Affinage

ADH5

Alcohol dehydrogenase class-3 · UniProt P11766

Length
374 aa
Mass
39.7 kDa
Annotated
2026-04-28
100 papers in source corpus 28 papers cited in narrative 28 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ADH5 (GSNOR/FDH) is a ubiquitously expressed, NAD⁺/NADH-dependent oxidoreductase that serves dual roles as the principal enzyme metabolizing S-nitrosoglutathione (GSNO) to control protein S-nitrosylation and as the primary cytoplasmic (and mitochondrial) formaldehyde dehydrogenase that detoxifies endogenous formaldehyde via its glutathione adduct S-hydroxymethylglutathione (PMID:28393572, PMID:37377022). Through GSNO catabolism, ADH5 denitrosylates a growing roster of substrates at defined cysteines—including AGT, CaMKIIα, TBK1, STING, FAK1, Akt, CDK5, MAPK14, and ANT1—thereby calibrating DNA repair, innate immunity, kinase signaling, synaptic plasticity, and mitochondrial integrity (PMID:20371487, PMID:28883020, PMID:34678655, PMID:38409248, PMID:36656716, PMID:35918012, PMID:38570588, PMID:37377022, PMID:29860106). ADH5 activity is itself regulated by product-feedback S-nitrosation of non-zinc cysteines, allosteric activation by GSNO, ATM–CHK2–p53-dependent translational induction under oxidative stress, NEDD4-mediated ubiquitin-proteasomal degradation, and transcriptional control by Sp1 (opposed by Sp3/Sp4 and FBI-1), NF-κB, and HSF1 (PMID:27064847, PMID:31766125, PMID:33245190, PMID:39846173, PMID:9867805, PMID:12004059, PMID:24654711, PMID:34788615). Digenic loss of ADH5 and ALDH2 causes AMeD syndrome (aplastic anemia, mental retardation, dwarfism) through toxic formaldehyde accumulation and hematopoietic stem cell failure (PMID:33355142, PMID:33512438).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1984 Medium

    Establishing the gene identity: ADH5 was shown to encode a dimeric formaldehyde dehydrogenase mapped to chromosome 4, providing the first molecular characterization of the enzyme later recognized as GSNOR.

    Evidence Biochemical isozyme analysis and somatic cell hybrid mapping

    PMID:6467984

    Open questions at the time
    • Single study; protein structure and catalytic mechanism unresolved
    • Substrate specificity beyond formaldehyde-GSH adduct not yet explored
  2. 1992 High

    Defining the gene structure and housekeeping expression: the ADH5 gene was shown to comprise nine exons with a CpG-island promoter lacking TATA/CAAT boxes, explaining its ubiquitous expression.

    Evidence Genomic cloning, primer extension, CAT reporter assay

    PMID:1446828

    Open questions at the time
    • Transcription factor binding not yet defined
    • No functional link to NO metabolism established
  3. 1999 High

    Identifying the core transcriptional machinery: Sp1 was established as the principal activator of ADH5 transcription through two cis-elements near the start site, with Sp3/Sp4 acting as competitive repressors—revealing how ubiquitous yet tunable expression is achieved.

    Evidence Mutagenesis of cis-elements, reporter assays in Sp1-null Drosophila SL2 cells, EMSA

    PMID:9867805

    Open questions at the time
    • Signal-responsive transcriptional regulation not yet addressed
    • No post-translational regulatory mechanism known
  4. 2002 High

    Revealing promoter fine-tuning: the POZ-domain factor FBI-1 was shown to repress ADH5 transcription by binding upstream of the Sp1 sites and disrupting Sp1–DNA interaction, adding a repressive layer to ADH5 regulation.

    Evidence EMSA, ChIP, GST pull-down, DNase I footprinting, reporter assay

    PMID:12004059

    Open questions at the time
    • Physiological context for FBI-1-mediated repression unclear
    • No connection to NO signaling yet
  5. 2010 High

    Linking GSNOR to cancer via denitrosylation of a DNA repair protein: GSNOR deficiency was shown to cause iNOS-dependent S-nitrosylation and proteasomal degradation of AGT, impairing O⁶-alkylguanine repair and promoting hepatocellular carcinoma—the first demonstration that GSNOR protects genome integrity through substrate-specific denitrosylation.

    Evidence GSNOR KO mice, carcinogen challenge, biochemical AGT quantification, epistasis with iNOS KO

    PMID:20371487

    Open questions at the time
    • Direct S-nitrosylation site on AGT not mapped
    • Mechanism of nitrosylation-induced AGT degradation not fully defined
  6. 2011 High

    Resolving the cell-autonomous origin of GSNOR's tumor-suppressive role: hepatocyte-specific, but not hematopoietic-lineage, GSNOR deletion recapitulated AGT depletion and genotoxic sensitivity, demonstrating that the protective function is intrinsic to the parenchymal cell.

    Evidence Conditional cell-type-specific KO mice, γH2AX staining, iNOS epistasis

    PMID:21385828

    Open questions at the time
    • Full spectrum of hepatocyte S-nitrosoproteome changes not catalogued
  7. 2014 High

    Discovering signal-responsive transcriptional induction: NF-κB was shown to bind the GSNOR promoter and activate transcription in response to NGF/TrkA/MEK signaling, while GSNOR overexpression suppressed neurite outgrowth—linking GSNOR transcription to differentiation signaling.

