transcription.

    Evidence Tandem MS of SF-1 ligands, ceramidase siRNA, and reporter assays in H295R cells

    PMID:16887917

    Open questions at the time
    • Structural basis of ligand exchange on SF-1 not resolved
    • In vivo relevance to human adrenal not tested
  14. 2007 High

    Quantified species-specific lyase substrate selectivity in purified fusion enzymes, all dependent on cytochrome b5.

    Evidence Purified P450c17-reductase fusion proteins from pig, guinea pig, bovine with radiolabeled substrates

    PMID:17786622

    Open questions at the time
    • Structural determinant of cross-species selectivity not defined
    • Human enzyme not included
  15. 2008 Medium

    Placed the ROCK/Rho pathway upstream of the lyase-activating phosphorylation, identifying ROCK1 as a priming kinase distinct from the unidentified effector.

    Evidence Kinase inhibitor panel, in vitro ROCK1 phosphorylation, and siRNA with lyase/hydroxylase ratios

    PMID:18187541

    Open questions at the time
    • Effector kinase that directly activates lyase not identified
    • Phosphosite still unmapped
  16. 2009 Medium

    Established DNA methylation of a promoter CpG island as the mechanism for tissue-specific CYP17A1 silencing.

    Evidence Bisulfite mapping, in vivo 5-aza-dCyd demethylation with urinary steroid readout, and HDAC inhibitors in Y1 cells

    PMID:19403566

    Open questions at the time
    • Factors directing tissue-specific methylation not identified
    • Rodent-based; human promoter methylation context separate
  17. 2011 Medium

    Identified MAMLD1 as a selective transcriptional regulator of Cyp17a1 in Leydig cells controlling androgen output.

    Evidence Two independent siRNAs with LC-MS steroid profiling in MLTC cells

    PMID:21559465

    Open questions at the time
    • Direct vs indirect regulation of the promoter not established
    • Mechanism of selectivity for Cyp17a1 unclear
  18. 2011 Medium

    Showed the human placenta expresses functional CYP17, expanding sites of de novo C19 steroid synthesis.

    Evidence RT-PCR, Western, IHC, and RIA of steroid products in trophoblasts and JEG-3

    PMID:21307141

    Open questions at the time
    • Physiological role of placental CYP17 activity not defined
    • Single-lab characterization
  19. 2014 High

    Defined the structural CYP17A1–b5 interface by identifying b5 Glu-48/Glu-49 and mapping two cross-linked contact sites, building a docked complex model.

    Evidence Mutagenesis, EDC zero-length cross-linking with MS, and protein docking

    PMID:25315771

    Open questions at the time
    • No co-crystal structure of the complex
    • How phosphorylation modulates this interface not addressed
  20. 2015 High

    Showed b5 acts allosterically by altering electron-transfer kinetics rather than only as an electron donor, providing a biophysical mechanism for lyase stimulation.

    Evidence Live-cell FRET, quartz crystal microbalance, and voltammetry with WT vs E48G/E49G b5

    PMID:26587646

    Open questions at the time
    • Relationship between kinetic stimulation and substrate orientation unresolved
    • In vivo quantitation of effect not established
  21. 2017 Medium

    Linked TSPYL transcription factors to CYP17A1 regulation and to clinical response to the CYP17 inhibitor abiraterone in prostate cancer.

    Evidence siRNA/overexpression with reporters plus clinical trial genotyping (n=87)

    PMID:29027195

    Open questions at the time
    • Direct TSPYL binding to CYP17A1 promoter not shown
    • Small clinical cohort
  22. 2017 Medium

    Revealed an Sp1–CYP17A1–DHEA axis driving chemoresistance via Sp1/DNMT3a competition that demethylates the promoter.

    Evidence ChIP, bisulfite sequencing, siRNA, and DHEA rescue in glioma cells

    PMID:28530704

    Open questions at the time
    • Generality beyond glioma not established
    • Direct link of DHEA to DNA-damage protection mechanism partial
  23. 2019 Medium

    Identified p38α (MAPK14) as the kinase mediating oxidative-stress-induced selective activation of 17,20-lyase activity.

    Evidence p38α inhibition and siRNA with LC-MS/MS steroid quantification in NCI-H295R cells

    PMID:30682387

    Open questions at the time
    • Whether p38α directly phosphorylates P450c17 not shown
    • Phosphosite not identified
  24. 2020 Medium

    Demonstrated in mice that CYP17A1 loss recapitulates human 46,XY DSD steroid phenotypes and links its products to lipoprotein metabolism and atherosclerosis.

    Evidence Knockout mice with plasma steroid MS and atherosclerosis quantification on Apoe-null background

    PMID:32472014

    Open questions at the time
    • Causal steroid mediating atherosclerosis effect not pinned
    • Single-lab phenotype
  25. 2020 High

    Showed in zebrafish that cyp17a1-derived steroids control sex determination and suppress FSHβ in a feedback loop governing testicular development.

    Evidence TALEN knockout with hormone rescue and fshβ morpholino epistasis

    PMID:30202919

    Open questions at the time
    • Mammalian conservation of FSHβ feedback detail not addressed
    • Behavioral defect mechanism not fully resolved
  26. 2020 Medium

    Linked ZNF217 as a negative regulator of CYP17A1 and androgen production in theca cells, with reduced ZNF217 in PCOS.

