Affinage

HSD17B4

Peroxisomal multifunctional enzyme type 2 · UniProt P51659

Round 2 corrected
Length
736 aa
Mass
79.7 kDa
Annotated
2026-04-28
130 papers in source corpus 12 papers cited in narrative 12 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HSD17B4 encodes peroxisomal multifunctional enzyme type 2 (MFE-2/D-bifunctional protein), a tri-domain enzyme that catalyzes two sequential steps of peroxisomal fatty acid β-oxidation—2-enoyl-CoA hydratase and D-3-hydroxyacyl-CoA dehydrogenase activities—required for degradation of very-long-chain fatty acids, pristanic acid, and bile acid intermediates (PMID:16756494, PMID:10343282). The N-terminal SDR-family dehydrogenase domain also oxidizes estradiol to estrone, and isoform 2 specifically inactivates testosterone and dihydrotestosterone; suppression of isoform 2 in prostate tumors shifts androgen metabolism toward active 17β-hydroxy forms and drives castration-resistant prostate cancer (PMID:29346776). Protein stability is regulated by CREBBP-mediated acetylation at K669, which targets HSD17B4 for chaperone-mediated autophagy degradation and is counteracted by SIRT3-mediated deacetylation (PMID:28296597, PMID:32678070). Biallelic loss-of-function mutations across the dehydrogenase and hydratase domains cause a phenotypic spectrum from lethal neonatal D-bifunctional protein deficiency to juvenile/adult-onset Perrault syndrome with cerebellar ataxia, sensorineural hearing loss, and hypergonadotropic hypogonadism (PMID:20673864, PMID:23181892).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1995 High

    Cloning of HSD17B4 established a new 80 kDa multidomain enzyme with N-terminal SDR-family 17β-HSD activity (estradiol → estrone), a central hydratase-homologous domain, and a C-terminal SCP-2-like domain, resolving the molecular identity of a previously uncharacterized oxidative 17β-hydroxysteroid dehydrogenase.

    Evidence cDNA cloning, sequence homology analysis, and overexpression in mammalian cells with enzymatic activity assays

    PMID:7487879

    Open questions at the time
    • Hydratase and SCP-2 activities of individual domains were not biochemically tested
    • Subcellular localization not directly demonstrated in this study
  2. 1999 High

    Biochemical dissection of each domain proved that HSD17B4 is a bona fide trifunctional peroxisomal enzyme: the N-terminal fragment is a D-3-hydroxyacyl-CoA dehydrogenase (with strict D-stereospecificity), the central domain is a 2-enoyl-CoA hydratase, and the C-terminal SCP-2-like domain transfers sterols and phospholipids between membranes.

    Evidence In vitro enzymatic assays with truncated recombinant proteins, stereospecificity testing, lipid transfer assays

    PMID:10343282

    Open questions at the time
    • Physiological significance of SCP-2-domain lipid transfer in vivo not tested
    • Relative contribution of HSD17B4 vs. L-bifunctional protein (HSD17B10) to total peroxisomal β-oxidation flux unresolved
  3. 2006 High

    The position of HSD17B4 as the principal D-specific MFE-2 in peroxisomal β-oxidation of very-long-chain fatty acids, pristanic acid, and bile acid intermediates was consolidated, establishing it as an essential node in peroxisomal lipid catabolism.

    Evidence Comprehensive biochemical review synthesizing substrate specificity studies across multiple laboratories

    PMID:16756494

    Open questions at the time
    • Structural basis for D-stereoselectivity not resolved at atomic level at this time
    • Regulation of MFE-2 enzyme activity in vivo unclear
  4. 2010 High

    Identification of compound heterozygous HSD17B4 mutations in Perrault syndrome patients revealed that partial loss of function produces a milder phenotype (ovarian dysgenesis, hearing loss, neurological features) distinct from lethal neonatal DBP deficiency, establishing a genotype–phenotype continuum for HSD17B4 deficiency.

    Evidence Whole-exome sequencing, structural modeling of missense mutation (Y217C), protein expression analysis in patient cells

    PMID:20673864

    Open questions at the time
    • Residual enzymatic activity of Y217C mutant not directly quantified
    • Whether ovarian dysgenesis is due to steroid or fatty acid metabolic defect not distinguished
  5. 2012 High

    Quantitation of residual hydratase and dehydrogenase activities in patient fibroblasts with mutations spanning both catalytic domains defined a new type IV DBP deficiency and directly correlated partial enzymatic loss with a mild, late-onset ataxia–deafness phenotype.