    Evidence Luciferase reporter, EMSA, ChIP, pharmacological inhibition, gain/loss-of-function in PC12 cells

    PMID:24654711

    Open questions at the time
    • Whether NF-κB regulation is generalizable beyond NGF/PC12 context unclear
    • Direct NOS isoform involvement in neurite outgrowth not tested
  8. 2016 High

    Revealing autoinhibitory feedback: S-nitrosation of GSNOR's own non-zinc cysteines was shown to inhibit enzyme activity with allosteric conformational changes near the active site—establishing a product-feedback mechanism that limits GSNOR activity under high nitrosative stress.

    Evidence In vitro enzyme assay, mass spectrometry, HDX-MS, site-directed cysteine mutagenesis

    PMID:27064847

    Open questions at the time
    • Physiological relevance of GSNOR self-nitrosation in vivo not demonstrated
    • Identity of specific inhibitory cysteines in vivo not fully resolved
  9. 2017 High

    Extending GSNOR function to synaptic plasticity and aging: age-dependent GSNOR upregulation was shown to reduce CaMKIIα S-nitrosylation at C280/C289, impairing synaptosomal CaMKIIα accumulation and LTP, while GSNOR KO rescued age-related cognitive decline.

    Evidence GSNOR transgenic and KO mice, Morris water maze, LTP recording, CaMKIIα site-directed mutagenesis

    PMID:28883020

    Open questions at the time
    • Whether direct GSNOR–CaMKIIα interaction occurs is unknown
    • Upstream signal driving age-dependent GSNOR induction not identified
  10. 2019 High

    Uncovering allosteric activation by substrate: GSNOR kinetics showed non-hyperbolic (cooperative) behavior with GSNO; mutagenesis of Lys188 and Lys323 at a distinct allosteric site abolished cooperativity—revealing a feed-forward mechanism that accelerates GSNO clearance at rising concentrations.

    Evidence Enzyme kinetics, HDX-MS, molecular docking, site-directed mutagenesis (K188A, K323A)

    PMID:31766125

    Open questions at the time
    • Crystal structure of GSNO-bound allosteric site not obtained
    • Physiological GSNO concentration dynamics in vivo not measured
  11. 2020 High

    Connecting ADH5 to a Mendelian disease: digenic ADH5/ALDH2 loss was shown to cause AMeD syndrome through toxic formaldehyde accumulation that damages DNA and exhausts hematopoietic stem cells, with an Adh5-E506K knockin mouse recapitulating the phenotype.

    Evidence Patient exome sequencing, formaldehyde tolerance assays, mouse knockin model, hematopoietic differentiation

    PMID:33355142

    Open questions at the time
    • Relative contribution of GSNO denitrosylase vs. formaldehyde dehydrogenase activity to disease unclear
    • Tissue-specific vulnerability beyond hematopoietic system not fully explored
  12. 2020 High

    Identifying oxidative-stress-responsive translational regulation: hydrogen peroxide and mitochondrial ROS were shown to induce GSNOR protein via ATM→CHK2→p53 signaling at the translational level, coupling GSNOR abundance to the cellular redox state and sustaining mitophagy.

    Evidence Pharmacological inhibitors, siRNA, redox-insensitive ATM mutant, mitophagy assays

    PMID:33245190

    Open questions at the time
    • Translational mechanism (IRES, uORF, etc.) not defined
    • Whether this regulation operates in vivo not established
  13. 2020 High

    Linking ADH5 to thermogenesis: BAT-specific ADH5 KO impaired cold-induced UCP1-dependent thermogenesis, and HSF1 was identified as an ADH5 transcriptional inducer in this tissue, connecting NO homeostasis to metabolic adaptation.

    Evidence BAT-specific KO mice, cold exposure, UCP1 S-nitrosylation measurement, HSF1 activator treatment

    PMID:34788615

    Open questions at the time
    • Direct HSF1 binding site on ADH5 promoter not mapped
    • UCP1 S-nitrosylation site not identified
  14. 2021 High

    Defining GSNOR's role in antiviral innate immunity: GSNOR deficiency increased S-nitrosylation of TBK1 at Cys423 (inhibiting its kinase activity and interferon production) and of STING at Cys257 (blocking cGAMP binding), establishing GSNOR as a prerequisite for effective cGAS-STING and TBK1 signaling.

    Evidence GSNOR KO MEFs/macrophages, viral replication assays, S-nitrosylation site mapping, cGAMP binding assay, in vivo infection models

    PMID:34678655 PMID:38409248

    Open questions at the time
    • Whether GSNOR directly denitrosylates TBK1/STING or acts only via GSNO clearance is unclear
    • Relative contribution of TBK1 vs. STING nitrosylation to immune phenotype not dissected
  15. 2022 High

    Extending denitrosylation targets to neurodegeneration: GSNOR deficiency was shown to S-nitrosylate CDK5 at Cys83, inhibiting CDK5 kinase activity and autophagy, and attenuating MPTP-induced dopaminergic neuron loss—positioning GSNOR as a modulator of Parkinson's disease pathology.

    Evidence GSNOR KO mice, MPTP model, GSNOR inhibitor N6022, S-nitrosylation site identification, CDK5 kinase assay

    PMID:35918012

    Open questions at the time
    • Whether CDK5 inhibition is neuroprotective or neurotoxic in long-term models not resolved
    • Effect of GSNOR inhibition on broader SNO-proteome in brain not profiled
  16. 2023 High

    Discovering mitochondrial localization and a cardiac-protective denitrosylation target: GSNOR was found in mitochondria where it denitrosylates ANT1 at Cys160; cardiac-specific GSNOR KO worsened heart failure, while mitochondria-targeted GSNOR or ANT1-C160A rescued mitochondrial and cardiac function.