    Evidence Overexpression and shRNA knockdown with steroid measurement and expression analysis in theca cells

    PMID:35668995

    Open questions at the time
    • Direct promoter binding by ZNF217 not demonstrated
    • Acts partly through DENND1A.V2/miR-130b-3p intermediates
  27. 2021 High

    Confirmed in tilapia that cyp17a1 steroids drive sex differentiation, spermatogenesis, and negative gonadotropin feedback, with hormone rescue restoring fertility.

    Evidence CRISPR/Cas9 knockout with radioimmunoassay, hormone rescue, and gene expression analysis

    PMID:34581801

    Open questions at the time
    • Specific steroid requirement at each developmental stage not fully dissected
  28. 2020 Medium

    Defined a miR-142-5p/JAK1/STAT1/Sp1/DNMT1/DAX1 cascade that represses P450c17 and testosterone under endocrine-disruptor exposure.

    Evidence Bidirectional Co-IP, ChIP, siRNA, and STAT1 activator in triclosan-exposed rat Leydig cells

    PMID:32084696

    Open questions at the time
    • DAX1 repression of P450c17 promoter shown indirectly
    • Multi-step cascade in a single exposure model

Open questions

Synthesis pass · forward-looking unresolved questions
  • The identity of the effector kinase and the precise serine phosphosite(s) that selectively activate 17,20-lyase activity, and a high-resolution structure of the phosphorylated CYP17A1–POR–b5 complex, remain undefined.
  • Effector kinase downstream of ROCK1/p38α unidentified
  • Phosphorylated residue not mapped
  • No experimental structure of the full redox-partner complex

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 6 GO:0016787 hydrolase activity 4
Localization
GO:0005783 endoplasmic reticulum 3
Pathway
R-HSA-1430728 Metabolism 5 R-HSA-1266738 Developmental Biology 4 R-HSA-1474165 Reproduction 4
Partners
CYB5AMAPK14PORPPP2CAROCK1SET

