Affinage

CYP51A1

Lanosterol 14-alpha demethylase · UniProt Q16850

Length
509 aa
Mass
57.3 kDa
Annotated
2026-06-09
100 papers in source corpus 24 papers cited in narrative 24 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

CYP51A1 encodes the microsomal cytochrome P450 lanosterol 14α-demethylase that catalyzes a committed step of cholesterol biosynthesis, oxidatively removing the 14α-methyl group from lanosterol and 24,25-dihydrolanosterol (PMID:8619637, PMID:21705796). Mouse knockout establishes it as the sole enzyme for this step in vivo: loss causes accumulation of lanosterol and 24,25-dihydrolanosterol, absence of downstream cholesterol precursors, and embryonic lethality from cardiac and vasculogenesis defects (PMID:21705796). Catalysis depends on conserved B′ helix/BC-loop and F/G-helix residues whose mutation abolishes sterol metabolism while leaving the heme-bound fold intact (PMID:12885242), and crystal structures of the human enzyme show that azoles bind primarily through hydrophobic, heme-coordinating interactions that drive conformational changes in the B′ helix and F-G loop (PMID:20149798); isoform-specific active-site residues such as fungal F145 uncouple inhibitor binding from substrate turnover and underlie selective azole inhibition (PMID:15314102). The gene is transcriptionally controlled by two distinct programs: SREBP-mediated sterol-feedback regulation in somatic cells, where oxysterols and LDL suppress expression by reducing SREBP-2 and its binding to the cyp51 SRE (PMID:8619637, PMID:11179193), and cAMP/CREMτ signaling acting on a proximal CRE2 element in testicular germ cells (PMID:10551787, PMID:16123160). The enzyme localizes to the endoplasmic reticulum and, in spermatids, undergoes cell-type-specific Golgi transport to acrosomal membranes where it synthesizes the meiosis-activating sterol FF-MAS (PMID:14630712), a function that partially mediates FSH-dependent oocyte meiotic resumption (PMID:19433477) yet is dispensable for spermatogenesis (PMID:23509403). Tissue-restricted loss reveals organ-specific roles: hepatocyte knockout produces fibrosis, inflammation, and senescence driven by impaired cholesterol synthesis (PMID:25739789), and in pancreatic cancer SREBF2-driven CYP51A1 upregulation prevents lysosomal cholesterol accumulation and suppresses alkalization-induced cell death via TMEM175 (PMID:40055353).

Mechanistic history

Synthesis pass · year-by-year structured walk · 23 steps
  1. 1996 High

    Establishing that the human gene product is a functional lanosterol 14α-demethylase under sterol-feedback control defined CYP51A1's catalytic identity and placed it in the cholesterol biosynthesis pathway.

    Evidence Heterologous expression in E. coli with enzymatic assay plus oxysterol-treated Northern blots in HepG2/H295R cells

    PMID:8619637

    Open questions at the time
    • Did not define the regulatory transcription factor mediating oxysterol suppression
    • No structural detail of the active site
  2. 1998 High

    Mapping clinical azole-resistance substitutions in fungal CYP51 to specific residues answered which active-site positions govern drug binding affinity.

    Evidence Functional expression of C. albicans mutants in S. cerevisiae with azole susceptibility testing

    PMID:9527767

    Open questions at the time
    • Affinity changes inferred from susceptibility, not all from purified enzyme kinetics
    • Did not address human enzyme selectivity
  3. 1999 High

    Quantitative comparison of purified human and fungal CYP51 showed only modest azole selectivity, reframing the basis of antifungal therapeutic windows.

    Evidence Purified recombinant enzymes, reconstituted kinetics, CO-difference and drug-binding spectroscopy

    PMID:10398344

    Open questions at the time
    • Did not resolve the structural determinants of the limited selectivity
    • Single substrate context
  4. 1999 High

    Identifying that germ-cell CYP51 transcription uses a cAMP/CREMτ-CRE2 program distinct from somatic SREBP-SRE control explained how one gene is tissue-specifically regulated.

    Evidence Cell-type-specific EMSA, CREM-knockout mice, and promoter-reporter assays

    PMID:10551787

    Open questions at the time
    • Did not establish the physiological output of germ-cell-specific expression
    • Cross-talk with sterol feedback unaddressed at this stage
  5. 2001 High

    Crystal structures of bacterial CYP51 with azoles defined the active-site access channel and showed resistance mutations act by altering conformational transitions rather than direct ligand contact.

    Evidence X-ray crystallography of M. tuberculosis CYP51 with 4-phenylimidazole and fluconazole

    PMID:11248033

    Open questions at the time
    • Bacterial ortholog channel topology may differ from human enzyme
    • No substrate-bound structure here
  6. 2001 High

    Demonstrating LDL-driven, SREBP-2-dependent suppression of CYP51, including in hypercholesterolemic arteries, connected the enzyme to systemic cholesterol homeostasis in vivo.

    Evidence Differential display, EMSA, promoter assays, cycloheximide/NLLN inhibitors, and a hypercholesterolemic pig model

    PMID:11179193

    Open questions at the time
    • Performed in porcine cells/tissue
    • Did not separate SREBP-2 from SREBP-1 contributions in all contexts
  7. 2001 Medium

    Probing a conserved C-terminal arginine and a natural Gly-to-Asp heme-ligand mutation distinguished residues required for folding/expression from those required for catalysis.

    Evidence Site-directed mutagenesis, CD/fluorescence, unfolding assays in M. tuberculosis CYP51, and modeling of a yeast heme-ligand mutant

    PMID:11373285 PMID:3046615

    Open questions at the time
    • Yeast mutant characterized by sequencing/modeling without reconstitution
    • Folding requirement not conserved to human ortholog
  8. 2003 High

    Systematic mutagenesis of B′ helix/BC-loop and F/G-helix residues, confirmed in the human ortholog, pinpointed the catalytic determinants of sterol 14α-demethylation.