    Evidence Cellular fractionation, immunofluorescence, colloidal gold staining, cardiac-specific KO, AAV9-mitochondrial GSNOR, ANT1 C160A mutagenesis, LC-MS/MS

    PMID:37377022

    Open questions at the time
    • Mitochondrial import mechanism for GSNOR not identified
    • Breadth of mitochondrial SNO targets beyond ANT1 unknown
  17. 2023 High

    Linking GSNOR loss to anoikis resistance in cancer: GSNOR deficiency was shown to S-nitrosylate FAK1 at Cys658, enhancing FAK1 autophosphorylation and conferring anoikis resistance; GSNOR-deficient tumors were sensitive to FAK1 inhibitors.

    Evidence Multiple tumor models, S-nitrosylation site mapping, FAK1 kinase assay, pharmacological FAK1 inhibition

    PMID:36656716

    Open questions at the time
    • Whether FAK1 S-nitrosylation drives metastasis in vivo not tested
    • Therapeutic window for FAK inhibition in GSNOR-low tumors not defined
  18. 2024 High

    Revealing a pro-inflammatory consequence of GSNOR loss: GSNOR deficiency S-nitrosylated MAPK14 at Cys211, augmenting its kinase activity and driving NLRP3 inflammasome transcription; double KO with Nlrp3 rescued sepsis and colitis severity.

    Evidence GSNOR KO macrophages, double KO mice, S-nitrosylation site ID, MAPK14 kinase assay, LPS sepsis and DSS colitis models

    PMID:38570588

    Open questions at the time
    • Whether MAPK14 Cys211 nitrosylation occurs in human inflammatory disease not shown
    • Role of other MAPKs as GSNOR targets not assessed
  19. 2025 High

    Identifying the E3 ligase controlling GSNOR turnover: NEDD4 was shown to ubiquitinate GSNOR and target it for proteasomal degradation during cardiac hypertrophy; enzyme-dead NEDD4 or non-ubiquitylatable GSNOR mutant blocked this degradation and inhibited hypertrophy.

    Evidence Mass spectrometry for E3 ligase identification, cardiomyocyte-specific NEDD4 KO, enzyme-dead mutant, non-ubiquitylatable GSNOR mutant

    PMID:39846173

    Open questions at the time
    • Specific ubiquitination sites on GSNOR not mapped
    • Whether NEDD4-GSNOR axis operates outside cardiac tissue unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the structural basis for substrate selectivity among diverse S-nitrosylated targets; the mechanism of GSNOR import into mitochondria; how the balance between GSNOR's denitrosylase and formaldehyde dehydrogenase activities is regulated in different tissues; and whether pharmacological GSNOR modulation can be therapeutically exploited in cancer, neurodegeneration, and heart failure.
  • No crystal structure of GSNOR bound to a protein S-nitrosylation substrate
  • Mitochondrial targeting signal or import mechanism unknown
  • No clinical trials of GSNOR-targeted therapy reported

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 9 GO:0016491 oxidoreductase activity 4
Localization
GO:0005829 cytosol 2 GO:0005739 mitochondrion 1
Pathway
R-HSA-73894 DNA Repair 5 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-168256 Immune System 3 R-HSA-1430728 Metabolism 2 R-HSA-8953897 Cellular responses to stimuli 2 R-HSA-5357801 Programmed Cell Death 1
Partners
AGTAKT1CAMK2ACDK5FAK1NEDD4STING1TBK1