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 P450c17 mutations R347H and R358Q selectively destroy 17,20-lyase activity while preserving 17α-hydroxylase activity by disrupting interactions with P450 oxidoreductase (OR) and cytochrome b5, not by altering the substrate-binding active site. Competitive inhibition experiments and kinetic analysis in yeast microsomes confirmed the mutations did not affect the active site. Addition of excess cytochrome b5 partially restored lyase activity, demonstrating that R347 is a crucial component of the b5 interaction site on the P450c17·OR complex. Site-directed mutagenesis, yeast microsomal expression, enzyme kinetics (Km determination), competitive inhibition assays, COS-1 cell transfection Molecular endocrinology (Baltimore, Md.) High 9892022
2003 CYP17 mutation E305G, located in the active site, selectively impairs 17,20-lyase activity for DHEA synthesis (delta5-pathway) while retaining 17α-hydroxylase activity, and paradoxically shows 11-fold greater catalytic efficiency (kcat/Km) for cleavage of 17α-hydroxyprogesterone to androstenedione (delta4-pathway). This provides genetic evidence that the active site residue E305 differentially controls substrate orientation for the two lyase reactions. Heterologous expression in HEK-293 cells and Saccharomyces cerevisiae, enzyme kinetics (kcat/Km), TLC steroid product analysis The Journal of biological chemistry High 14504283
2002 Protein phosphatase 2A (PP2A), but not PP4, physically associates with P450c17 (co-immunoprecipitation) and selectively inhibits 17,20-lyase activity without affecting 17α-hydroxylase activity. Phosphoprotein SET inhibits PP2A and thereby promotes 17,20-lyase activity. siRNA-mediated suppression of PP2A increased 17,20-lyase activity. PP2A is thus a post-translational regulator that dephosphorylates P450c17 to suppress androgen biosynthesis. Co-immunoprecipitation, phosphatase inhibitor treatment (okadaic acid, fostriecin, cantharidin), siRNA knockdown, microsomal enzyme activity assays in NCI-H295A adrenal cells The Journal of biological chemistry High 12444089
2001 F417C mutation in P450c17, reported as causing isolated 17,20-lyase deficiency, does not form a classical P450 difference spectrum and lacks both 17α-hydroxylase and 17,20-lyase activities when expressed in yeast microsomes or COS-7 cells, demonstrating it causes complete loss of function rather than selective lyase deficiency. R347H and R358Q remain the only two mutations proven to cause isolated 17,20-lyase deficiency. Heterologous expression in yeast microsomes and COS-7 cells, P450 difference spectroscopy, enzyme activity assays The Journal of clinical endocrinology and metabolism High 11549685
2004 Cationic charges at Arg347, Arg358, and Arg449 of human CYP17 are essential for cytochrome b5-dependent acyl-carbon cleavage (lyase and direct cleavage) activities. Substitution with non-cationic residues reduced both activities to 3–4% of wild-type, while lysine substitutions restored sensitivity to cytochrome b5 and recovered acyl-carbon cleavage. All mutants retained wild-type 17α-hydroxylase activity, confirming these arginines are specifically required for b5-mediated C–C bond cleavage. Site-directed mutagenesis, heterologous expression, cytochrome b5 stimulation assays, enzyme activity measurements The Journal of steroid biochemistry and molecular biology High 15555906
2014 Glu-48 and Glu-49 of cytochrome b5 are essential for stimulating CYP17A1 17,20-lyase activity; alanine/glycine substitutions abolished all stimulation, while conservative Asp substitutions retained partial activity. Zero-length chemical cross-linking (EDC) identified two CYP17A1–b5 contact sites: CYP17A1 residues Lys-84–Lys-89 interact with b5 residues 53–73, and CYP17A1 Arg-347 interacts with b5 residues 40–52 (Glu-42). Protein docking using these constraints defined the structural interface of the CYP17A1–b5 complex. Site-directed mutagenesis, zero-length cross-linking with EDC, mass spectrometric peptide identification, protein docking calculations, enzyme activity assays The Journal of biological chemistry High 25315771
2008 Serine phosphorylation of P450c17, which selectively increases 17,20-lyase activity, is upstream-regulated by the ROCK/Rho pathway. ROCK inhibitors suppressed 17,20-lyase activity and P450c17 phosphorylation in NCI-H295A cells and in COS-1 cells transfected with P450c17. ROCK1 phosphorylated P450c17 in vitro, but this phosphorylation alone did not increase lyase activity, indicating ROCK acts as a priming kinase upstream of the effector kinase. ERK1/2 and PKA/PI3K/Akt pathways were excluded as direct regulators. Kinase inhibitor panel, microarray expression of kinases, in vitro phosphorylation assay (ROCK1 + P450c17), siRNA, 17,20-lyase/17α-hydroxylase activity ratios Endocrinology Medium 18187541
2015 Cytochrome b5 alters the kinetics of electron transfer to CYP17A1 via allosteric protein–protein interaction. FRET analysis in living cells demonstrated close interactions between P450c17 and cytochrome b5. Quartz crystal microbalance confirmed specific protein–protein interaction in lipid membranes. Voltammetry showed wild-type b5 (but not E48G/E49G mutant b5) altered electron-transfer kinetics to P450c17, establishing a kinetic (electronic conductivity) mechanism for b5 regulation. FRET in live cells, quartz crystal microbalance, voltammetry (electrochemistry), in silico modeling, in vivo and in vitro reconstitution PloS one High 26587646
1994 Homology modeling of P450c17 on the P450cam crystal structure and site-directed mutagenesis identified residues L102, G111, G301, and M369/I371 as near or within the active site. Mutants G111D and G301I abolished both 17α-hydroxylase and 17,20-lyase activities. L102Y and M369L+I371L retained 50–80% hydroxylase and 70–100% lyase activity. No combination of mutations converted P450c17 to a 21-hydroxylase, indicating that the model correctly predicts gross architecture but cannot predict atomic specificity of substrate orientation. Homology modeling (MIDAS-plus on P450cam structure), site-directed mutagenesis, COS-1 cell transfection, radiochemical TLC activity assays Molecular endocrinology (Baltimore, Md.) Medium 8015556