    Evidence Site-directed mutagenesis with activity and ligand-binding spectroscopy in M. tuberculosis and human CYP51

    PMID:12885242

    Open questions at the time
    • Catalytic chemistry of the three-step oxidation not dissected per residue
    • No human co-crystal at this stage
  9. 2003 High

    Tracking CYP51 from the ER through the Golgi to spermatid acrosomal membranes revealed cell-type-specific trafficking that localizes FF-MAS synthesis to sperm.

    Evidence Confocal microscopy, fractionation, immuno-EM, and acrosomal enzymatic assays across three mammalian species

    PMID:14630712

    Open questions at the time
    • Trafficking machinery directing Golgi/acrosomal targeting not identified
    • Functional necessity of acrosomal FF-MAS not yet tested
  10. 2004 High

    Showing that fungal F145 uncouples fluconazole binding from substrate turnover established isoform-specific active-site topology as the basis of inhibitor selectivity.

    Evidence Mutagenesis across fungal, human, and bacterial CYP51 with paired activity and binding assays

    PMID:15314102

    Open questions at the time
    • Did not provide structural images of the altered topology
    • Limited to selected residues
  11. 2005 High

    Defining CYP51 as a cAMP immediate-early gene whose induction consumes lanosterol linked acute hormonal signaling to sterol flux independently of SREBP.

    Evidence Forskolin induction, CRE2 reporter assays, EMSA, and GC-MS sterol analysis in JEG-3 cells

    PMID:16123160

    Open questions at the time
    • Physiological trigger of cAMP induction in vivo not defined
    • Single cell-line context
  12. 2007 Medium

    Identifying the heme-binding protein Dap1/PGRMC1 ortholog as a positive regulator of CYP51 activity introduced a post-transcriptional support factor for the enzyme.

    Evidence Yeast genetic epistasis, sterol accumulation, and drug sensitivity assays

    PMID:17954932

    Open questions at the time
    • No direct biochemical interaction between Dap1 and CYP51 shown
    • Demonstrated only in yeast ortholog
  13. 2008 Medium

    Linking CREM-dependent circadian oscillation of hepatic Cyp51 to the lathosterol/cholesterol ratio extended its regulation to diurnal metabolic rhythms.

    Evidence Circadian profiling in Crem-knockout mice, promoter assays, and GC-MS sterol profiling

    PMID:18775413

    Open questions at the time
    • Direct CREM occupancy of the rhythmic promoter not shown in vivo
    • Physiological consequence of lost rhythmicity unaddressed
  14. 2009 Medium

    siRNA knockdown showing partial loss of FSH-induced, but not LH-induced, oocyte meiotic resumption defined CYP51's MAS product as a selective mediator of FSH-dependent meiosis.

    Evidence siRNA in mouse follicle/cumulus cultures with germinal vesicle breakdown readout

    PMID:19433477

    Open questions at the time
    • Single functional method, single lab
    • Only partial effect; redundant pathways not defined
  15. 2010 High

    Apo, ketoconazole-, and econazole-bound human CYP51 structures revealed the hydrophobic azole-binding mode and ligand-induced B′/F-G conformational changes in the human enzyme directly.

    Evidence Three X-ray crystal structures of human CYP51

    PMID:20149798

    Open questions at the time
    • No substrate-bound human structure
    • Did not capture the catalytic intermediates
  16. 2011 High

    A substrate-analog co-crystal of trypanosomal CYP51 specified substrate orientation and the rigidity of the conserved binding cavity, informing mechanism-based inhibition.

    Evidence X-ray crystallography with MCP and inhibition assays across orthologs

    PMID:22135275

    Open questions at the time
    • Parasite ortholog, not human enzyme
    • Mechanism-based inhibition driven by non-conserved residue I105
  17. 2011 High

    Constitutive Cyp51 knockout established the enzyme as the unique, non-redundant catalyst of this biosynthetic step in vivo and tied its loss to lethal cardiovascular developmental defects.

    Evidence Knockout mouse with sterol metabolite profiling, expression analysis, and histopathology

    PMID:21705796

    Open questions at the time
    • Cell-autonomous versus systemic contributions to lethality unresolved
    • Did not separate sterol depletion from substrate-accumulation toxicity
  18. 2013 High

    Germ-cell-specific knockout that ablated MAS without impairing fertility showed de novo MAS synthesis in male germ cells is dispensable for spermatogenesis.

    Evidence Conditional Cyp51 knockout with sterol profiling, histopathology, and fertility assessment

    PMID:23509403

    Open questions at the time
    • Did not exclude MAS supply from somatic testicular cells
    • Female germ-cell requirement not tested here
  19. 2015 High

    Hepatocyte-specific knockout linked impaired cholesterol synthesis directly to liver fibrosis, inflammation, and senescence, identifying the cellular triggers and dietary rescue.

    Evidence Liver-specific conditional knockout with histopathology, expression profiling, and dietary intervention

    PMID:25739789

    Open questions at the time
    • Relative roles of cholesterol-ester depletion versus substrate accumulation only partly resolved
    • Sex-biased dietary rescue mechanism unexplained
  20. 2017 Medium

    Defining a T3/FSH → TRβ → PI3K/Akt → GATA-4 axis driving CYP51A1 expression connected the enzyme to ovarian steroidogenesis regulation.

    Evidence siRNA knockdown, PI3K inhibition, Western blot, and steroid hormone assays in mouse follicle cultures

    PMID:28938463

    Open questions at the time
    • Direct GATA-4 occupancy of the CYP51A1 promoter not demonstrated
    • Single lab, correlative pathway linkage
  21. 2019 High

    Systematic enzymatic assay of 28 clinical CaCYP51 mutants quantified how single and double substitutions raise azole IC50, refining the molecular basis of antifungal resistance.