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1984 Human formaldehyde dehydrogenase (FDH/ADH5) is a dimeric enzyme encoded on chromosome 4, with a functional molecule composed of two identical subunits. Biochemical isozyme analysis, somatic cell hybrid mapping Cytogenetics and cell genetics Medium 6467984
1992 ADH5 (FDH) gene is composed of nine exons and eight introns; its 5' region is a CpG island lacking TATA and CAAT boxes, consistent with ubiquitous expression; two major transcription start points were identified; and a 1.5-kb upstream fragment drives transcription in heterologous cells. Genomic cloning, primer extension, reporter gene (CAT) assay Gene High 1446828
1999 Sp1 drives ADH5/FDH transcription through two core cis-elements (−22 bp to +22 bp); Sp3 and Sp4 repress transcription by competing with Sp1 for these same binding sites via their zinc-finger domains. Mutagenesis of cis-elements, reporter assay in Drosophila SL2 cells (lacking Sp1), EMSA The Journal of biological chemistry High 9867805
2000 The human ADH5 gene produces at least two transcript variants via alternative polyadenylation/splicing at a composite internal/terminal exon, generating C-terminal multiplicity; the full-length variant is the major transcript in adult liver. PCR amplification of 3'-cDNA ends, Northern blot, genomic sequencing Biochemical and biophysical research communications Medium 11095947
2002 The POZ domain transcription factor FBI-1 binds the ADH5/FDH promoter (−38 to −22 bp) in vitro and in vivo, represses ADH5/FDH transcription by directly interacting with the zinc-finger domain of Sp1, and interferes with Sp1 binding to GC boxes. EMSA, ChIP, GST pull-down, DNase I footprinting, reporter assay The Journal of biological chemistry High 12004059
2010 GSNOR (ADH5) deficiency leads to S-nitrosylation and proteasomal degradation of the DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT), impairing repair of O6-alkylguanines and promoting hepatocarcinogenesis; this is abrogated by concomitant iNOS deficiency. GSNOR knockout mice, carcinogen challenge, biochemical AGT quantification, epistasis with iNOS KO Science translational medicine High 20371487
2010 Overexpression of fdh (Drosophila GSNOR homolog) in the fan-shaped body (but not mushroom body) impairs visual pattern memory; the defect is rescued by co-expression of cGMP-dependent protein kinase (PKG), linking GSNOR-dependent NO/S-nitrosation metabolism to learning and memory via the NO-cGMP-PKG pathway. Gal4/UAS system for tissue-specific overexpression in Drosophila, behavioral assays, enzymatic activity measurement Nitric oxide : biology and chemistry Medium 20932929
2011 Targeted hepatocyte-specific deletion of GSNOR (ADH5), but not hematopoietic-lineage deletion, leads to S-nitrosylation and depletion of AGT, increased DNA double-strand breaks, and elevated sensitivity to nitrosamine-induced genotoxicity; this is abolished by iNOS co-deficiency. Conditional (cell-type-specific) knockout mice, liver AGT quantification, γH2AX staining, epistasis with iNOS Carcinogenesis High 21385828
2013 GSNOR (ADH5) deficiency promotes hepatocellular carcinoma at the tumor initiation stage; pharmacological iNOS inhibition (1400W) after carcinogen exposure rescues AGT depletion and O6-ethyldeoxyguanosine repair and reduces HCC multiplicity in GSNOR-deficient mice to wild-type levels. GSNOR KO mice, pharmacological iNOS inhibition, DNA adduct measurement, tumor endpoint analysis Cancer research High 23440427
2013 GSNOR deficiency in mesenchymal stem cells impairs vasculogenesis by downregulating PDGFRα, a receptor essential for VEGF-A action; restoration through NOS inhibition or GHRH agonists normalizes tube formation via PDGFRα. GSNOR KO MSCs, Matrigel tube-forming assay, pharmacological NOS inhibition, in vivo implantation Proceedings of the National Academy of Sciences of the United States of America High 23288904
2016 Human GSNOR (ADH5) is inhibited by S-nitrosation of conserved non-zinc-coordinating cysteine residues; nitrosation causes decreased tryptophan fluorescence, increased thermal aggregation, and increased polydispersity, with allosteric conformational changes near the substrate- and coenzyme-binding pockets detected by HDX-MS; DTT restores activity. In vitro enzyme assay with nitroso donors, mass spectrometry (S-nitrosation detection), HDX-MS, site-directed mutagenesis of cysteines, fluorescence, thermal stability assays Biochemistry High 27064847
2017 GSNOR (ADH5) metabolizes GSNO (S-nitrosoglutathione), S-hydroxymethylglutathione (the spontaneous formaldehyde-glutathione adduct), and some alcohols; it modulates NO bioavailability and indirectly regulates protein S-nitrosylation through GSNO-mediated transnitrosation. Enzymatic substrate characterization (review of biochemical data) Critical reviews in biochemistry and molecular biology High 28393572
2017 GSNOR (ADH5) expression increases in the hippocampus during aging; GSNOR transgenic mice show cognitive impairment, LTP defects, and lower dendritic spine density; these are associated with decreased S-nitrosation of CaMKIIα at C280/C289, reducing CaMKIIα synaptosomal accumulation and downstream p(S831)-GluR1 signaling; GSNOR KO mice rescue age-related cognitive impairment. Transgenic overexpression and KO mice, behavioral tests (Morris water maze, fear conditioning, Y-maze), LTP recording, synaptosomal fractionation, site-directed mutagenesis of CaMKIIα S-nitrosation sites The Journal of neuroscience High 28883020
2018 GSNOR deficiency increases S-nitrosylation of Akt at Cys224 in T cells, reducing Akt phosphorylation at Ser473 and impairing Akt signaling; HHcy induces GSNOR, reducing S-nitrosylation and activating T cells, promoting atherosclerosis; adoptive transfer of GSNOR-/- T cells reduces atherosclerosis. Site-directed mutagenesis of Akt C224, GSNOR KO and ApoE KO mice, adoptive transfer, S-nitrosylation measurement Redox biology High 29860106