2002 cAMP/PKA-dependent transcription of human CYP17 in adrenocortical H295R cells requires MKP-1, a nuclear dual-specificity phosphatase. PKA directly phosphorylated MKP-1 in vitro and cAMP increased 32P-MKP-1 in immunoprecipitates. Antisense silencing of MKP-1 attenuated cAMP-stimulated CYP17 expression; silencing of ERK1/2 increased CYP17 expression. The mechanism involves MKP-1-mediated regulation of SF-1 phosphorylation state. In vitro kinase assay (PKA + GST-MKP-1), 32P metabolic labeling, antisense oligonucleotide knockdown, reporter gene transfection, RT-PCR The Journal of biological chemistry Medium 12506119
2006 Sphingosine (SPH) and lyso-sphingomyelin are endogenous ligands of steroidogenic factor-1 (SF-1) in adrenocortical H295R cells, identified by tandem mass spectrometry. cAMP stimulation decreased SF-1-bound SPH. siRNA silencing of ceramidases increased CYP17 mRNA, indicating SPH acts as an inhibitory ligand for SF-1. SPH antagonized cAMP- and SRC-1-stimulated CYP17 reporter gene activity, establishing that lipid ligand exchange on SF-1 regulates CYP17 transcription. Tandem mass spectrometry of SF-1 ligands, siRNA knockdown of ceramidases, reporter gene assays, RT-PCR Endocrinology Medium 16887917
2001 The transcription factor SET binds to the -418/-399 region of the rat P450c17 gene promoter and activates its transcription in Leydig cells (MA-10) and neuronal precursor cells. SET expression precedes P450c17 expression in the embryonic genital ridge and developing gonads, suggesting SET initiates P450c17 expression. Xenopus oocyte nuclear injection confirmed that SET binding to this DNA element activates transcription across all oocyte stages. Gel shift/EMSA assays, reporter gene transfection (Leydig MA-10 cells), Xenopus oocyte nuclear injection, Western blot, ontogenic expression profiling DNA and cell biology Medium 11749720
2009 Tissue-specific silencing of the CYP17A1 gene in rodent adrenals (but not testis) is mediated by DNA methylation. A methylated CpG island was identified in the CYP17 promoter of rat adrenal (but not testis) DNA by bisulfite modification. Treatment of rats with the methyltransferase inhibitor 5-aza-deoxycytidine induced CYP17 expression and 17α-hydroxylase activity (tetrahydrocortisol excretion). Both methyltransferase and HDAC inhibitors induced CYP17A1 expression in mouse Y1 adrenocortical cells that normally lack CYP17 expression. Bisulfite modification/sequencing, 5-aza-dCyd treatment in vivo (rat), urinary steroid metabolite analysis, HDAC inhibitor treatment, reporter gene assay in Y1 cells The Journal of endocrinology Medium 19403566
2004 Deletion of the mouse P450c17 gene causes embryonic lethality by embryonic day 7, prior to gastrulation. P450c17 protein is expressed in embryonic endoderm at E7. 17-hydroxylase activity rises sharply between E6 and E7, and C17,20-lyase activity is present at E7. Supplementation with DHEA, 17-OH pregnenolone, pregnenolone, or progesterone failed to rescue the lethality, indicating essential but uncharacterized functions for P450c17 products in early embryogenesis. Gene targeting (knockout mouse), immunocytochemistry, enzyme assay of wild-type embryos, hormone pellet supplementation Molecular and cellular biology High 15169901
1991 In yeast co-expressing bovine P450c17 (CYP17A1), P450c21, and NADPH-P450 reductase, progesterone is first converted to 17α-hydroxyprogesterone by P450c17 (82%) and then to 11-deoxycortisol by P450c21; conversion to androstenedione was less than 3%, demonstrating that bovine P450c17 has very low C17,20-lyase activity toward the delta4-substrate 17α-hydroxyprogesterone in this reconstituted system. Recombinant yeast co-expression, metabolic conversion assay with radiolabeled progesterone, product identification Pharmacogenetics Medium 1844874
1997 Protein kinase-mediated phosphorylation of CYP17 in rat testicular microsomes enhances substrate (progesterone) binding affinity (Kd decreased from 71 to 43 nM) and accelerates proteolytic degradation of the enzyme 2.5-fold. Both effects are blocked by protein kinase inhibitors bisindolylmaleimide and KT5720 (PKA inhibitor). hCG-induced CYP17 inactivation in situ is also prevented by bisindolylmaleimide, indicating PKA-driven phosphorylation underlies the biphasic steroidogenic response. Optical difference spectroscopy (substrate binding), in situ kinase inhibitor treatment, microsomal degradation assay, pharmacological inhibitors Biochemical and biophysical research communications Medium 9070288
2019 Oxidative stress (from palmitate, H2O2, or 4-HNE) increases 17,20-lyase activity of adrenal P450c17 through activation of p38α (MAPK14). Oxidant exposure increased p38α phosphorylation and DHEA production in NCI-H295R cells without altering P450c17 expression, POR, or b5 levels. Both p38α inhibition and siRNA silencing attenuated the oxidant-induced DHEA increase while 17OHP production remained relatively stable, establishing p38α as the kinase mediating oxidative stress-induced selective activation of P450c17 17,20-lyase activity. Pharmacological p38α inhibition, siRNA knockdown, LC-MS/MS steroid quantification, western blot for phospho-p38α, NCI-H295R cell treatment with oxidants Molecular and cellular endocrinology Medium 30682387
2007 Purified recombinant fusion proteins (P450c17 linked to NADPH-P450 reductase) from pig, guinea pig, and bovine showed species-specific differences in C17,20-lyase substrate selectivity: porcine P450c17 has b5-stimulated lyase activity toward both 17α-OH-P4 (→ androstenedione) and 17α-OH-P5 (→ DHEA); guinea pig P450c17 converts 17α-OH-P4 but not 17α-OH-P5; bovine P450c17 converts 17α-OH-P5 but not 17α-OH-P4. Cytochrome b5 was required for all lyase reactions. Recombinant fusion protein expression in E. coli, purification, in vitro enzyme activity assay with radiolabeled substrates, cytochrome b5 stimulation Drug metabolism reviews High 17786622