    Evidence Purified recombinant mutant enzymes with IC50 determination and whole-cell MIC assays

    PMID:30783005

    Open questions at the time
    • Structural basis of each substitution's effect not co-crystallized
    • Limited to fungal enzyme
  22. 2019 Medium

    Mutagenesis and comparative structural analysis explaining human CYP51 resistance to inhibition, plus novel irreversible inhibitors, validated the human enzyme as a druggable target.

    Evidence Site-directed mutagenesis, comparative structural analysis, compound synthesis, and inhibition assays

    PMID:31663733

    Open questions at the time
    • No co-crystal of human enzyme with the new compounds reported
    • Mechanistic basis inferred from comparative structure-function
  23. 2025 Medium

    Defining a SREBF2-CYP51A1-lysosomal cholesterol-TMEM175 axis that suppresses alkalization-induced death uncovered a cytoprotective role for CYP51A1 in pancreatic cancer.

    Evidence Drug mass spectrometry, transcriptomics, lipid metabolomics, genetic/pharmacological inhibition, and multiple in vivo tumor models

    PMID:40055353

    Open questions at the time
    • Pathway inferred from correlative and loss-of-function data without full biochemical reconstitution
    • Direct effect of CYP51 product on lysosomal cholesterol not isolated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CYP51A1's catalytic chemistry, trafficking, and tissue-specific transcriptional programs are coordinately controlled in human physiology and disease remains incompletely defined.
  • No human substrate-bound crystal structure
  • Trafficking machinery to acrosomal membranes unidentified
  • Direct physical regulator(s) of human CYP51 activity not biochemically defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 4
Localization
GO:0005783 endoplasmic reticulum 1 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-74160 Gene expression (Transcription) 3
Partners
PGRMC1TMEM175