2019 GSNOR exhibits allosteric activation by its substrate GSNO; kinetic analysis revealed non-hyperbolic behavior with Hill coefficient ~1.75; an allosteric GSNO-binding site comprises residues Asn185, Lys188, Gly321, and Lys323 near the structural Zn2+-binding domain; site-directed mutagenesis of Lys188Ala and Lys323Ala abolishes allosteric behavior. Enzyme kinetics, molecular docking, HDX-MS, site-directed mutagenesis Antioxidants (Basel, Switzerland) High 31766125
2019 GSNOR co-localizes with nNOS at the sarcolemma of skeletal muscle cells and co-immunoprecipitates with nNOS in C2C12 cells and myofibers; GSNOR expression decreases in models of muscular dystrophy, aging, and ALS. Co-immunoprecipitation, co-localization (immunofluorescence), C2C12 differentiation model Cell death & disease Medium 31043586
2020 Digenic loss of ADH5 (formaldehyde dehydrogenase) and ALDH2 causes AMeD syndrome (aplastic anemia, mental retardation, dwarfism) due to formaldehyde accumulation and resultant DNA damage that overwhelms hematopoietic stem cell capacity; Adh5 E506K/E506K mice recapitulate features including dwarfism and hematopoietic failure. Patient exome sequencing, cellular formaldehyde tolerance assays, mouse knockin model (E506K), hematopoietic differentiation assays Science advances High 33355142
2020 GSNOR (ADH5) is induced at the translational level by hydrogen peroxide and mitochondrial ROS downstream of ATM kinase, which phosphorylates and activates CHK2 and p53; this ATM/GSNOR axis sustains mitophagy and protects against nitrosative and oxidative stress. Selective pharmacological inhibitors, siRNA knockdown, redox-insensitive ATM mutant expression, cell viability and mitophagy assays EMBO reports High 33245190
2020 ADH5 loss in brown adipose tissue impairs cold-induced UCP1-dependent thermogenesis and worsens obesity-associated metabolic dysfunction; ADH5 expression is induced by the transcription factor HSF1, and HSF1 activation increases Adh5 expression and improves UCP1-mediated respiration. BAT-specific ADH5 KO, cold exposure, UCP1 S-nitrosylation measurement, HSF1 activator treatment, metabolic phenotyping Cell reports High 34788615
2021 ADH5 is the primary defense against endogenous formaldehyde, with ALDH2 providing backup; ADH5/ALDH2-deficient iPSCs show defective cell expansion upon hematopoietic differentiation with increased DNA damage, which is reversed by an ALDH2 agonist (compound C1). Patient-derived iPSCs, hematopoietic differentiation assays, DNA damage quantification, SCE analysis, pharmacological rescue Blood High 33512438
2021 GSNOR deficiency enhances S-nitrosylation of TBK1 at Cys423, inhibiting TBK1 kinase activity and reducing interferon production, thereby impairing antiviral innate immune responses to HSV-1 and VSV. GSNOR KO MEFs and macrophages, viral replication assays, S-nitrosylation site identification, Gsnor-/- mouse infection model Redox biology High 34678655
2021 ADH5-maintained SNO homeostasis facilitates STING activation; GSNO induces S-nitrosylation of STING at Cys257, inhibiting its binding to cGAMP; ADH5 metabolizes GSNO to prevent this inhibitory S-nitrosylation, thereby licensing STING-dependent innate immunity against HSV-1 and Listeria. Adh5 KO mice, S-nitrosylation site mapping (Cys257 of STING), cGAMP binding assay, viral and bacterial infection models Nature communications High 38409248
2022 GSNOR deficiency leads to CDK5 S-nitrosylation at Cys83, inhibiting CDK5 kinase activity and CDK5-mediated autophagy, and attenuating MPTP-induced dopaminergic neuron loss in a Parkinson's disease mouse model. GSNOR KO mice, MPTP model, GSNOR inhibitor N6022, S-nitrosylation site identification, CDK5 kinase activity assay Free radical biology & medicine High 35918012
2023 GSNOR is localized in mitochondria (in addition to cytoplasm); mitochondrial GSNOR denitrosylates ANT1 at Cys160, preventing mitochondrial dysfunction; cardiac-specific GSNOR KO worsens pressure-overload heart failure; restoring mitochondrial GSNOR or expressing non-nitrosylatable ANT1 C160A improves mitochondrial function and cardiac performance. Cellular fractionation, immunofluorescence, colloidal gold staining, cardiac-specific KO mice, AAV9-mediated mitochondria-targeted GSNOR overexpression, biotin-switch/LC-MS/MS for S-nitrosylation site identification, ANT1 C160A mutagenesis Circulation research High 37377022
2023 GSNOR deficiency induces S-nitrosylation of focal adhesion kinase 1 (FAK1) at Cys658, enhancing FAK1 autophosphorylation and providing cancer cells with anoikis resistance; GSNOR-deficient tumors are sensitive to FAK1 inhibitors. Multiple tumor models, S-nitrosylation site mapping (C658), FAK1 kinase activity assay, pharmacological FAK1 inhibitors, GSNOR KO Cell reports High 36656716
2024 GSNOR deficiency leads to S-nitrosylation of MAPK14 (p38) at Cys211, augmenting MAPK14 kinase activity and promoting NLRP3 and IL-1β transcription; GSNOR-/-Nlrp3-/- double KO mice show reduced severity of LPS-induced septic shock and DSS-induced colitis. GSNOR KO macrophages, double KO mice, S-nitrosylation site identification, MAPK14 kinase activity assay, in vivo disease models Cellular & molecular immunology High 38570588
2025 NEDD4 E3 ubiquitin ligase ubiquitinates GSNOR, targeting it for proteasomal degradation during cardiac hypertrophy; NEDD4 enzyme-dead mutant and non-ubiquitylatable GSNOR mutant decrease GSNOR ubiquitination and inhibit hypertrophic growth; cardiac-specific NEDD4 deficiency inhibits hypertrophy. Mass spectrometry for ubiquitin ligase identification, NEDD4 cardiomyocyte-specific KO mice, enzyme-dead NEDD4 mutant, GSNOR non-ubiquitylatable mutant, NEDD4 inhibitor (IBM) Circulation research High 39846173
2014 NF-κB binds an essential responsive sequence (−88 to −73 bp) in the GSNOR promoter in response to NGF/TrkA/MEK1/2 signaling to activate GSNOR transcription; GSNOR overexpression suppresses NGF-induced PC12 neurite outgrowth, while GSNOR knockdown promotes differentiation. Luciferase reporter assay, EMSA, ChIP, pharmacological inhibition of TrkA and MEK1/2, GSNOR overexpression and knockdown Free radical research High 24654711