2011 MAMLD1 knockdown in mouse Leydig tumor cells (MLTCs) with two independent siRNAs significantly reduced Cyp17a1 expression and consequently decreased 17-OH pregnenolone, 17-OH progesterone, DHEA, androstenedione, and testosterone concentrations in culture media, while pregnenolone and progesterone concentrations were unaffected. Other testosterone-biosynthesis genes were not significantly altered, placing MAMLD1 as a selective transcriptional regulator of Cyp17a1 in Leydig cells. siRNA knockdown (two independent siRNAs), steroid metabolite quantification by LC-MS, RT-PCR gene expression analysis in MLTCs PloS one Medium 21559465
2017 In glioma cells, CYP17A1 upregulation by TMZ resistance is caused by Sp1-mediated DNA demethylation: Sp1 competes with DNMT3a for binding to the CYP17A1 promoter in TMZ-resistant cells, reducing promoter methylation and increasing CYP17A1 expression. The resulting DHEA production attenuates TMZ-induced DNA damage and apoptosis, establishing a Sp1–CYP17A1–DHEA axis in chemoresistance. ChIP (Sp1 and DNMT3a binding to CYP17A1 promoter), bisulfite sequencing, siRNA knockdown, DHEA supplementation, cytotoxicity assays in glioma cells Oncogenesis Medium 28530704
2020 In zebrafish cyp17a1 knockout, deficiency of androgens and estrogens causes female-to-male sex reversal in XX fish (rescued by testosterone or estradiol), testicular hypertrophy and enhanced spermatogenesis associated with constitutively elevated FSHβ, and compromised male secondary sex characters and mating behaviors despite intact spermatogenesis. FSHβ depletion rescued testicular hypertrophy in KO males, establishing that cyp17a1-derived steroids normally suppress FSHβ in a feedback loop controlling testicular development. TALEN-generated cyp17a1 knockout zebrafish, hormone rescue experiments, fshβ morpholino knockdown, histological analysis, plasma steroid measurement Endocrinology High 30202919
2021 In Nile tilapia, cyp17a1 mutation caused female-to-male sex reversal in XX fish with marked decline in E2 and testosterone; sex reversal was rescued by T or E2 administration, and ovarian characteristics were maintained after E2 cessation. In XY cyp17a1 mutants, deficiency of T and 11-KT caused meiotic initiation delays, vas deferens obstruction, and sterility due to excessive apoptosis and abnormal mitochondrial morphology; 11-KT treatment rescued dysspermia. Excessive upregulation of gonadotropin and gonadotropin receptor genes was observed, confirming a negative steroid feedback loop. CRISPR/Cas9-generated cyp17a1 knockout in Nile tilapia, steroid radioimmunoassay, hormone rescue, histology, gene expression analysis Endocrinology High 34581801
2020 CYP17A1-deficient XY mice phenotypically resemble human 46,XY DSD: complete lack of testosterone in XY KO mice (confirmed by plasma steroid analysis), progesterone accumulation in XX KO mice, and elevated corticosterone in both sexes. Both sexes are infertile. On an Apoe KO atherogenic background, CYP17A1/Apoe double KO XY mice developed significantly more atherosclerotic lesions than Apoe KO male controls, associated with altered lipid profiles, linking CYP17A1-derived steroids to lipoprotein metabolism. Gene knockout in mice, plasma steroid mass spectrometry, atherosclerosis lesion quantification, lipidomic profiling Scientific reports Medium 32472014
2020 In triclosan (TCS)-exposed rat Leydig cells, overexpressed miR-142-5p suppresses the JAK1/STAT1 pathway; STAT1 interacts with and regulates Sp1 (demonstrated by bidirectional Co-IP); Sp1 binds the DNMT1 promoter (shown by ChIP) and regulates DNMT1 expression; reduced DNMT1 induces DAX1 transcription and translation, which in turn inhibits steroidogenic P450c17, suppressing testosterone production. This establishes a miR-142-5p/JAK1/STAT1/Sp1/DNMT1/DAX1/P450c17 cascade. Bidirectional Co-IP (STAT1/Sp1), ChIP (Sp1 at DNMT1 promoter), siRNA, STAT1 activator, RT-qPCR, western blot, in vivo rat exposure model The Science of the total environment Medium 32084696
2022 ZNF217, a zinc finger transcription factor, negatively regulates CYP17A1 expression and androgen production in ovarian theca cells. Forced expression of ZNF217 in PCOS theca cells reduced DHEA production, CYP17A1 mRNA, and DENND1A.V2 mRNA while increasing miR-130b-3p. Conversely, shRNA knockdown of ZNF217 in normal theca cells increased DENND1A.V2 and CYP17A1 mRNA. Western blot confirmed reduced ZNF217 protein in PCOS theca cells. Forced overexpression and shRNA knockdown of ZNF217, steroid secretion measurement, RT-qPCR, western blot, immunofluorescence, immunohistochemistry Journal of the Endocrine Society Medium 35668995
2017 TSPYL1, TSPYL2, and TSPYL4 transcription factors regulate CYP17A1 expression in prostate cancer cells. A common TSPYL1 SNP (rs3828743, Pro62Ser) abolishes TSPYL1's ability to suppress CYP3A4 expression; CYP17A1 expression was also regulated by TSPYLs. In a prospective clinical trial, the variant TSPYL1 SNP genotype was associated with worse response to abiraterone acetate, linking TSPYL-mediated CYP17A1 transcriptional regulation to drug metabolism and clinical outcome. siRNA/overexpression of TSPYL family members, reporter gene assay, RT-PCR, clinical trial genotyping (n=87 patients) Clinical pharmacology and therapeutics Medium 29027195
2011 The human placenta (syncytiotrophoblasts) expresses CYP17 mRNA and protein and has demonstrable 17α-hydroxylase/lyase activity, producing 17α-hydroxyprogesterone and androstenedione de novo. Expression and activity were confirmed in both primary trophoblasts and JEG-3 cells. Activity was significantly increased by 22-hydroxycholesterol, indicating substrate availability is rate-limiting. RT-PCR, Western blot, immunohistochemistry, RIA of steroid products (17α-OHP, androstenedione) in conditioned media The Journal of clinical endocrinology and metabolism Medium 21307141
2002 Human adipose tissue expresses P450c17 mRNA and has 17α-hydroxylase enzymatic activity, demonstrated by conversion of [14C]-progesterone to 17α-hydroxylated products in dispersed cell homogenates. A novel form of P450c17 cDNA with a 156 bp in-frame deletion in the first exon was also identified in adipose tissue. RT-PCR/Southern blot, TLC-based enzyme activity assay with [14C]-progesterone substrate European journal of endocrinology Medium 11834432

