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Showing ADH5 — GSNOR is a alias.

ADH5

Alcohol dehydrogenase class-3 · UniProt P11766

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

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ADH5 (also called GSNOR, chi-ADH/FDH) is a ubiquitously expressed, NADH-dependent enzyme that serves as the master controller of cellular S-nitrosylation and as the primary cellular defense against formaldehyde, catabolizing S-nitrosoglutathione (GSNO) and formaldehyde-glutathione adducts to govern the nitrosative and aldehyde load across many tissues (PMID:20371487, PMID:33355142). As a denitrosylase, ADH5 limits the S-nitrosation of a broad substrate set, and its loss therefore drives substrate-specific gain or loss of function: it protects the DNA-repair protein AGT/MGMT from S-nitrosylation-driven degradation, with iNOS acting upstream so that hepatocyte-specific loss promotes O6-alkylguanine accumulation, DNA double-strand breaks, and hepatocarcinogenesis (PMID:20371487, PMID:21385828, PMID:23440427). The same denitrosylase logic tunes innate immunity and inflammation—ADH5 keeps TBK1 (Cys423) and STING (Cys257) free of inhibitory S-nitrosation to permit interferon production (PMID:34678655, PMID:38409248), while restraining MAPK14 (Cys211)-driven NLRP3 inflammasome activation (PMID:38570588)—and modulates kinase signaling on Akt (Cys224) in T cells (PMID:29860106), FAK1 (Cys658) in anoikis resistance (PMID:36656716), CaMKIIα (Cys280/289) in synaptic plasticity (PMID:28883020), and CDK5 (Cys83) in autophagy (PMID:35918012). A mitochondrial pool of ADH5 denitrosylates ANT1 (Cys160) to preserve membrane potential and protect against heart failure (PMID:37377022), and it denitrosylates Beclin-1 (Cys351) to limit autophagy-driven adipose remodeling (PMID:41730881). ADH5 expression is activated by Sp1 and repressed by Sp3/Sp4 competition and by FBI-1/POZ-domain sequestration of Sp1 (PMID:9867805, PMID:12004059), induced via NF-κB downstream of NGF (PMID:24654711) and by an ATM→CHK2→p53 redox cascade (PMID:33245190), and its protein level is set by NEDD4-mediated ubiquitination and degradation (PMID:39846173); the enzyme is itself feedback-regulated by inhibitory S-nitrosation of non-zinc-coordinating cysteines and by allosteric activation through a GSNO-binding site (Lys188, Lys323) (PMID:27064847, PMID:31766125). Combined deficiency of ADH5 and ALDH2 causes AMeD syndrome, in which impaired formaldehyde clearance drives hematopoietic stem cell failure, dwarfism, and DNA damage (PMID:33355142, PMID:33512438).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1992 Medium

    Established the genomic architecture and ubiquitous-expression promoter of ADH5, providing the foundation for understanding its broad tissue distribution.

    Evidence Genomic cloning, primer extension, and CAT reporter assay in CV-1 cells

    PMID:1446828

    Open questions at the time
    • Did not identify the trans-acting factors driving the promoter
    • No link yet to enzymatic function
  2. 2002 High

    Defined how ADH5 transcription is set by competing GC-box factors, showing Sp1 activates and Sp3/Sp4 and FBI-1 repress via interference with Sp1 binding.

    Evidence Cis-element mutagenesis, EMSA, and reporter assays in SL2 cells (1999); GST pulldown, ChIP, and DNase I footprinting for FBI-1–Sp1 (2002)

    PMID:12004059 PMID:9867805

    Open questions at the time
    • Did not establish how these inputs respond to nitrosative or metabolic state
    • Physiological contexts that engage each factor unresolved
  3. 2013 High

    Linked ADH5/GSNOR loss to cancer by showing it protects the DNA-repair enzyme AGT/MGMT from iNOS-driven S-nitrosylation and degradation, placing iNOS upstream of GSNOR-controlled hepatocarcinogenesis.

    Evidence GSNOR-knockout, hepatocyte-specific conditional KO, and iNOS double-KO/inhibitor mouse studies with AGT immunoblot, DNA-adduct, and tumor endpoints

    PMID:20371487 PMID:21385828 PMID:23440427

    Open questions at the time
    • Did not define the full set of repair-relevant denitrosylation substrates
    • Cell-autonomous vs systemic contributions not fully separated
  4. 2016 High

    Revealed that GSNOR is autoregulated, with inhibitory S-nitrosation of non-zinc cysteines reducing catalytic activity and altering binding-pocket conformation, establishing feedback control of the denitrosylase by its own product.