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 S-nitrosylation from GSNOR deficiency impairs DNA repair and promotes hepatocarcinogenesis. Science translational medicine 122 20371487
2017 The role of S-nitrosoglutathione reductase (GSNOR) in human disease and therapy. Critical reviews in biochemistry and molecular biology 111 28393572
2011 Function of S-nitrosoglutathione reductase (GSNOR) in plant development and under biotic/abiotic stress. Plant signaling & behavior 107 21543898
1999 Sp3 and Sp4 can repress transcription by competing with Sp1 for the core cis-elements on the human ADH5/FDH minimal promoter. The Journal of biological chemistry 99 9867805
2016 S-Nitrosation of Conserved Cysteines Modulates Activity and Stability of S-Nitrosoglutathione Reductase (GSNOR). Biochemistry 88 27064847
2011 GSNOR-mediated de-nitrosylation in the plant defence response. Plant science : an international journal of experimental plant biology 88 21893250
2013 S-nitrosoglutathione reductase (GSNOR) enhances vasculogenesis by mesenchymal stem cells. Proceedings of the National Academy of Sciences of the United States of America 86 23288904
2008 FDH: an aldehyde dehydrogenase fusion enzyme in folate metabolism. Chemico-biological interactions 83 18848533
2002 POZ domain transcription factor, FBI-1, represses transcription of ADH5/FDH by interacting with the zinc finger and interfering with DNA binding activity of Sp1. The Journal of biological chemistry 83 12004059
1990 Improved methods for genotype determination of human alcohol dehydrogenase (ADH) at ADH 2 and ADH 3 loci by using polymerase chain reaction-directed mutagenesis. Clinical chemistry 80 2208651
2020 Digenic mutations in ALDH2 and ADH5 impair formaldehyde clearance and cause a multisystem disorder, AMeD syndrome. Science advances 70 33355142
2019 GSNOR provides plant tolerance to iron toxicity via preventing iron-dependent nitrosative and oxidative cytotoxicity. Nature communications 70 31467270
1979 Genetics and ontogeny of alcohol dehydrogenase isozymes in the mouse: evidence for a cis-acting regulator gene (Adt-i) controlling C2 isozyme expression in reproductive tissues and close linkage of Adh-3 and Adt-i on chromosome 3. Biochemical genetics 60 518534
2011 S-Nitrosoglutathione reductase (GSNOR) mediates the biosynthesis of jasmonic acid and ethylene induced by feeding of the insect herbivore Manduca sexta and is important for jasmonate-elicited responses in Nicotiana attenuata. Journal of experimental botany 50 21622839
2009 Genetic variants of GSNOR and ADRB2 influence response to albuterol in African-American children with severe asthma. Pediatric pulmonology 50 19514054
2020 The Emerging Role of GSNOR in Oxidative Stress Regulation. Trends in plant science 49 33004257
2020 Redox activation of ATM enhances GSNOR translation to sustain mitophagy and tolerance to oxidative stress. EMBO reports 49 33245190
2015 Sulfido and cysteine ligation changes at the molybdenum cofactor during substrate conversion by formate dehydrogenase (FDH) from Rhodobacter capsulatus. Inorganic chemistry 49 25803130
1992 Cloning and characterization of the ADH5 gene encoding human alcohol dehydrogenase 5, formaldehyde dehydrogenase. Gene 46 1446828
2023 Mitochondrial GSNOR Alleviates Cardiac Dysfunction via ANT1 Denitrosylation. Circulation research 45 37377022
2021 Redox sensor QSOX1 regulates plant immunity by targeting GSNOR to modulate ROS generation. Molecular plant 45 33962063
2016 S-nitrosoglutathione reductase (GSNOR) activity is down-regulated during pepper (Capsicum annuum L.) fruit ripening. Nitric oxide : biology and chemistry 43 28039071
2017 Chronicles of a reductase: Biochemistry, genetics and physio-pathological role of GSNOR. Free radical biology & medicine 42 28533171
2011 Targeted deletion of GSNOR in hepatocytes of mice causes nitrosative inactivation of O6-alkylguanine-DNA alkyltransferase and increased sensitivity to genotoxic diethylnitrosamine. Carcinogenesis 42 21385828
2015 Quantitative proteomics analysis reveals that S-nitrosoglutathione reductase (GSNOR) and nitric oxide signaling enhance poplar defense against chilling stress. Planta 40 26232921
2013 Hepatocarcinogenesis driven by GSNOR deficiency is prevented by iNOS inhibition. Cancer research 37 23440427
1977 The genetics of alpha-hydroxyacid oxidase and alcohol dehydrogenase in the mouse: evidence for multiple gene loci and linkage between Hao-2 and Adh-3. Genetics 37 604164
2017 Increased GSNOR Expression during Aging Impairs Cognitive Function and Decreases S-Nitrosation of CaMKIIα. The Journal of neuroscience : the official journal of the Society for Neuroscience 36 28883020
2005 Deactivation of formate dehydrogenase (FDH) in solution and at gas-liquid interfaces. Biotechnology progress 33 16321049
2021 Analysis of disease model iPSCs derived from patients with a novel Fanconi anemia-like IBMFS ADH5/ALDH2 deficiency. Blood 31 33512438
2020 The failure of two major formaldehyde catabolism enzymes (ADH5 and ALDH2) leads to partial synthetic lethality in C57BL/6 mice. Genes and environment : the official journal of the Japanese Environmental Mutagen Society 31 32514323
1997 Folate and 10-formyltetrahydrofolate dehydrogenase (FDH) expression in the central nervous system of the mature rat. Brain research 30 9359603
2021 Quantitative Proteome Profiling of a S-Nitrosoglutathione Reductase (GSNOR) Null Mutant Reveals a New Class of Enzymes Involved in Nitric Oxide Homeostasis in Plants. Frontiers in plant science 27 34956283