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 Human CYP51A1 cDNA expressed in E. coli encodes a functional lanosterol 14α-demethylase enzyme, establishing the catalytic identity of the human gene product. Expression is regulated by oxysterols: 25-hydroxycholesterol suppresses CYP51 mRNA in HepG2 and H295R cells, similar to other cholesterol biosynthesis genes. Heterologous expression in E. coli with enzymatic activity assay; Northern blot with oxysterol treatment Archives of biochemistry and biophysics High 8619637
1999 Purified human CYP51 and Candida albicans CYP51 show similar substrate affinity constants (Km ~20–29 µM) and Vmax values in reconstituted enzymatic assays. Both enzymes give type II spectra with azole drugs, but ketoconazole and itraconazole show less than 10-fold selectivity for fungal over human CYP51 when measured with purified enzymes—an order of magnitude lower than previously reported using unpurified preparations. Heterologous expression in yeast (GAL10), protein purification, reconstituted enzymatic assay, CO difference spectra, drug binding spectroscopy Yeast High 10398344
1999 CYP51 transcription in testicular germ cells is driven by cAMP/CREMτ binding to a conserved CRE2 element in the CYP51 proximal promoter, while somatic CYP51 transcription is driven by SREBP-1a binding to a conserved SRE1 element. CREM−/− mice lack germ-cell-specific CYP51 mRNAs while somatic transcripts are unaffected, demonstrating two distinct tissue-specific regulatory pathways for the same gene. Gel-shift/EMSA with germ cell and somatic nuclear extracts; CREM knockout mice; promoter-reporter transfection assays Molecular endocrinology High 10551787
2001 Crystal structures of Mycobacterium tuberculosis CYP51 at 2.1–2.2 Å in complex with 4-phenylimidazole and fluconazole reveal: a bent I helix and open BC-loop conformation defining an active-site access channel running along the heme plane; a second channel analogous to P450BM3 that is not open at the surface; and that azole resistance mutations in C. albicans map to regions orchestrating conformational transitions rather than to residues directly contacting fluconazole. X-ray crystallography (2.1 and 2.2 Å resolution co-crystal structures) Proceedings of the National Academy of Sciences of the United States of America High 11248033
2001 LDL downregulates CYP51 mRNA in porcine vascular endothelial cells through a mechanism dependent on SREBP-2: LDL reduces SREBP-2 levels, decreases SREBP-SREBP-response-element (SRE) interaction at the cyp51-SRE as shown by gel-shift assay, and reduces CYP51 promoter activity. Cycloheximide blocks the LDL-mediated CYP51 suppression, and an inhibitor of SREBP catabolism (NLLN) abolishes the effect. SREBP-2 and CYP51 mRNA are also co-decreased in the arterial wall of hypercholesterolemic pigs in vivo. mRNA differential display; Northern blot; gel-shift/EMSA; promoter-reporter transfection; Western blot; in vivo hypercholesterolemic pig model Circulation research High 11179193
2001 Conserved arginine (Arg-448) near the C-terminus of M. tuberculosis CYP51 is required for folding/expression in E. coli; truncation abolishes P450 expression, whereas substitutions (R448K, R448I, R448A) in the folded protein have no effect on catalytic activity or native structure. Importantly, C-terminal truncation of human and C. albicans CYP51 orthologs does not abolish P450 expression, showing that despite sequence conservation, the folding pathway requirement for this residue is not conserved across the CYP51 family. Site-directed mutagenesis; E. coli expression; CD spectroscopy; tryptophan fluorescence; equilibrium and kinetic unfolding assays; enzymatic activity assays The Journal of biological chemistry High 11373285
2003 Site-directed mutagenesis of seven conserved residues in the B′ helix/BC loop and helices F and G of M. tuberculosis CYP51 (Y76, F83, G84, D90, L172, G175, R194) abolishes lanosterol metabolism. All mutants retain normal spectral properties, heme incorporation, and azole binding, indicating these residues are specifically required for catalytic activity rather than overall protein fold. Corresponding mutations in human CYP51 produce the same pattern, confirming evolutionary conservation of these active-site residues. Site-directed mutagenesis; E. coli expression; enzymatic activity assays; ligand-binding spectroscopy; protein purification Biochemistry High 12885242
2003 Mammalian CYP51 localizes to the endoplasmic reticulum of most cells and undergoes cell-type-specific intracellular transport through the Golgi to acrosomal membranes of spermatids (mouse, bull, ram), where it synthesizes FF-MAS (follicular fluid meiosis-activating sterol) in the presence of acrosomal NADPH-P450 reductase. In mouse liver, CYP51 is retrieved back to the ER from the trans-Golgi and not transported further. Glycosylated high-molecular-mass CYP51-immunoreactive proteins in acrosomal and Golgi fractions indicate posttranslational glycosylation in the Golgi. Immunofluorescence/confocal microscopy; subcellular fractionation; Western blot; enzymatic activity assay with acrosomal fractions; immunoelectron microscopy Endocrinology High 14630712
2004 Fluconazole binding and substrate metabolism are uncoupled in CYP51: F145L mutation in C. albicans CYP51 (residue conserved only in fungi) causes a 5-fold increase in fluconazole IC50 with no effect on substrate turnover, while Y132H in C. albicans and the corresponding Y145H in human CYP51 show no effect on fluconazole binding or substrate metabolism. The homologous F89H mutation in M. tuberculosis CYP51 abolishes both substrate binding and metabolism. This demonstrates isoform-specific active-site topology differences. Site-directed mutagenesis; enzymatic activity assays; spectral binding assays; IC50 determination Journal of lipid research High 15314102
2010 Crystal structures of human CYP51 in ligand-free, ketoconazole-bound, and econazole-bound states reveal: azole binding occurs primarily through hydrophobic interactions with conserved active-site residues; ligand binding induces substantial conformational changes in the B′ helix and F-G loop; the substrate/inhibitor access channel topology differs from M. tuberculosis CYP51 and resembles other mammalian sterol-metabolizing P450s. X-ray crystallography (three crystal structures: apo, ketoconazole-bound, econazole-bound) Journal of molecular biology High 20149798
2011 Crystal structure of Trypanosoma brucei CYP51 complexed with the substrate analog 14α-methylenecyclopropyl-Δ7-24,25-dihydrolanosterol (MCP) at high resolution specifies substrate orientation in the conserved CYP51 binding cavity. The structure shows structural rigidity of the CYP51 substrate-binding cavity and explains mechanism-based inhibition of T. cruzi CYP51 by MCP (driven by residue I105), while F105-containing T. brucei and L. infantum CYP51s are only competitively inhibited. X-ray crystallography (substrate analog co-crystal structure); enzymatic inhibition assays Journal of lipid research High 22135275
2011 Mouse knockout of Cyp51 leads to embryonic lethality at day E15 with accumulation of CYP51 substrates (lanosterol and 24,25-dihydrolanosterol) and absence of downstream cholesterol precursors, confirming CYP51 is the sole enzyme responsible for this biosynthetic step in vivo. Lethality results from cardiac hypoplasia, ventricular septal defects, and vasculogenesis defects. Upstream cholesterol biosynthesis genes are upregulated (10 genes), and sonic hedgehog and retinoic acid signaling pathways are altered as downstream molecular consequences. Constitutive knockout mouse model; sterol metabolite profiling; gene expression analysis; histopathology The Journal of biological chemistry High 21705796