    Evidence Patient fibroblast enzymatic activity assays (pristanic acid β-oxidation, hydratase, dehydrogenase) with exome-confirmed compound heterozygous mutations

    PMID:23181892

    Open questions at the time
    • Whether residual activity thresholds can predict disease severity remains untested prospectively
    • Tissue-specific consequences of partial loss not assessed
  6. 2014 Medium

    A male patient with HSD17B4 deficiency and azoospermia expanded the phenotypic spectrum to include male infertility, indicating that peroxisomal β-oxidation via HSD17B4 is required for spermatogenesis.

    Evidence Exome sequencing (12 kb deletion + missense), elevated pristanic:phytanic acid ratio confirming peroxisomal dysfunction

    PMID:24602372

    Open questions at the time
    • Mechanistic link between HSD17B4 loss and spermatogenic failure not established
    • Single case report; prevalence of male infertility in HSD17B4 deficiency unclear
  7. 2017 High

    Discovery that CREBBP acetylates HSD17B4 at K669 to trigger chaperone-mediated autophagy degradation, counteracted by SIRT3 deacetylation, revealed a post-translational switch controlling HSD17B4 protein levels in response to steroid hormones (estrone, DHT).

    Evidence Site-directed mutagenesis of K669, Co-IP of CREBBP and SIRT3, CMA assays, migration/invasion assays in MCF7 cells, IHC of breast cancer tissues

    PMID:28296597

    Open questions at the time
    • Whether K669 acetylation regulates catalytic activity directly, or only protein turnover, is not determined
    • Identity of the CMA receptor recognizing acetylated HSD17B4 not established
  8. 2017 High

    Cytisine-linked isoflavonoids selectively bind the SCP-2-like C-terminal domain and inhibit hydratase (but not dehydrogenase) activity, establishing domain-selective pharmacological targeting of HSD17B4.

    Evidence Biotin-modified ligand pull-down, domain-specific truncation constructs, separate enzymatic assays for hydratase vs. dehydrogenase, siRNA knockdown proliferation assays

    PMID:28868548

    Open questions at the time
    • Mechanism by which C-terminal binding allosterically inhibits the central hydratase domain is unknown
    • In vivo pharmacokinetics and selectivity not assessed
  9. 2018 High

    Isoform-specific analysis resolved a long-standing question about HSD17B4's androgen role: only isoform 2 catalyzes inactivation of testosterone and DHT, and its selective suppression in castration-resistant prostate cancer shifts the androgen metabolic balance toward active 17β-OH forms driving AR signaling.

    Evidence Splice form cloning with isoform-specific enzymatic assays, patient tumor RNA analysis, genetic silencing with LC-MS androgen metabolite quantification, AR activity readouts

    PMID:29346776

    Open questions at the time
    • Mechanism of isoform 2 splicing regulation during CRPC progression not identified
    • Whether restoring isoform 2 can reverse CRPC in vivo is untested
  10. 2020 High

    Replication of the K669 acetylation–CMA degradation axis in prostate cancer cells confirmed it as a general regulatory mechanism across hormone-responsive tissues, and demonstrated that HSD17B4 protein levels directly modulate cancer cell proliferation, migration, and invasion.

    Evidence Co-IP, K669 mutagenesis, CMA assays, siRNA knockdown and overexpression phenotyping, IHC in prostate cancer tissues

    PMID:32678070

    Open questions at the time
    • Relative contribution of HSD17B4's β-oxidation vs. steroid-metabolizing activities to cancer cell phenotypes not deconvolved
    • In vivo tumor model validation absent

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis for domain-selective catalysis (especially how C-terminal SCP-2 binding by small molecules inhibits the central hydratase domain), the mechanism coupling isoform 2 splicing to CRPC progression, and the tissue-specific determinants that distinguish lethal neonatal from adult-onset HSD17B4 deficiency remain unresolved.
  • No full-length human HSD17B4 crystal structure capturing interdomain communication
  • Isoform 2 splicing regulators unidentified
  • Tissue-specific thresholds of residual activity needed to prevent organ-specific pathology unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 5 GO:0016853 isomerase activity 3 GO:0008289 lipid binding 1
Localization
GO:0005777 peroxisome 2
Pathway
R-HSA-1430728 Metabolism 4 R-HSA-1643685 Disease 2 R-HSA-9612973 Autophagy 2
Partners
CREBBPSIRT3