2018 GSNOR modulates hyperhomocysteinemia-induced T cell activation and atherosclerosis by switching Akt S-nitrosylation to phosphorylation. Redox biology 26 29860106
2018 Denitrosylate and live longer: how ADH5/GSNOR links mitophagy to aging. Autophagy 24 30029585
2006 Leucovorin-induced resistance against FDH growth suppressor effects occurs through DHFR up-regulation. Biochemical pharmacology 22 16712799
2024 N6022 attenuates cerebral ischemia/reperfusion injury-induced microglia ferroptosis by promoting Nrf2 nuclear translocation and inhibiting the GSNOR/GSTP1 axis. European journal of pharmacology 20 38574838
2021 ADH5-mediated NO bioactivity maintains metabolic homeostasis in brown adipose tissue. Cell reports 19 34788615
2018 S-nitrosoglutathione reductase (GSNOR) inhibitor as an immune modulator in experimental autoimmune encephalomyelitis. Free radical biology & medicine 19 29694854
2023 FDH/Hases-S-chain mediated electron redistributing in Citrobacter freundii JH@FeS during degradation of sulfamethoxazole and nitrate. Water research 18 37572458
2021 GSNOR facilitates antiviral innate immunity by restricting TBK1 cysteine S-nitrosation. Redox biology 18 34678655
2006 Modular organization of FDH: Exploring the basis of hydrolase catalysis. Protein science : a publication of the Protein Society 18 16597835
2001 Mammalian alcohol dehydrogenase of higher classes: analyses of human ADH5 and rat ADH6. Chemico-biological interactions 18 11306061
2022 GSNOR regulates ganoderic acid content in Ganoderma lucidum under heat stress through S-nitrosylation of catalase. Communications biology 17 35017648
2013 Improvement of ethanol productivity and energy efficiency by degradation of inhibitors using recombinant Zymomonas mobilis (pHW20a-fdh). Biotechnology and bioengineering 17 23475631
2011 Transcription of fdh and hyd in Syntrophobacter spp. and Methanospirillum spp. as a diagnostic tool for monitoring anaerobic sludge deprived of molybdenum, tungsten and selenium. Environmental microbiology 17 21332622
2010 Nitric oxide metabolism controlled by formaldehyde dehydrogenase (fdh, homolog of mammalian GSNOR) plays a crucial role in visual pattern memory in Drosophila. Nitric oxide : biology and chemistry 17 20932929
2021 GSNOR Contributes to Demethylation and Expression of Transposable Elements and Stress-Responsive Genes. Antioxidants (Basel, Switzerland) 16 34356361
2020 Mitophagy contributes to alpha-tocopheryl succinate toxicity in GSNOR-deficient hepatocellular carcinoma. Biochemical pharmacology 16 32112881
2016 Tumor Suppressor Roles of the Denitrosylase GSNOR. Critical reviews in oncogenesis 16 29431087
2011 Dose-Dependent Change in Elimination Kinetics of Ethanol due to Shift of Dominant Metabolizing Enzyme from ADH 1 (Class I) to ADH 3 (Class III) in Mouse. International journal of hepatology 16 22164338
1992 Alcohol dehydrogenase genes: restriction fragment length polymorphisms for ADH4 (pi-ADH) and ADH5 (chi-ADH) and construction of haplotypes among different ADH classes. Human genetics 16 1362387
2019 nNOS/GSNOR interaction contributes to skeletal muscle differentiation and homeostasis. Cell death & disease 15 31043586
2013 The influence of genetic polymorphisms in XRCC3 and ADH5 genes on the frequency of genotoxicity biomarkers in workers exposed to formaldehyde. Environmental and molecular mutagenesis 15 23355119
2007 Protein engineering applications of industrially exploitable enzymes: Geobacillus stearothermophilus LDH and Candida methylica FDH. Biochemical Society transactions 15 18031276
2025 NEDD4-Mediated GSNOR Degradation Aggravates Cardiac Hypertrophy and Dysfunction. Circulation research 14 39846173
2022 Arginase-1 Deletion in Erythrocytes Promotes Vascular Calcification via Enhanced GSNOR (S-Nitrosoglutathione Reductase) Expression and NO Signaling in Smooth Muscle Cells. Arteriosclerosis, thrombosis, and vascular biology 14 36252109
2022 GABA keeps nitric oxide in balance by regulating GSNOR to enhance disease resistance of harvested tomato against Botrytis cinerea. Food chemistry 13 35640428
2024 S-nitrosothiol homeostasis maintained by ADH5 facilitates STING-dependent host defense against pathogens. Nature communications 12 38409248
2021 Synthesis and characterization of ordered mesoporous silicas for the immobilization of formate dehydrogenase (FDH). International journal of biological macromolecules 12 33621575
2000 Human class V alcohol dehydrogenase (ADH5): A complex transcription unit generates C-terminal multiplicity. Biochemical and biophysical research communications 12 11095947
2012 Analysis of mammalian alcohol dehydrogenase 5 (ADH5): characterisation of rat ADH5 with comparisons to the corresponding human variant. Chemico-biological interactions 11 23159888
1984 Human formaldehyde dehydrogenase (FDH) and its assignment to chromosome 4. Cytogenetics and cell genetics 11 6467984
2023 GSNOR deficiency promotes tumor growth via FAK1 S-nitrosylation. Cell reports 10 36656716
2019 Tailoring of recombinant FDH: effect of histidine tag location on solubility and catalytic properties of Chaetomium thermophilum formate dehydrogenase (CtFDH). Preparative biochemistry & biotechnology 10 31030612
2016 What's My Substrate? Computational Function Assignment of Candida parapsilosis ADH5 by Genome Database Search, Virtual Screening, and QM/MM Calculations. Journal of chemical information and modeling 10 27387009