2005 CYP51 is an immediate early response gene: exposure of JEG-3 cells to forskolin (cAMP pathway activator) causes a rapid 4-fold induction of CYP51 mRNA within 2 h (returning to baseline by 4 h), mediated through the CYP51-CRE2 element. The inducible cAMP early repressor (ICER) attenuates this response. The cAMP-dependent induction is independent of SREBP and correlates with increased consumption of lanosterol substrate, demonstrating cross-talk between cAMP signaling and cholesterol feedback regulation of CYP51. Northern blot; promoter-reporter transfection assay; EMSA; GC-MS sterol analysis Endocrinology High 16123160
2007 The heme-binding protein Dap1 (yeast ortholog of human PGRMC1) activates Erg11/Cyp51 (yeast CYP51); cells lacking Dap1 accumulate the Erg11 substrate and are hypersensitive to Erg11 inhibitors. Elevated levels of Erg11 suppress loss of Dap1, placing Dap1 as a positive regulator upstream of CYP51 activity in the sterol biosynthesis pathway. Heme binding by Dap1 is required for this function. Genetic epistasis (Dap1 overexpression suppresses dap1Δ); yeast genetics; sterol accumulation assay; drug sensitivity assay The Journal of biological chemistry Medium 17954932
2008 CREM isoforms regulate the circadian expression of Cyp51 in mouse liver: Cyp51 mRNA oscillates with minimal expression between CT12–CT16 and peak at CT20–CT24 in wild-type mice. In Crem−/− livers, Cyp51 loses circadian expression. Overexpressed CREMτ and ICER influence CYP51 promoter activity. This circadian regulation is reflected in oscillation of the lathosterol/cholesterol ratio detected by GC-MS. Circadian gene expression analysis in Crem knockout mice; promoter-reporter assays; GC-MS sterol profiling Biochemical and biophysical research communications Medium 18775413
2009 CYP51 knockdown in follicular granulosa cells by siRNA moderately blocks FSH-induced oocyte meiotic resumption (23–30% reduction in germinal vesicle breakdown rate) in follicle-enclosed and cumulus-enclosed oocyte models, while LH-induced meiotic resumption is unaffected. This places CYP51 (via MAS sterol production) as a partial mediator specifically of the FSH-dependent pathway for initiating oocyte meiosis. siRNA knockdown in mouse follicle cultures; oocyte meiosis assay (GVBD measurement) Journal of lipid research Medium 19433477
2013 Male germ cell-specific knockout of Cyp51 in mice results in 85–89% reduction of Cyp51 mRNA and protein in germ cells, with accumulation of CYP51 substrates (lanosterol, 24,25-dihydrolanosterol) and substantially reduced meiosis-activating sterol (MAS) levels. Despite absence of MAS from germ cells, testicular morphology, sperm production, and reproductive performance are normal, providing in vivo evidence that de novo MAS synthesis in male germ cells is not essential for spermatogenesis. Conditional (germ cell-specific) Cyp51 knockout mouse; quantitative metabolic sterol profiling; histopathology; reproductive performance assessment Journal of lipid research High 23509403
2015 Hepatocyte-specific knockout of Cyp51 (LKO) in mice causes hepatomegaly with oval cell proliferation, fibrosis, and inflammation without steatosis. The key cellular trigger is reduced cholesterol esters leading to cell cycle arrest and senescence-associated secretory phenotype; elevated CYP51 substrates promote the integrated stress response. Liver injury is ameliorated by dietary fats (female-biased) or dietary cholesterol (both sexes), demonstrating that defective cholesterol synthesis is an independent determinant of liver inflammation and fibrosis. Hepatocyte-specific Cyp51 conditional knockout mouse; histopathology; gene expression profiling; dietary intervention Scientific reports High 25739789
2017 FSH upregulates CYP51A1 expression in granulosa cells, and this effect is enhanced by T3 (triiodothyronine). CYP51A1 knockdown blocks T3/FSH-induced estradiol and progesterone synthesis and decreases cell viability. This regulation is mediated through thyroid hormone receptor β activation of the PI3K/Akt pathway, with downstream activation of phospho-GATA-4; GATA-4 siRNA knockdown diminishes CYP51 expression and steroid levels, identifying GATA-4 as a transcriptional mediator of CYP51A1 in granulosa cells. siRNA knockdown; PI3K inhibitor; Western blot; hormone assay (E2/P4); RT-PCR; mouse preantral follicle culture Endocrinology Medium 28938463
2019 Purified recombinant C. albicans CYP51 proteins containing 23 single and 5 double clinical amino acid substitutions were assayed in reconstituted enzymatic assays. Double substitutions Y132H+K143R and Y132F+K143R confer the greatest increases in fluconazole IC50 (22.1- and 15.3-fold). Several single substitutions (K143R, S279F, S405F, G448E, G450E) reduce enzyme inhibition by fluconazole ≥2-fold. Itraconazole is the most effective inhibitor of mutant CaCYP51, whereas posaconazole MIC is least affected by CYP51 mutations in whole-cell assays. Heterologous expression in E. coli; protein purification; reconstituted enzymatic activity assays with IC50 determination; whole-cell MIC assays Antimicrobial agents and chemotherapy High 30783005
2019 Site-directed mutagenesis and comparative structural analysis across CYP51 orthologs identified the molecular basis for human CYP51 resistance to inhibition. Two newly synthesized compounds inhibit human CYP51 functionally irreversibly with potency approaching current clinical azoles, validating human CYP51 as a druggable target. Site-directed mutagenesis; comparative structural analysis of CYP51 orthologs; synthesis of novel compounds; enzymatic inhibition assays Journal of medicinal chemistry Medium 31663733
2025 CYP51A1 acts as a suppressor of alkalization-induced cell death in pancreatic cancer: intracellular alkalization (via JTC801) decreases ER cholesterol, activating SREBF2 which upregulates CYP51A1; CYP51A1 activity prevents cholesterol accumulation in lysosomes, enabling TMEM175-dependent lysosomal proton efflux that inhibits cell death. Genetic or pharmacological CYP51A1 inhibition enhances JTC801 efficacy in xenograft, syngeneic orthotopic, and patient-derived tumor models. Mass spectrometry-based drug analysis; transcriptomic screens; lipid metabolomics; genetic inhibition (knockout); pharmacological inhibition; animal tumor models (xenograft, syngeneic orthotopic, patient-derived) Nature communications Medium 40055353
1998 Five amino acid substitutions in C. albicans CYP51A1 (G129A, Y132H, S405F, G464S, R467K) identified in azole-resistant clinical isolates contribute to reduced azole affinity. By functional expression of mutant CYP51A1 in S. cerevisiae and site-directed mutagenesis of wild-type, each single mutation (except G129A) measurably reduces affinity for specific azole derivatives, establishing these residues as determinants of azole binding. Heterologous expression in S. cerevisiae; site-directed mutagenesis; azole susceptibility testing; functional complementation Antimicrobial agents and chemotherapy High 9527767
2001 A single amino acid substitution Gly-310→Asp in yeast CYP51 (lanosterol 14-demethylase) converts the enzyme to an inactive form (P450SG1) in which the 6th ligand to heme iron becomes histidine instead of water, inactivating the enzyme. This was established by cloning, sequencing, and molecular modeling of the active site. Gene cloning and sequencing; site-directed mutagenesis (natural mutant); molecular modeling of active site Biochemical and biophysical research communications Medium 3046615