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 ACTH receptor, CYP11A1, CYP17 and CYP21A2 genes are expressed in skin. The Journal of clinical endocrinology and metabolism 186 8675607
1999 P450c17 mutations R347H and R358Q selectively disrupt 17,20-lyase activity by disrupting interactions with P450 oxidoreductase and cytochrome b5. Molecular endocrinology (Baltimore, Md.) 156 9892022
2010 CYP17 inhibitors for prostate cancer therapy. The Journal of steroid biochemistry and molecular biology 150 21092758
2013 CYP17 inhibitors--abiraterone, C17,20-lyase inhibitors and multi-targeting agents. Nature reviews. Urology 127 24276076
2002 Protein phosphatase 2A and phosphoprotein SET regulate androgen production by P450c17. The Journal of biological chemistry 112 12444089
2003 CYP17 mutation E305G causes isolated 17,20-lyase deficiency by selectively altering substrate binding. The Journal of biological chemistry 95 14504283
2008 CYP17 inhibition as a hormonal strategy for prostate cancer. Nature clinical practice. Urology 91 18985049
2004 CYP17 gene polymorphisms: prevalence and associations with hormone levels and related factors. a HuGE review. American journal of epidemiology 90 15466495
2009 CYP17 blockade by abiraterone: further evidence for frequent continued hormone-dependence in castration-resistant prostate cancer. British journal of cancer 89 19223900
2008 Targeting CYP17: established and novel approaches in prostate cancer. Current opinion in pharmacology 87 18619560
2014 The diverse chemistry of cytochrome P450 17A1 (P450c17, CYP17A1). The Journal of steroid biochemistry and molecular biology 86 25482340
2006 Sphingosine regulates the transcription of CYP17 by binding to steroidogenic factor-1. Endocrinology 81 16887917
2007 Characterization, expression and transcriptional regulation of P450c17-I and -II in the medaka, Oryzias latipes. Biochemical and biophysical research communications 79 17723227
2003 P450c17 deficiency in Brazilian patients: biochemical diagnosis through progesterone levels confirmed by CYP17 genotyping. The Journal of clinical endocrinology and metabolism 77 14671162
2002 Association of the CYP17 gene and CYP19 gene polymorphisms with risk of endometriosis in Japanese women. Human reproduction (Oxford, England) 75 11925378
2018 Characterization of Sexual Trait Development in cyp17a1-Deficient Zebrafish. Endocrinology 73 30202919
2009 Role of DNA methylation in the tissue-specific expression of the CYP17A1 gene for steroidogenesis in rodents. The Journal of endocrinology 70 19403566
1996 Mutation of cytochrome P-45017 alpha gene (CYP17) in a Japanese patient previously reported as having glucocorticoid-responsive hyperaldosteronism: with a review of Japanese patients with mutations of CYP17. The Journal of clinical endocrinology and metabolism 70 8855840
2011 The human placenta expresses CYP17 and generates androgens de novo. The Journal of clinical endocrinology and metabolism 67 21307141
2002 A polymorphism in the CYP17 gene and risk of prostate cancer. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 67 11895872
2000 Sex differentiation and mRNA expression of P450c17, P450arom and AMH in gonads of the chicken. Molecular reproduction and development 61 10602270
2000 CYP17 promoter polymorphism and breast cancer in Australian women under age forty years. Journal of the National Cancer Institute 60 11036113
1998 Role of cytochrome P450c17 in polycystic ovary syndrome. Molecular and cellular endocrinology 60 9922107
1994 Modeling and mutagenesis of the active site of human P450c17. Molecular endocrinology (Baltimore, Md.) 60 8015556
2003 HSD17B1 and CYP17 polymorphisms and breast cancer risk among Chinese women in Singapore. International journal of cancer 59 12584742
2002 CAMP-dependent protein kinase enhances CYP17 transcription via MKP-1 activation in H295R human adrenocortical cells. The Journal of biological chemistry 58 12506119
2004 Cloning of zebrafish ovarian P450c17 (CYP17, 17alpha-hydroxylase/17, 20-lyase) and characterization of its expression in gonadal and extra-gonadal tissues. General and comparative endocrinology 57 14697311
2002 The CYP17 MspA1 polymorphism and breast cancer risk: a meta-analysis. Mutagenesis 55 11880540
2000 Molecular cloning and characterization of Japanese eel ovarian P450c17 (CYP17) cDNA. General and comparative endocrinology 54 10753574
2013 CYP17A1: a biochemistry, chemistry, and clinical review. Current topics in medicinal chemistry 48 23688130
2018 HSD3B1 and Response to a Nonsteroidal CYP17A1 Inhibitor in Castration-Resistant Prostate Cancer. JAMA oncology 46 29049452
2004 Deletion of the mouse P450c17 gene causes early embryonic lethality. Molecular and cellular biology 46 15169901
2001 Pitfalls in characterizing P450c17 mutations associated with isolated 17,20-lyase deficiency. The Journal of clinical endocrinology and metabolism 46 11549685
2016 CYP17 inhibitors in prostate cancer: latest evidence and clinical potential. Therapeutic advances in medical oncology 45 27482286
2017 Upregulation of CYP17A1 by Sp1-mediated DNA demethylation confers temozolomide resistance through DHEA-mediated protection in glioma. Oncogenesis 44 28530704