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 HSD17B4 encodes a novel 80 kDa human 17β-hydroxysteroid dehydrogenase (type IV, 736 amino acids) with three distinct domain regions: an N-terminal short-chain alcohol dehydrogenase domain with 17β-HSD activity, a central domain homologous to the bifunctional Candida tropicalis enzyme and yeast FOX2 (hydratase activity), and a C-terminal domain homologous to sterol carrier protein 2. When overexpressed in mammalian cells, it catalyzes a unidirectional oxidative 17β-HSD reaction (estradiol → estrone). mRNA is expressed in many tissues, highest in liver, heart, prostate, and testes. cDNA cloning, sequence homology analysis, overexpression in mammalian cells with enzymatic activity assay The Biochemical journal High 7487879
1999 HSD17B4 is a multifunctional peroxisomal enzyme: the full 80 kDa protein and its N-terminal 32 kDa cleavage fragment (aa 1–323) both catalyze dehydrogenase reactions on steroids at C17 and on D-3-hydroxyacyl-CoA (but not L-stereoisomers); the central domain (aa 324–596) catalyzes 2-enoyl-acyl-CoA hydratase activity with high efficiency; and the C-terminal domain (aa 597–737) facilitates transfer of 7-dehydrocholesterol and phosphatidylcholine between membranes in vitro. The HSD17B4 gene is induced by progesterone and PPARα ligands (clofibrate) and repressed by phorbol esters. Loss-of-function mutations cause a fatal form of Zellweger syndrome. Biochemical domain dissection, in vitro enzymatic assays with truncated proteins, stereospecificity testing, lipid transfer assay, gene expression studies with pharmacological agents Journal of molecular endocrinology High 10343282
2006 HSD17B4 (D-bifunctional protein) is established as a core peroxisomal fatty acid β-oxidation enzyme with both 2-enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase activities, acting on the D-stereoisomer of 3-hydroxyacyl-CoA intermediates. It is the mammalian multifunctional enzyme type 2 (MFE-2) required for oxidation of very-long-chain fatty acids, pristanic acid, and bile acid intermediates in peroxisomes. Biochemical characterization and review of peroxisomal enzyme activities; substrate specificity assays documented across the field Annual review of biochemistry High 16756494
2010 Compound heterozygous mutations in HSD17B4 (p.Y217C in the dehydrogenase domain predicted by structural analysis to destabilize the domain, and p.Y568X causing very low transcript levels) cause Perrault syndrome (ovarian dysgenesis, sensorineural deafness, neurological manifestations). Expression of mutant HSD17B4 protein in the compound heterozygote was severely reduced, establishing that partial loss of HSD17B4 function underlies this milder phenotype overlapping with lethal DBP deficiency. Whole-exome sequencing, Sanger confirmation of variants, structural modeling of missense mutation, protein expression analysis in patient cells American journal of human genetics High 20673864
2012 Compound heterozygous mutations spanning both the dehydrogenase domain (p.Ala34Val) and hydratase domain (p.Ile516Thr) of HSD17B4 define a novel type IV DBP deficiency. Fibroblast studies showed markedly reduced but detectable hydratase and dehydrogenase activities and reduced pristanic acid β-oxidation, with normal VLCFA levels, establishing that partial residual activity in both domains produces a distinct, mild, late-onset phenotype (sensorineural hearing loss, cerebellar and sensory ataxia). Exome sequencing, Sanger confirmation, fibroblast enzymatic activity assays (pristanic acid β-oxidation, hydratase activity, dehydrogenase activity), biochemical serum/urine analysis Orphanet journal of rare diseases High 23181892
2014 A heterozygous 12 kb deletion of exons 10–13 of HSD17B4 compounded with a rare missense variant (p.A196V) causes adult-onset HSD17B4-deficiency in a male presenting with cerebellar ataxia, peripheral neuropathy, hearing loss, and azoospermia — the first reported male case with infertility. Mildly elevated pristanic:phytanic acid and arachidonic:docosahexaenoic acid ratios confirmed dysfunctional peroxisomal fatty acid oxidation. Targeted exome sequencing, computational CNV inference from exome data, Sanger confirmation, retrospective biochemical review (serum lipid ratios, muscle biopsy) BMC medical genetics Medium 24602372