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 Crystal structure of cytochrome P450 14alpha -sterol demethylase (CYP51) from Mycobacterium tuberculosis in complex with azole inhibitors. Proceedings of the National Academy of Sciences of the United States of America 417 11248033
1998 Amino acid substitutions in the cytochrome P-450 lanosterol 14alpha-demethylase (CYP51A1) from azole-resistant Candida albicans clinical isolates contribute to resistance to azole antifungal agents. Antimicrobial agents and chemotherapy 368 9527767
2010 Structural basis of human CYP51 inhibition by antifungal azoles. Journal of molecular biology 195 20149798
2012 Fungal cytochrome P450 sterol 14α-demethylase (CYP51) and azole resistance in plant and human pathogens. Applied microbiology and biotechnology 175 22684327
1996 The ubiquitously expressed human CYP51 encodes lanosterol 14 alpha-demethylase, a cytochrome P450 whose expression is regulated by oxysterols. Archives of biochemistry and biophysics 156 8619637
2014 Design and optimization of highly-selective fungal CYP51 inhibitors. Bioorganic & medicinal chemistry letters 137 24948565
2001 The 14alpha-Demethylasse(CYP51A1) Gene is Overexpressed in Venturia inaequalis Strains Resistant to Myclobutanil. Phytopathology 132 18944284
2014 Resistance to antifungals that target CYP51. Journal of chemical biology 130 25320648
2013 Biochemical analysis of a multifunctional cytochrome P450 (CYP51) enzyme required for synthesis of antimicrobial triterpenes in plants. Proceedings of the National Academy of Sciences of the United States of America 130 23940321
2013 Characterization of the sterol 14α-demethylases of Fusarium graminearum identifies a novel genus-specific CYP51 function. The New phytologist 124 23442154
2006 Overexpression of the 14alpha-demethylase target gene (CYP51) mediates fungicide resistance in Blumeriella jaapii. Applied and environmental microbiology 119 16597960
2011 Targeting Trypanosoma cruzi sterol 14α-demethylase (CYP51). Advances in parasitology 98 21820552
2018 CYP51 as drug targets for fungi and protozoan parasites: past, present and future. Parasitology 92 29642960
2000 Sterol 14-demethylase P450 (CYP51) provides a breakthrough for the discussion on the evolution of cytochrome P450 gene superfamily. Biochemical and biophysical research communications 89 10891326
2003 Many facets of mammalian lanosterol 14alpha-demethylase from the evolutionarily conserved cytochrome P450 family CYP51. Archives of biochemistry and biophysics 88 12464255
2011 Mouse knockout of the cholesterogenic cytochrome P450 lanosterol 14alpha-demethylase (Cyp51) resembles Antley-Bixler syndrome. The Journal of biological chemistry 86 21705796
2011 Sterol 14alpha-demethylase (CYP51) as a therapeutic target for human trypanosomiasis and leishmaniasis. Current topics in medicinal chemistry 83 21619513
2004 CYP51--the omnipotent P450. Molecular and cellular endocrinology 82 15026190
2008 CYP51: A major drug target in the cytochrome P450 superfamily. Lipids 81 18769951
1997 Cloning and expression in Escherichia coli of the obtusifoliol 14 alpha-demethylase of Sorghum bicolor (L.) Moench, a cytochrome P450 orthologous to the sterol 14 alpha-demethylases (CYP51) from fungi and mammals. The Plant journal : for cell and molecular biology 77 9076987
2010 Expression, purification, and characterization of Aspergillus fumigatus sterol 14-alpha demethylase (CYP51) isoenzymes A and B. Antimicrobial agents and chemotherapy 75 20660663
2004 CYP51 from Trypanosoma brucei is obtusifoliol-specific. Biochemistry 75 15311940
2003 Conservation in the CYP51 family. Role of the B' helix/BC loop and helices F and G in enzymatic function. Biochemistry 74 12885242
2008 Evolution of the CYP51 gene in Mycosphaerella graminicola: evidence for intragenic recombination and selective replacement. Molecular plant pathology 70 18705872
1999 Cyclic adenosine 3',5'-monophosphate(cAMP)/cAMP-responsive element modulator (CREM)-dependent regulation of cholesterogenic lanosterol 14alpha-demethylase (CYP51) in spermatids. Molecular endocrinology (Baltimore, Md.) 69 10551787
1996 Structure and mapping of the human lanosterol 14alpha-demethylase gene (CYP51) encoding the cytochrome P450 involved in cholesterol biosynthesis; comparison of exon/intron organization with other mammalian and fungal CYP genes. Genomics 68 8975714
2010 Heterologous expression of mutated eburicol 14alpha-demethylase (CYP51) proteins of Mycosphaerella graminicola to assess effects on azole fungicide sensitivity and intrinsic protein function. Applied and environmental microbiology 64 20305029
2009 Analysis of the CYP51 gene and encoded protein in propiconazole-resistant isolates of Mycosphaerella fijiensis. Pest management science 63 19418481
1998 CYP51-like gene of Mycobacterium tuberculosis actually encodes a P450 similar to eukaryotic CYP51. Journal of biochemistry 63 9756611
2009 Trypanosoma cruzi CYP51 inhibitor derived from a Mycobacterium tuberculosis screen hit. PLoS neglected tropical diseases 62 19190730
1999 Characteristics of the heterologously expressed human lanosterol 14alpha-demethylase (other names: P45014DM, CYP51, P45051) and inhibition of the purified human and Candida albicans CYP51 with azole antifungal agents. Yeast (Chichester, England) 59 10398344
1988 A single amino acid substitution converts cytochrome P450(14DM) to an inactive form, cytochrome P450SG1: complete primary structures deduced from cloned DNAS. Biochemical and biophysical research communications 59 3046615
2007 Regulation of iron homeostasis mediated by the heme-binding protein Dap1 (damage resistance protein 1) via the P450 protein Erg11/Cyp51. The Journal of biological chemistry 57 17954932
2011 Structural complex of sterol 14α-demethylase (CYP51) with 14α-methylenecyclopropyl-Delta7-24, 25-dihydrolanosterol. Journal of lipid research 55 22135275