2008 Pathways leading to phosphorylation of p450c17 and to the posttranslational regulation of androgen biosynthesis. Endocrinology 44 18187541
2007 Elevated expression of P450c17 (CYP17) during testicular formation in the frog. General and comparative endocrinology 44 17434514
2023 Non-steroidal CYP17A1 Inhibitors: Discovery and Assessment. Journal of medicinal chemistry 43 37191389
2013 Endurance exercise and conjugated linoleic acid (CLA) supplementation up-regulate CYP17A1 and stimulate testosterone biosynthesis. PloS one 43 24223995
2014 Risk for estrogen-dependent diseases in relation to phthalate exposure and polymorphisms of CYP17A1 and estrogen receptor genes. Environmental science and pollution research international 41 25030786
2006 CYP17, CYP1A1 and COMT polymorphisms and the risk of adenomyosis and endometriosis in Taiwanese women. Human reproduction (Oxford, England) 41 16527884
2021 Cyp17a1 is Required for Female Sex Determination and Male Fertility by Regulating Sex Steroid Biosynthesis in Fish. Endocrinology 40 34581801
2006 Human fetal ovary development involves the spatiotemporal expression of p450c17 protein. The Journal of clinical endocrinology and metabolism 40 16822821
2002 Expression and enzymatic activity of the P450c17 gene in human adipose tissue. European journal of endocrinology 40 11834432
2001 Linkage and association of CYP17 gene in hereditary and sporadic prostate cancer. International journal of cancer 40 11668516
1995 Occurrence of cytochrome P450c17 mRNA and dehydroepiandrosterone biosynthesis in the rat gastrointestinal tract. Molecular and cellular endocrinology 40 7649357
2012 Increased expression of P450scc and CYP17 in development of endogenous hyperandrogenism in a rat model of PCOS. Endocrine 39 22798247
2017 Resveratrol inhibits androgen production of human adrenocortical H295R cells by lowering CYP17 and CYP21 expression and activities. PloS one 36 28323907
2014 Catalytically relevant electrostatic interactions of cytochrome P450c17 (CYP17A1) and cytochrome b5. The Journal of biological chemistry 36 25315771
2008 Immunohistochemical detection and biological activities of CYP17 (P450c17) in the indifferent gonad of the frog Rana rugosa. The Journal of steroid biochemistry and molecular biology 36 18675354
2006 A novel point mutation in P450c17 (CYP17) causing combined 17alpha-hydroxylase/17,20-lyase deficiency. The Journal of clinical endocrinology and metabolism 36 16569739
1991 Progesterone metabolism in recombinant yeast simultaneously expressing bovine cytochromes P450c17 (CYP17A1) and P450c21 (CYP21B1) and yeast NADPH-P450 oxidoreductase. Pharmacogenetics 35 1844874
2020 CYP17A1 deficient XY mice display susceptibility to atherosclerosis, altered lipidomic profile and atypical sex development. Scientific reports 34 32472014
2012 Polymorphisms in CYP17 and CYP3A4 and prostate cancer in men of African descent. The Prostate 34 23129512
2017 TSPYL Family Regulates CYP17A1 and CYP3A4 Expression: Potential Mechanism Contributing to Abiraterone Response in Metastatic Castration-Resistant Prostate Cancer. Clinical pharmacology and therapeutics 33 29027195
2003 Alternative splicing and differential expression of P450c17 (CYP17) in gonads during sex transformation in the rice field eel. Biochemical and biophysical research communications 33 12849996
2001 Developmental gonadal expression of the transcription factor SET and its target gene, P450c17 (17alpha-hydroxylase/c17,20 lyase). DNA and cell biology 33 11749720
1992 Distinct biochemical mechanisms for cAMP-dependent transcription of CYP17 and CYP21. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 32 1311271
2007 Increased metastatic lymph node 64 and CYP17 expression are associated with high stage prostate cancer. The Journal of endocrinology 31 17592021
2004 The cationic charges on Arg347, Arg358 and Arg449 of human cytochrome P450c17 (CYP17) are essential for the enzyme's cytochrome b5-dependent acyl-carbon cleavage activities. The Journal of steroid biochemistry and molecular biology 31 15555906
2020 Association of the CYP17 and CYP19 gene polymorphisms in women with polycystic ovary syndrome from Punjab, Pakistan. Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology 30 32960117
2016 Specificity of anti-prostate cancer CYP17A1 inhibitors on androgen biosynthesis. Biochemical and biophysical research communications 29 27395338
2008 CYP17 inhibitors for prostate cancer treatment--an update. Current medicinal chemistry 29 18473796
2015 Mechanistic Scrutiny Identifies a Kinetic Role for Cytochrome b5 Regulation of Human Cytochrome P450c17 (CYP17A1, P450 17A1). PloS one 28 26587646
2011 Hypospadias risk and polymorphism in SRD5A2 and CYP17 genes: case-control study among Indian children. The Journal of urology 28 21511288
2014 Inhibition of CYP17A1 activity by resveratrol, piceatannol, and synthetic resveratrol analogs. The Prostate 27 24610083
1995 Seventeen alpha-hydroxylase deficiency with one base pair deletion of the cytochrome P450c17 (CYP17) gene. The Journal of clinical endocrinology and metabolism 27 7629254