2016 Compound heterozygous mutations in HSD17B4 (one nonsense/deletion + one missense in each of three families) cause juvenile-onset D-bifunctional protein deficiency with slowly progressive cerebellar ataxia, sensorineural deafness, and hypergonadotropic hypogonadism, consolidating the phenotypic spectrum of HSD17B4-associated disease. Linkage analysis (SNP microarray), exome sequencing, clinical and MRI characterization across 5 patients from 3 families Neurology. Genetics Medium 27790638
2017 Estrone (E1) upregulates acetylation of HSD17B4 at lysine 669 (K669), promoting its degradation via chaperone-mediated autophagy (CMA). CREBBP acts as the acetyltransferase writer and SIRT3 as the deacetylase eraser controlling K669 acetylation. A K669 mutation that prevents acetylation blocks CMA-mediated degradation and confers migratory and invasive properties to MCF7 breast cancer cells upon E1 treatment. K669 acetylation level is inversely correlated with HSD17B4 protein level in human breast cancer tissues. Site-directed mutagenesis (K669), Co-IP of CREBBP and SIRT3 with HSD17B4, CMA assay, migration/invasion assays in MCF7 cells, IHC of breast cancer tissues, acetylation mass spectrometry Autophagy High 28296597
2017 Cytisine-linked isoflavonoids (CLIFs) bind specifically to the C-terminus (SCP-2-like domain) of HSD17B4 and selectively inhibit its enoyl-CoA hydratase activity without affecting the D-3-hydroxyacyl-CoA dehydrogenase activity. This was demonstrated using a biotin-modified CLIF pull-down assay to identify HSD17B4 as the target, and confirmed with truncated HSD17B4 constructs. HSD17B4 knockdown inhibited prostate and colon cancer cell proliferation, supporting HSD17B4 as a druggable cancer target. Biotin-modified ligand pull-down/affinity capture, domain-specific truncation constructs, enzymatic activity assays (hydratase vs. dehydrogenase), siRNA knockdown with proliferation assay Organic & biomolecular chemistry High 28868548
2018 Of five alternative splice forms of HSD17B4, only isoform 2 encodes an enzyme capable of inactivating testosterone and dihydrotestosterone by oxidation to their 17-keto forms. Expression of isoform 2 is specifically suppressed during development of castration-resistant prostate cancer (CRPC) in patients. Genetic silencing of isoform 2 shifts the metabolic balance toward 17β-OH androgens (testosterone and DHT), stimulates androgen receptor (AR) signaling, and drives CRPC development. Alternative splice form cloning and enzymatic activity assays, patient tumor RNA analysis, genetic silencing of isoform 2 with androgen metabolite measurement (mass spectrometry), AR activity readouts Cell reports High 29346776
2020 Dihydrotestosterone (DHT) treatment increases HSD17B4 acetylation at K669, promoting its degradation via chaperone-mediated autophagy (CMA) in prostate cancer cells. SIRT3 directly interacts with HSD17B4 to inhibit its K669 acetylation and enhance protein stability, while CREBBP promotes K669 acetylation and HSD17B4 degradation. HSD17B4 knockdown suppressed PCa cell proliferation, migration, and invasion, while overexpression had opposite effects. K669 acetylation level was negatively correlated with HSD17B4 protein in prostate cancer tissues. Co-IP of SIRT3 and CREBBP with HSD17B4, site-directed mutagenesis (K669), CMA assay, siRNA knockdown and overexpression with proliferation/migration/invasion assays, IHC of prostate cancer tissues Aging High 32678070
2020 Four patients with HSD17B4 mutations (including biallelic mutations affecting the dehydrogenase domain) showed variable phenotypes including polymicrogyria, sensorineural hearing loss, seizures, adrenal insufficiency, and nystagmus. Normal VLCFA levels were found in two of three patients tested, demonstrating that normal peroxisomal biomarkers do not exclude HSD17B4/DBP deficiency. Whole exome sequencing, Sanger confirmation, peroxisomal β-oxidation assay, brain MRI, clinical characterization Molecular genetics and metabolism reports Medium 32904102