2020 Mutations and Overexpression of CYP51 Associated with DMI-Resistance in Colletotrichum gloeosporioides from Chili. Plant disease 52 31951509
1998 Elevated expression of lanosterol 14alpha-demethylase (CYP51) and the synthesis of oocyte meiosis-activating sterols in postmeiotic germ cells of male rats. Endocrinology 52 9564839
1994 Occurrence of a P450 showing high homology to yeast lanosterol 14-demethylase (P450(14DM)) in the rat liver. Biochemical and biophysical research communications 49 8024575
2017 CYP51 is an essential drug target for the treatment of primary amoebic meningoencephalitis (PAM). PLoS neglected tropical diseases 47 29284029
2012 CYP51 structures and structure-based development of novel, pathogen-specific inhibitory scaffolds. International journal for parasitology. Drugs and drug resistance 47 23504044
2019 The Evolution of Azole Resistance in Candida albicans Sterol 14α-Demethylase (CYP51) through Incremental Amino Acid Substitutions. Antimicrobial agents and chemotherapy 45 30783005
2016 Overexpression of the CYP51A1 Gene and Repeated Elements are Associated with Differential Sensitivity to DMI Fungicides in Venturia inaequalis. Phytopathology 44 26863444
2004 Fluconazole binding and sterol demethylation in three CYP51 isoforms indicate differences in active site topology. Journal of lipid research 44 15314102
2001 Folding requirements are different between sterol 14alpha-demethylase (CYP51) from Mycobacterium tuberculosis and human or fungal orthologs. The Journal of biological chemistry 42 11373285
1999 Optimized expression and catalytic properties of a wheat obtusifoliol 14alpha-demethylase (CYP51) expressed in yeast. Complementation of erg11Delta yeast mutants by plant CYP51. European journal of biochemistry 40 10336628
2016 Mutations in the CYP51 gene reduce DMI sensitivity in Parastagonospora nodorum populations in Europe and China. Pest management science 39 27860315
2021 Targeted Genome Mining Reveals the Biosynthetic Gene Clusters of Natural Product CYP51 Inhibitors. Journal of the American Chemical Society 38 33857369
2007 Synthesis, antifungal and antimycobacterial activities of new bis-imidazole derivatives, and prediction of their binding to P450(14DM) by molecular docking and MM/PBSA method. Bioorganic & medicinal chemistry 36 17888669
2017 Role of CYP51 in the Regulation of T3 and FSH-Induced Steroidogenesis in Female Mice. Endocrinology 35 28938463
2003 A functional cytochrome P450 lanosterol 14 alpha-demethylase CYP51 enzyme in the acrosome: transport through the Golgi and synthesis of meiosis-activating sterols. Endocrinology 35 14630712
2020 Transformation of berberine to its demethylated metabolites by the CYP51 enzyme in the gut microbiota. Journal of pharmaceutical analysis 34 34765276
2015 A novel sterol regulatory element-binding protein gene (sreA) identified in penicillium digitatum is required for prochloraz resistance, full virulence and erg11 (cyp51) regulation. PloS one 34 25699519
2001 LDL downregulates CYP51 in porcine vascular endothelial cells and in the arterial wall through a sterol regulatory element binding protein-2-dependent mechanism. Circulation research 34 11179193
2015 Lessons from hepatocyte-specific Cyp51 knockout mice: impaired cholesterol synthesis leads to oval cell-driven liver injury. Scientific reports 33 25739789
2003 Conservation and cloning of CYP51: a sterol 14 alpha-demethylase from Mycobacterium smegmatis. Biochemical and biophysical research communications 33 12565899
2019 Induced expression of CYP51 associated with difenoconazole resistance in the pathogenic Alternaria sect. on potato in China. Pest management science 32 31785067
1998 Lanosterol 14alpha-demethylase (CYP51) and spermatogenesis. Drug metabolism and disposition: the biological fate of chemicals 32 9860928
1996 Isolation and molecular characterisation of the gene encoding eburicol 14 alpha-demethylase (cYP51) from Penicillium italicum. Molecular & general genetics : MGG 32 8628233
2008 X-ray structure of 4,4'-dihydroxybenzophenone mimicking sterol substrate in the active site of sterol 14alpha-demethylase (CYP51). The Journal of biological chemistry 31 18367444
1997 Structural and evolutionary studies on sterol 14-demethylase P450 (CYP51), the most conserved P450 monooxygenase: I. Structural analyses of the gene and multiple sizes of mRNA. Journal of biochemistry 30 9498553
2008 CREM modulates the circadian expression of CYP51, HMGCR and cholesterogenesis in the liver. Biochemical and biophysical research communications 29 18775413
2019 Validation of Human Sterol 14α-Demethylase (CYP51) Druggability: Structure-Guided Design, Synthesis, and Evaluation of Stoichiometric, Functionally Irreversible Inhibitors. Journal of medicinal chemistry 28 31663733
2016 Co-Occurrence of Two Allelic Variants of CYP51 in Erysiphe necator and Their Correlation with Over-Expression for DMI Resistance. PloS one 28 26839970
1997 Cloning and functional expression in yeast of a cDNA coding for an obtusifoliol 14alpha-demethylase (CYP51) in wheat. Biochemical and biophysical research communications 28 9016788
2019 Calcium signaling pathway is involved in non-CYP51 azole resistance in Aspergillus fumigatus. Medical mycology 27 30816964
2000 Lanosterol 14alpha-demethylase (CYP51), NADPH-cytochrome P450 reductase and squalene synthase in spermatogenesis: late spermatids of the rat express proteins needed to synthesize follicular fluid meiosis activating sterol. The Journal of endocrinology 27 10927636
1996 The three human cytochrome P450 lanosterol 14 alpha-demethylase (CYP51) genes reside on chromosomes 3, 7, and 13: structure of the two retrotransposed pseudogenes, association with a line-1 element, and evolution of the human CYP51 family. Archives of biochemistry and biophysics 27 8809088