2016 A case of familial dysalbuminemic hyperthyroxinemia (FDH) in Japan: FDH as a possible differential diagnosis of syndrome of inappropriate secretion of thyroid-stimulating hormone (SITSH). Endocrine journal 10 27904073
2022 GSNOR deficiency attenuates MPTP-induced neurotoxicity and autophagy by facilitating CDK5 S-nitrosation in a mouse model of Parkinson's disease. Free radical biology & medicine 9 35918012
2020 High-level heterologous expression of active Chaetomium thermophilum FDH in Pichia pastoris. Enzyme and microbial technology 9 32423672
2020 The Physiological Implications of S-Nitrosoglutathione Reductase (GSNOR) Activity Mediating NO Signalling in Plant Root Structures. Antioxidants (Basel, Switzerland) 9 33266126
2024 GSNOR overexpression enhances CAR-T cell stemness and anti-tumor function by enforcing mitochondrial fitness. Molecular therapy : the journal of the American Society of Gene Therapy 8 38549378
2022 Analysis of NIA and GSNOR family genes and nitric oxide homeostasis in response to wheat-leaf rust interaction. Scientific reports 8 35039546
2024 GSNOR negatively regulates the NLRP3 inflammasome via S-nitrosation of MAPK14. Cellular & molecular immunology 7 38570588
2021 Bronchopulmonary Dysplasia and Pulmonary Hypertension. The Role of Smooth Muscle adh5. American journal of respiratory cell and molecular biology 7 33780653
2020 Targeting GSNOR for functional recovery in a middle-aged mouse model of stroke. Brain research 7 32418890
2014 Activation of GSNOR transcription by NF-κB negatively regulates NGF-induced PC12 differentiation. Free radical research 7 24654711
2018 S-Nitrosoglutathione Reductase (GSNOR) Deficiency Results in Secondary Hypogonadism. The journal of sexual medicine 6 29606625
2021 [Aldehyde degradation deficiency (ADD) syndrome: discovery of a novel fanconi anemia-like inherited BMF syndrome due to combined ADH5/ALDH2 deficiency]. [Rinsho ketsueki] The Japanese journal of clinical hematology 5 34219079
2021 Trigenic ADH5/ALDH2/ADGRV1 mutations in myelodysplasia with Usher syndrome. Heliyon 5 34458631
2020 Familial Dysalbuminemic Hyperthyroxinemia (FDH), Albumin Gene Variant (R218S), and Risk of Miscarriages in Offspring. The American journal of the medical sciences 5 32665066
2025 Phytophthora Disrupts Plant Immunity by Manipulating Nitric Oxide Homeostasis Through GSNOR Inhibition. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 4 40539224
2024 Differential S-nitrosylation and characterization of purified S-nitrosoglutathione reductase (GSNOR) from Brassica juncea shows multiple forms of the enzyme. Plant physiology and biochemistry : PPB 4 38330777
2023 Stable and Reusable Fe3 O4 /ZIF-8 Composite for Encapsulation of FDH Enzyme under Mild Conditions Applicable to CO2 Reduction. Chemistry (Weinheim an der Bergstrasse, Germany) 4 37294852
2023 Effects of the major formaldehyde catalyzer ADH5 on phenotypes of fanconi anemia zebrafish model. Molecular biology reports 4 37615925
2021 GSNOR and ALDH2 alleviate traumatic spinal cord injury. Brain research 4 33545099
2021 S-nitrosoglutathione reductase (GSNOR) deficiency accelerates cardiomyocyte differentiation of induced pluripotent stem cells. The journal of cardiovascular aging 4 34790975
2019 A Chinese Family with Familial Dysalbuminemic Hyperthyroxinemia (FDH) due to R242H Mutation on Human Albumin Gene: Reevaluating the Role of FDH in Patients with Asymptomatic Hyperthyroxinemia. International journal of endocrinology 4 31582975
2019 Evidence for an Allosteric S-Nitrosoglutathione Binding Site in S-Nitrosoglutathione Reductase (GSNOR). Antioxidants (Basel, Switzerland) 4 31766125
1983 Aldehyde oxidase and alcohol dehydrogenase genetics in the mouse. New alleles for the Aox-2 and Adh-3 loci. Animal blood groups and biochemical genetics 4 6372555
2024 Melatonin derivative 6a protects Caenorhabditis elegans from formaldehyde neurotoxicity via ADH5. Free radical biology & medicine 3 39127141
2024 The role of S-nitrosoglutathione reductase (GSNOR) in T cell-mediated immunopathology of experimental autoimmune encephalomyelitis (EAE). Neuroscience 3 39532197
2021 GSNOR regulates cardiomyocyte differentiation and maturation through protein S-nitrosylation. The journal of cardiovascular aging 3 34790976
1997 Genetic mapping of a possible new alcohol dehydrogenase sequence to mouse chromosome 3 at the Adh-1/Adh-3 complex. Biochemical genetics 3 9241435
2025 GSNOR plays roles in growth, pathogenicity, and stress resistance by modulating mitochondrial protein COX6B S-nitrosylation in Colletotrichum gloeosporioides. mBio 2 40407326
2025 ADH5/ALDH2 dehydrogenases and DNA polymerase theta protect normal and malignant hematopoietic cells from formaldehyde challenge: therapeutic implications. Leukemia 2 40640557
2026 S-nitrosylation of GSNOR and LCD facilitates cadmium-induced programmed cell death in tomato seedlings. The New phytologist 1 41612626
2025 Design, Synthesis, and Anti-ischemic Stroke Activity Evaluation of Novel GSNOR Inhibitors. Journal of medicinal chemistry 1 40494828
2025 The Central Role of GSNOR: Decoding Nitric Oxide Signaling for Crop Stress Tolerance. International journal of molecular sciences 1 41373639
2023 Immunohistochemical Staining Characteristics of Low-Grade Invasive Ductal Carcinoma Using the ADH5 Cocktail (CK5/14, P63, and CK7/18): A Potential Interpretative Pitfall. Diagnostics (Basel, Switzerland) 1 37761331
2004 The fdh operon of Sulfurospirillum multivorans. FEMS microbiology letters 1 15321667