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2010 Network organization of the human autophagy system. Nature 1286 20562859
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2005 Nucleolar proteome dynamics. Nature 934 15635413
2006 Biochemistry of mammalian peroxisomes revisited. Annual review of biochemistry 761 16756494
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2013 Plastics derived endocrine disruptors (BPA, DEHP and DBP) induce epigenetic transgenerational inheritance of obesity, reproductive disease and sperm epimutations. PloS one 609 23359474
2020 Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms. Science (New York, N.Y.) 564 33060197
2017 Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15. Science (New York, N.Y.) 533 28302793
2006 Rhythmic CLOCK-BMAL1 binding to multiple E-box motifs drives circadian Dbp transcription and chromatin transitions. Nature genetics 467 16474407
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2015 A Dynamic Protein Interaction Landscape of the Human Centrosome-Cilium Interface. Cell 433 26638075
2016 Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing. Cell 423 26871637
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2006 The circadian PAR-domain basic leucine zipper transcription factors DBP, TEF, and HLF modulate basal and inducible xenobiotic detoxification. Cell metabolism 400 16814730
2000 CLOCK, an essential pacemaker component, controls expression of the circadian transcription factor DBP. Genes & development 343 10733528
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2013 Vitamin D and DBP: the free hormone hypothesis revisited. The Journal of steroid biochemistry and molecular biology 322 24095930
2008 The SDR (short-chain dehydrogenase/reductase and related enzymes) nomenclature initiative. Chemico-biological interactions 315 19027726
2015 Inhibition of the Mitochondrial Protease ClpP as a Therapeutic Strategy for Human Acute Myeloid Leukemia. Cancer cell 293 26058080
1993 Circadian transcription of the cholesterol 7 alpha hydroxylase gene may involve the liver-enriched bZIP protein DBP. Genes & development 275 8405996
2013 Roquin promotes constitutive mRNA decay via a conserved class of stem-loop recognition motifs. Cell 263 23663784
2010 Mass spectrometric analysis of lysine ubiquitylation reveals promiscuity at site level. Molecular & cellular proteomics : MCP 262 21139048
2012 Systems-wide analysis of ubiquitylation dynamics reveals a key role for PAF15 ubiquitylation in DNA-damage bypass. Nature cell biology 243 23000965
1997 The DBP gene is expressed according to a circadian rhythm in the suprachiasmatic nucleus and influences circadian behavior. The EMBO journal 238 9362490
2009 Genes related to sex steroids, neural growth, and social-emotional behavior are associated with autistic traits, empathy, and Asperger syndrome. Autism research : official journal of the International Society for Autism Research 223 19598235
1990 Expression of the liver-enriched transcriptional activator protein DBP follows a stringent circadian rhythm. Cell 212 2261643
2015 ∆F508 CFTR interactome remodelling promotes rescue of cystic fibrosis. Nature 209 26618866
2011 Toward an understanding of the protein interaction network of the human liver. Molecular systems biology 207 21988832
1995 Molecular cloning of a novel widely expressed human 80 kDa 17 beta-hydroxysteroid dehydrogenase IV. The Biochemical journal 204 7487879
2012 Functional genomics identifies therapeutic targets for MYC-driven cancer. Proceedings of the National Academy of Sciences of the United States of America 203 22623531
2000 Role of DBP in the circadian oscillatory mechanism. Molecular and cellular biology 203 10848603
2018 An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations. Nature communications 201 29568061
2010 Mutations in the DBP-deficiency protein HSD17B4 cause ovarian dysgenesis, hearing loss, and ataxia of Perrault Syndrome. American journal of human genetics 199 20673864
2020 Systems analysis of RhoGEF and RhoGAP regulatory proteins reveals spatially organized RAC1 signalling from integrin adhesions. Nature cell biology 194 32203420
2014 25(OH)D2 half-life is shorter than 25(OH)D3 half-life and is influenced by DBP concentration and genotype. The Journal of clinical endocrinology and metabolism 191 24885631
1999 Circadian expression of the steroid 15 alpha-hydroxylase (Cyp2a4) and coumarin 7-hydroxylase (Cyp2a5) genes in mouse liver is regulated by the PAR leucine zipper transcription factor DBP. Molecular and cellular biology 135 10490589
2011 Dimerization of Plasmodium vivax DBP is induced upon receptor binding and drives recognition of DARC. Nature structural & molecular biology 116 21743458
2003 Vitamin D binding protein-macrophage activating factor (DBP-maf) inhibits angiogenesis and tumor growth in mice. Neoplasia (New York, N.Y.) 104 12659668