2013 Induced overexpression of cytochrome P450 sterol 14α-demethylase gene (CYP51) correlates with sensitivity to demethylation inhibitors (DMIs) in Sclerotinia homoeocarpa. Pest management science 26 23408719
2015 Dynamics of CYP51: implications for function and inhibitor design. Journal of molecular recognition : JMR 25 25601796
2005 Recent progress in the CYP51 research focusing on its unique evolutionary and functional characteristics as a diversozyme P450. Frontiers in bioscience : a journal and virtual library 25 15769645
2005 Cholesterogenic lanosterol 14alpha-demethylase (CYP51) is an immediate early response gene. Endocrinology 25 16123160
2001 The amino acid residues affecting the activity and azole susceptibility of rat CYP51 (sterol 14-demethylase P450). Journal of biochemistry 25 11328599
2020 Molecular Dynamics Investigations of Binding Mechanism for Triazoles Inhibitors to CYP51. Frontiers in molecular biosciences 24 33102531
2008 Analysis of the CTNS gene in nephropathic cystinosis Mexican patients: report of four novel mutations and identification of a false positive 57-kb deletion genotype with LDM-2/exon 4 multiplex PCR assay. Genetic testing 24 18752449
2016 Trypanosoma brucei CYP51: Essentiality and Targeting Therapy in an Experimental Model. PLoS neglected tropical diseases 21 27855164
2020 Two Point Mutations on CYP51 Combined With Induced Expression of the Target Gene Appeared to Mediate Pyrisoxazole Resistance in Botrytis cinerea. Frontiers in microbiology 20 32714305
2016 Targeting CYP51 for drug design by the contributions of molecular modeling. Fundamental & clinical pharmacology 20 27487199
2015 Identification and functional characterization of the CYP51 gene from the yeast Xanthophyllomyces dendrorhous that is involved in ergosterol biosynthesis. BMC microbiology 20 25906980
2015 Acyl-Carbon Bond Cleaving Cytochrome P450 Enzymes: CYP17A1, CYP19A1 and CYP51A1. Advances in experimental medicine and biology 20 26002733
1998 Expression, purification, reconstitution and inhibition of Ustilago maydis sterol 14 alpha-demethylase (CYP51; P450(14DM)). FEMS microbiology letters 20 9868783
1996 Increased resistance to 14 alpha-demethylase inhibitors (DMIs) in Aspergillus niger by coexpression of the Penicillium italicum eburicol 14 alpha-demethylase (cyp51) and the A. niger cytochrome P450 reductase (cprA) genes. Journal of biotechnology 20 8879162
2023 In silico prediction of Antifungal compounds from Natural sources towards Lanosterol 14-alpha demethylase (CYP51) using Molecular docking and Molecular dynamic simulation. Journal of molecular graphics & modelling 19 36848730
2023 Strategies of targeting CYP51 for IFIs therapy: Emerging prospects, opportunities and challenges. European journal of medicinal chemistry 19 37480712
2015 Ligand tunnels in T. brucei and human CYP51: Insights for parasite-specific drug design. Biochimica et biophysica acta 19 26493722
2013 Polymorphisms of CYP51A1 from cholesterol synthesis: associations with birth weight and maternal lipid levels and impact on CYP51 protein structure. PloS one 19 24358204
2010 Functional expression and characterization of CYP51 from dandruff-causing Malassezia globosa. FEMS yeast research 19 21114623
2005 Effects of Y132H and F145L substitutions on the activity, azole resistance and spectral properties of Candida albicans sterol 14-demethylase P450 (CYP51): a live example showing the selection of altered P450 through interaction with environmental compounds. Journal of biochemistry 19 15944416
2022 Analysis of Cyp51 protein sequences shows 4 major Cyp51 gene family groups across fungi. G3 (Bethesda, Md.) 18 36130263
2019 New Insights into the Cyp51 Contribution to Azole Resistance in Aspergillus Section Nigri. Antimicrobial agents and chemotherapy 18 31061160
2014 CYP51A1 induced by growth differentiation factor 9 and follicle-stimulating hormone in granulosa cells is a possible predictor for unfertilization. Reproductive sciences (Thousand Oaks, Calif.) 18 24711211
2009 Reducing CYP51 inhibits follicle-stimulating hormone induced resumption of mouse oocyte meiosis in vitro. Journal of lipid research 18 19433477
2025 CYP51A1 drives resistance to pH-dependent cell death in pancreatic cancer. Nature communications 17 40055353
2006 Biodiversity of CYP51 in trypanosomes. Biochemical Society transactions 17 17073776
2022 CYP51 Mutations in the Fusarium solani Species Complex: First Clue to Understand the Low Susceptibility to Azoles of the Genus Fusarium. Journal of fungi (Basel, Switzerland) 16 35628788
2022 Potential dual inhibition of SE and CYP51 by eugenol conferring inhibition of Candida albicans: Computationally curated study with experimental validation. Computers in biology and medicine 16 36327880
2021 Human Lanosterol 14-Alpha Demethylase (CYP51A1) Is a Putative Target for Natural Flavonoid Luteolin 7,3'-Disulfate. Molecules (Basel, Switzerland) 16 33924405
2021 CYP51 Paralogue Structure Is Associated with Intrinsic Azole Resistance in Fungi. mBio 16 34607450
2000 Structure of the pig sterol 14alpha-demethylase (CYP51) gene and its expression in the testis and other tissues. Journal of biochemistry 16 10788789
2022 Triazole Derivatives Target 14α-Demethylase (LDM) Enzyme in Candida albicans Causing Ergosterol Biosynthesis Inhibition. Journal of fungi (Basel, Switzerland) 15 35887444
2013 Male germ cell-specific knockout of cholesterogenic cytochrome P450 lanosterol 14α-demethylase (Cyp51). Journal of lipid research 15 23509403
2006 CYP121, CYP51 and associated redox systems in Mycobacterium tuberculosis: towards deconvoluting enzymology of P450 systems in a human pathogen. Biochemical Society transactions 15 17073780

Missed literature

Know a paper Affinage missed for CYP51A1? Flag it for the maintainers and the community.

No submissions yet.