2019 CYP17A1 and Androgen-Receptor Expression in Prostate Carcinoma Tissues and Cancer Cell Lines. Current urology 26 31933595
1996 Hypersecretion of androgens by polycystic ovaries: the role of genetic factors in the regulation of cytochrome P450c17 alpha. Bailliere's clinical endocrinology and metabolism 26 8773744
2019 Oxidative stress increases the 17,20-lyase-catalyzing activity of adrenal P450c17 through p38α in the development of hyperandrogenism. Molecular and cellular endocrinology 25 30682387
2010 CYP17 polymorphisms and prostate cancer outcomes. The Prostate 25 20503394
2005 Genetic polymorphism of CYP17 and breast cancer risk in Korean women. Experimental & molecular medicine 25 15761247
2003 A polymorphism in the CYP17 gene relates to the risk of recurrent pregnancy loss. Molecular human reproduction 25 14561815
2012 Association study of CYP17 and HSD11B1 in polycystic ovary syndrome utilizing comprehensive gene coverage. Molecular human reproduction 24 22238371
2008 Complex assembly on the human CYP17 promoter. Molecular and cellular endocrinology 24 19007851
2011 Mamld1 knockdown reduces testosterone production and Cyp17a1 expression in mouse Leydig tumor cells. PloS one 23 21559465
2010 17α-Hydroxylase (CYP17) expression and subsequent androstenedione production in the human ovary. Reproductive sciences (Thousand Oaks, Calif.) 23 20720262
2022 The PCOS GWAS Candidate Gene ZNF217 Influences Theca Cell Expression of DENND1A.V2, CYP17A1, and Androgen Production. Journal of the Endocrine Society 22 35668995
2020 miR-142-5p/DAX1-dependent regulation of P450c17 contributes to triclosan-mediated testosterone suppression. The Science of the total environment 22 32084696
2015 CYP17A1 and CYP2E1 variants associated with high altitude polycythemia in Tibetans at the Qinghai-Tibetan Plateau. Gene 22 25917616
2009 CYP17 and CYP2C19 gene polymorphisms in patients with endometriosis. Reproductive biomedicine online 22 20113968
2020 Zebrafish cyp17a1 knockout reveals that androgen-mediated signaling is important for male brain sex differentiation. General and comparative endocrinology 21 32283058
2004 A polymorphism in the CYP17 gene and intrauterine fetal growth restriction. Molecular human reproduction 21 14665706
2004 CYP17 and SULT1A1 gene polymorphisms in Indian breast cancer. Breast cancer (Tokyo, Japan) 21 15604994
2015 Acyl-Carbon Bond Cleaving Cytochrome P450 Enzymes: CYP17A1, CYP19A1 and CYP51A1. Advances in experimental medicine and biology 20 26002733
2020 Human DENND1A.V2 Drives Cyp17a1 Expression and Androgen Production in Mouse Ovaries and Adrenals. International journal of molecular sciences 19 32268539
2020 CYP17 gene polymorphic sequence variation is associated with hyperandrogenism in Kashmiri women with polycystic ovarian syndrome. Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology 19 32456493
2020 Comparative Dynamics and Functional Mechanisms of the CYP17A1 Tunnels Regulated by Ligand Binding. Journal of chemical information and modeling 19 32530640
2014 Association of CYP17A1 gene -34T/C polymorphism with polycystic ovary syndrome in Han Chinese population. Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology 19 25208301
2021 Aberrant H19 Expression Disrupts Ovarian Cyp17 and Testosterone Production and Is Associated with Polycystic Ovary Syndrome in Women. Reproductive sciences (Thousand Oaks, Calif.) 18 34655046
2015 The CYP17 MspA1 Polymorphism and the Gender Dysphoria. The journal of sexual medicine 18 25929975
2009 CYP17 gene polymorphism and its association in north Indian prostate cancer patients. Anticancer research 18 19443382
2007 Prenatal alcohol exposure, CYP17 gene polymorphisms and fetal growth restriction. European journal of obstetrics, gynecology, and reproductive biology 18 17875358
2004 Expression of cytochrome P450c17 and other steroid-converting enzymes in the rat kidney throughout the life-span. The Journal of steroid biochemistry and molecular biology 18 15261307
1998 Orphan receptors, proto-oncogenes and other nuclear factors regulate P450C17 gene transcription. Endocrine research 18 9888531
2017 Seasonal expression of P450c17 and 5α-reductase-2 in the scented gland of male muskrats (Ondatra zibethicus). General and comparative endocrinology 17 28919450
2007 Comparison of the 17 alpha-hydroxylase/C17,20-lyase activities of porcine, guinea pig and bovine P450c17 using purified recombinant fusion proteins containing P450c17 linked to NADPH-P450 reductase. Drug metabolism reviews 17 17786622
1997 Protein phosphorylation changes ligand-binding efficiency of cytochrome P450c17 (CYP17) and accelerates its proteolytic degradation: putative relevance for hormonal regulation of CYP17 activity. Biochemical and biophysical research communications 17 9070288
2009 Polymorphism in CYP17, GSTM1 and the progesterone receptor genes and its relationship with mammographic density. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas 16 19330259
2009 Synaptophysin immunoreactivity in adrenocortical adenomas: a correlation between synaptophysin and CYP17A1 expression. European journal of endocrinology 16 19755404

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