2000 The transcription factor DBP affects circadian sleep consolidation and rhythmic EEG activity. The Journal of neuroscience : the official journal of the Society for Neuroscience 102 10632591
2020 Effect of polystyrene on di-butyl phthalate (DBP) bioavailability and DBP-induced phytotoxicity in lettuce. Environmental pollution (Barking, Essex : 1987) 93 33120154
2012 Circadian Dbp transcription relies on highly dynamic BMAL1-CLOCK interaction with E boxes and requires the proteasome. Molecular cell 93 22981862
2014 Red blood cell invasion by Plasmodium vivax: structural basis for DBP engagement of DARC. PLoS pathogens 90 24415938
1991 Chicken vitellogenin gene-binding protein, a leucine zipper transcription factor that binds to an important control element in the chicken vitellogenin II promoter, is related to rat DBP. Molecular and cellular biology 90 1922023
2017 Biodegradation of di-n-butyl phthalate (DBP) by a novel endophytic Bacillus megaterium strain YJB3. The Science of the total environment 72 29112835
1999 Unique multifunctional HSD17B4 gene product: 17beta-hydroxysteroid dehydrogenase 4 and D-3-hydroxyacyl-coenzyme A dehydrogenase/hydratase involved in Zellweger syndrome. Journal of molecular endocrinology 70 10343282
2004 Neonatal exposure to di(n-butyl) phthalate (DBP) alters male reproductive-tract development. Journal of toxicology and environmental health. Part A 60 15513902
2017 Role of PI3K/AKT/mTOR signaling pathway in DBP-induced apoptosis of testicular sertoli cells in vitro. Environmental toxicology and pharmacology 59 28578144
2015 Short term exposure to di-n-butyl phthalate (DBP) disrupts ovarian function in young CD-1 mice. Reproductive toxicology (Elmsford, N.Y.) 59 25765776
2011 Cellular DBP and E4BP4 proteins are critical for determining the period length of the circadian oscillator. FEBS letters 58 21635892
2004 Rhythmic expression of DEC1 and DEC2 in peripheral tissues: DEC2 is a potent suppressor for hepatic cytochrome P450s opposing DBP. Genes to cells : devoted to molecular & cellular mechanisms 58 15066123
2020 Complete biodegradation of di-n-butyl phthalate (DBP) by a novel Pseudomonas sp. YJB6. The Science of the total environment 55 33162130
2012 Specific combination of compound heterozygous mutations in 17β-hydroxysteroid dehydrogenase type 4 (HSD17B4) defines a new subtype of D-bifunctional protein deficiency. Orphanet journal of rare diseases 55 23181892
2020 The role of DBP gene polymorphisms in the prevalence of new coronavirus disease 2019 infection and mortality rate. Journal of medical virology 53 32770768
2014 The causal effect of vitamin D binding protein (DBP) levels on calcemic and cardiometabolic diseases: a Mendelian randomization study. PLoS medicine 53 25350643
1993 Synergy between transcription factors DBP and C/EBP compensates for a haemophilia B Leyden factor IX mutation. Nature genetics 52 8499951
2019 Structural basis for neutralization of Plasmodium vivax by naturally acquired human antibodies that target DBP. Nature microbiology 50 31133752
2017 Oxidative Damage and Genetic Toxicity Induced by DBP in Earthworms (Eisenia fetida). Archives of environmental contamination and toxicology 49 28913550
2008 Alteration of DBP levels in CSF of patients with MS by proteomics analysis. Cellular and molecular neurobiology 48 18807170
1999 Effect of cis-, trans-diamminedichloroplatinum(II) and DBP on human serum albumin. Journal of inorganic biochemistry 48 10643655
2013 Short-term neonatal/prepubertal exposure of dibutyl phthalate (DBP) advanced pubertal timing and affected hypothalamic kisspeptin/GPR54 expression differently in female rats. Toxicology 47 24056307
2023 Unravelling High-Molecular-Weight DBP Toxicity Drivers in Chlorinated and Chloraminated Drinking Water: Effect-Directed Analysis of Molecular Weight Fractions. Environmental science & technology 46 37418586
2009 Long-term effects of developmental exposure to di-n-butyl-phthalate (DBP) on rat prostate: proliferative and inflammatory disorders and a possible role of androgens. Toxicology 45 19549552
1992 Role of the liver-enriched transcription factor DBP in expression of the cytochrome P450 CYP2C6 gene. Molecular and cellular biology 45 1588973
2018 Biodegradation of di-butyl phthalate (DBP) by a novel endophytic bacterium Bacillus subtilis and its bioaugmentation for removing DBP from vegetation slurry. Journal of environmental management 42 30025259
2020 Amplification of Duffy binding protein-encoding gene allows Plasmodium vivax to evade host anti-DBP humoral immunity. Nature communications 41 32075983
2018 Effects of two environmental endocrine disruptors di-n-butyl phthalate (DBP) and mono-n-butyl phthalate (MBP) on human sperm functions in vitro. Reproductive toxicology (Elmsford, N.Y.) 41 30391722
2017 Maternal exposure to di-n-butyl phthalate (DBP) induces renal fibrosis in adult rat offspring. Oncotarget 41 28415704
2015 Structural analysis of the synthetic Duffy Binding Protein (DBP) antigen DEKnull relevant for Plasmodium vivax malaria vaccine design. PLoS neglected tropical diseases 39 25793371
2018 Exposure to DBP and High Iodine Aggravates Autoimmune Thyroid Disease Through Increasing the Levels of IL-17 and Thyroid-Binding Globulin in Wistar Rats. Toxicological sciences : an official journal of the Society of Toxicology 37 29385629
2017 Acetylation targets HSD17B4 for degradation via the CMA pathway in response to estrone. Autophagy 37 28296597
2017 The shadow of dichloroacetonitrile (DCAN), a typical nitrogenous disinfection by-product (N-DBP), in the waterworks and its backwash water reuse. Chemosphere 37 28467950
2020 Characteristics of low and high SUVA precursors: Relationships among molecular weight, fluorescence, and chemical composition with DBP formation. The Science of the total environment 35 32498213
2018 Loss of an Androgen-Inactivating and Isoform-Specific HSD17B4 Splice Form Enables Emergence of Castration-Resistant Prostate Cancer. Cell reports 34 29346776
2018 DEP and DBP induce cytotoxicity in mouse embryonic stem cells and abnormally enhance neural ectoderm development. Environmental pollution (Barking, Essex : 1987) 34 29414342
2016 Maternal exposure to di-n-butyl phthalate (DBP) induces combined anorectal and urogenital malformations in male rat offspring. Reproductive toxicology (Elmsford, N.Y.) 34 27079746
2014 Next generation sequencing with copy number variant detection expands the phenotypic spectrum of HSD17B4-deficiency. BMC medical genetics 34 24602372
2013 Variations in the vitamin D-binding protein (DBP) gene are related to lower 25-hydroxyvitamin D levels in healthy girls: a cross-sectional study. Hormone research in paediatrics 33 23548751
2009 Knocking out the MFE-2 gene of Candida bombicola leads to improved medium-chain sophorolipid production. FEMS yeast research 32 19416371
1994 Chromosomal localization and cDNA cloning of the human DBP and TEF genes. Genomics 32 7835883
1989 Fatty acids bound to vitamin D-binding protein (DBP) from human and bovine sera. Biochemistry international 32 2673244
2019 The role of ANXA5 in DBP-induced oxidative stress through ERK/Nrf2 pathway. Environmental toxicology and pharmacology 31 31404886
2001 Baculovirus-expressed vitamin D-binding protein-macrophage activating factor (DBP-maf) activates osteoclasts and binding of 25-hydroxyvitamin D(3) does not influence this activity. Journal of cellular biochemistry 31 11255236
2019 Enzyme mimetic activities of spinel substituted nanoferrites (MFe2O4): A review of synthesis, mechanism and potential applications. Materials science & engineering. C, Materials for biological applications 30 30889678
2006 Inhibition of angiogenesis by vitamin D-binding protein: characterization of anti-endothelial activity of DBP-maf. Angiogenesis 30 16400520
2019 Use of the Adverse Outcome Pathway (AOP) framework to evaluate species concordance and human relevance of Dibutyl phthalate (DBP)-induced male reproductive toxicity. Reproductive toxicology (Elmsford, N.Y.) 29 31260805
2017 Potential involvement of Fgf10/Fgfr2 and androgen receptor (AR) in renal fibrosis in adult male rat offspring subjected to prenatal exposure to di-n-butyl phthalate (DBP). Toxicology letters 29 28919491
2011 The endocrine disruptors dibutyl phthalate (DBP) and diethylstilbestrol (DES) influence Leydig cell regeneration following ethane dimethane sulphonate treatment of adult male rats. International journal of andrology 29 22150342
2009 Reproductive toxicity and pharmacokinetics of di-n-butyl phthalate (DBP) following dietary exposure of pregnant rats. Birth defects research. Part B, Developmental and reproductive toxicology 28 19585553
2023 Are New Phthalate Ester Substitutes Safer than Traditional DBP and DiBP? Comparative Endocrine-Disrupting Analyses on Zebrafish Using In Vivo, Transcriptome, and In Silico Approaches. Environmental science & technology 27 37677100
2023 DEHP and DBP, common phthalates, induce glucose metabolism disorders in rats via oxidative damage of PI3K/Akt/GLUT4 signaling. Environmental pollution (Barking, Essex : 1987) 27 37977363
2020 Maternal exposure to Di-n-butyl phthalate (DBP) aggravate gestational diabetes mellitus via FoxM1 suppression by pSTAT1 signalling. Ecotoxicology and environmental safety 26 32810643
2022 Adult Exposure to Di-N-Butyl Phthalate (DBP) Induces Persistent Effects on Testicular Cell Markers and Testosterone Biosynthesis in Mice. International journal of molecular sciences 25 35955852
2019 Exposure of DBP in gestation induces inflammation of testicular Sertoli cells in progeny by activating NLRP3 inflammasomes. The Science of the total environment 25 31863983
2019 Effects of bok choy on the dissipation of dibutyl phthalate (DBP) in mollisol and its possible mechanisms of biochemistry and microorganisms. Ecotoxicology and environmental safety 24 31201960
2015 Gestational and lactational exposition to Di-N-butyl-phthalate (DBP) increases inflammation and preneoplastic lesions in prostate of wistar rats after carcinogenic N-methyl-N-nitrosourea (MNU) plus testosterone protocol. Environmental toxicology 24 25728413
2015 Plasticizer DBP Activates NLRP3 Inflammasome through the P2X7 Receptor in HepG2 and L02 Cells. Journal of biochemical and molecular toxicology 24 26586371
2021 DBP-GAPred: An intelligent method for prediction of DNA-binding proteins types by enhanced evolutionary profile features with ensemble learning. Journal of bioinformatics and computational biology 23 34291709
2020 Intrauterine exposure to low-dose DBP in the mice induces obesity in offspring via suppression of UCP1 mediated ER stress. Scientific reports 23 33004990
2022 Integrated toxicity assessment of DEHP and DBP toward aquatic ecosystem based on multiple trophic model assays. Environmental science and pollution research international 22 35804233
2021 Environmentally relevant perinatal exposure to DBP disturbs testicular development and puberty onset in male mice. Toxicology 21 34280466
2017 Pathological complete response of HER2-positive breast cancer to trastuzumab and chemotherapy can be predicted by HSD17B4 methylation. Oncotarget 21 28186977
2016 PI3K regulates BMAL1/CLOCK-mediated circadian transcription from the Dbp promoter. Bioscience, biotechnology, and biochemistry 20 27022680
2011 Circadian transcriptional factor DBP regulates expression of Kiss1 in the anteroventral periventricular nucleus. Molecular and cellular endocrinology 20 21458520
2003 The anabolic effects of vitamin D-binding protein-macrophage activating factor (DBP-MAF) and a novel small peptide on bone. Critical reviews in eukaryotic gene expression 20 14696974
2020 Acetylation-mediated degradation of HSD17B4 regulates the progression of prostate cancer. Aging 19 32678070
2022 Sporoderm-broken spores of Ganoderma lucidum alleviates liver injury induced by DBP and BaP co-exposure in rat. Ecotoxicology and environmental safety 18 35696964
2017 Developing antineoplastic agents that target peroxisomal enzymes: cytisine-linked isoflavonoids as inhibitors of hydroxysteroid 17-beta-dehydrogenase-4 (HSD17B4). Organic & biomolecular chemistry 18 28868548
2010 Functional and morphological reproductive aspects in male rats exposed to di-n-butyl phthalate (DBP) in utero and during lactation. Journal of toxicology and environmental health. Part A 18 20563931
2021 USP15 participates in DBP-induced testicular oxidative stress injury through regulating the Keap1/Nrf2 signaling pathway. The Science of the total environment 17 34088152
2018 Maternal exposure to di-n-butyl phthalate (DBP) promotes epithelial-mesenchymal transition via regulation of autophagy in uroepithelial cell. Toxicology 17 30053495
2018 Differences in Root Physiological and Proteomic Responses to Dibutyl Phthalate Exposure between Low- and High-DBP-Accumulation Cultivars of Brassica parachinensis. Journal of agricultural and food chemistry 17 30525579
1987 Polymorphism of the vitamin D binding protein (DBP) among primates: an evolutionary analysis. American journal of physical anthropology 17 3675739
2020 Four patients with D-bifunctional protein (DBP) deficiency: Expanding the phenotypic spectrum of a highly variable disease. Molecular genetics and metabolism reports 16 32904102
2020 Multi-omics analyses identify HSD17B4 methylation-silencing as a predictive and response marker of HER2-positive breast cancer to HER2-directed therapy. Scientific reports 16 32968149
2018 Global Picture of Protein Regulation in Response to Dibutyl Phthalate (DBP) Stress of Two Brassica parachinensis Cultivars Differing in DBP Accumulation. Journal of agricultural and food chemistry 16 29683662
2017 PDGFRA, HSD17B4 and HMGB2 are potential therapeutic targets in polycystic ovarian syndrome and breast cancer. Oncotarget 16 29050221
2014 Co-metabolic biodegradation of DBP by Paenibacillus sp. S-3 and H-2. Current microbiology 16 24504631
2002 Reduced levels of DEAD-box proteins DBP-RB and p72 in fetal Down syndrome brains. Neurochemical research 16 12462412
2022 A novel comparative study for electrochemical urea biosensor design: Effect of different ferrite nanoparticles (MFe2O4, M: Cu, Co, Ni, Zn) in urease immobilized composite system. Bioelectrochemistry (Amsterdam, Netherlands) 15 36401962
2016 Characteristics and DBP formation of dissolved organic matter from leachates of fresh and aged leaf litter. Chemosphere 15 26991382
2016 Heterozygous mutations in HSD17B4 cause juvenile peroxisomal D-bifunctional protein deficiency. Neurology. Genetics 15 27790638
2010 Pathway modeling of microarray data: a case study of pathway activity changes in the testis following in utero exposure to dibutyl phthalate (DBP). Toxicology and applied pharmacology 15 20850466
2020 The Paralogous Krüppel-like Factors 9 and 13 Regulate the Mammalian Cellular Circadian Clock Output Gene Dbp. Journal of biological rhythms 14 32241200
2017 DEC2 Blocks the Effect of the ARNTL2/NPAS2 Dimer on the Expression of PER3 and DBP. Journal of circadian rhythms 14 30210560