    Evidence In vitro activity assays with DTT reversal, MS, HDX-MS, fluorescence, and site-directed mutagenesis across human, plant, and yeast enzymes

    PMID:27064847

    Open questions at the time
    • In vivo significance of inhibitory nitrosation under physiological NO flux not quantified
    • Interplay with allosteric activation not resolved
  5. 2017 High

    Extended GSNOR's denitrosylase role to the brain, showing it controls CaMKIIα (Cys280/289) S-nitrosation, synaptic accumulation, and LTP, with age-related overexpression causing cognitive decline.

    Evidence Neuron-specific transgenic and knockout mice, behavioral testing, LTP electrophysiology, biotin-switch, and CaMKIIα site mutagenesis

    PMID:28883020

    Open questions at the time
    • Drivers of age-related GSNOR upregulation in hippocampus unspecified
    • Effect on other neuronal substrates not assessed
  6. 2019 High

    Provided the kinetic and structural basis for GSNOR's positive feedback, identifying an allosteric GSNO-binding site (Lys188, Lys323) that activates the enzyme at high substrate concentrations.

    Evidence Enzyme kinetics (Hill analysis), docking, molecular dynamics, HDX-MS, and K188A/K323A mutagenesis

    PMID:31766125

    Open questions at the time
    • Allosteric site occupancy under cellular GSNO levels not measured
    • Crosstalk with inhibitory cysteine nitrosation unresolved
  7. 2021 High

    Defined ADH5 as the primary formaldehyde defense whose combined loss with ALDH2 causes AMeD syndrome, linking aldehyde clearance to hematopoietic stem cell maintenance and genome stability.

    Evidence Patient-derived cells and iPSCs, ADH5/ALDH2 double-KO/knock-in mice, hematopoietic differentiation, SCE and DNA-damage assays, and ALDH2 agonist rescue

    PMID:33355142 PMID:33512438

    Open questions at the time
    • Relative tissue thresholds for formaldehyde toxicity not fully mapped
    • Connection between formaldehyde and denitrosylase functions of ADH5 not integrated
  8. 2022 High

    Showed GSNOR coordinates antiviral and inflammatory signaling by keeping TBK1 (Cys423), STING (Cys257), and MAPK14 (Cys211) appropriately denitrosylated, balancing interferon production against NLRP3 inflammasome activation.

    Evidence Knockout MEFs/macrophages, viral and bacterial infection models, biotin-switch site mapping, kinase and cGAMP-binding assays, and double-knockout epistasis

    PMID:34678655 PMID:38409248 PMID:38570588

    Open questions at the time
    • Stimulus-specific control of which substrate dominates not resolved
    • Spatial coupling of GSNOR to immune signaling complexes unknown
  9. 2023 High

    Identified a mitochondrial pool of GSNOR that denitrosylates ANT1 (Cys160) to preserve membrane potential and protect the heart, expanding the enzyme's role beyond the cytoplasm.

    Evidence Cell fractionation, immunofluorescence, immuno-EM, cardiac-specific KO and mitochondria-targeted AAV9 rescue, MS site mapping, and ANT1 C160A mutant

    PMID:37377022

    Open questions at the time
    • Mechanism of mitochondrial import not defined
    • Full mitochondrial substrate repertoire unknown
  10. 2025 High

    Established that GSNOR protein levels are controlled post-translationally by NEDD4-mediated ubiquitination, providing a degradation switch that drives cardiac hypertrophy when GSNOR is lost.

    Evidence MS identification of NEDD4, cardiomyocyte-specific NEDD4 KO, ubiquitination assays, enzyme-dead and non-ubiquitylatable mutants, TAC model, and clinical samples

    PMID:39846173

    Open questions at the time
    • Signals activating NEDD4 toward GSNOR not fully defined
    • Interaction with transcriptional and translational regulation not integrated
  11. 2026 High

    Connected GSNOR denitrosylase activity to autophagy-driven adipose aging by showing it denitrosylates Beclin-1 (Cys351) to limit Beclin-1–ATG14 interaction and beige-to-white adipocyte conversion.

    Evidence Adipose-specific knock-in and knockout mice, aging cohorts, biotin-switch, Beclin-1 C351A mutant, and Beclin-1/ATG14 co-IP

    PMID:41730881

    Open questions at the time
    • Generality of Beclin-1 control across autophagy contexts unknown
    • Relationship to CDK5-mediated autophagy regulation not reconciled

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ADH5's formaldehyde-clearance and protein-denitrosylase functions are coordinated within a single tissue, and what determines substrate selectivity among its many reported targets, remains unresolved.
  • No unifying model linking aldehyde detoxification and S-nitrosylation control
  • Substrate selection rules for denitrosylation not defined
  • Spatial organization of cytoplasmic vs mitochondrial pools relative to substrates incompletely mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0098772 molecular function regulator activity 4 GO:0016491 oxidoreductase activity 2
Localization
GO:0005739 mitochondrion 1 GO:0005829 cytosol 1
Pathway
R-HSA-8953897 Cellular responses to stimuli 4 R-HSA-1430728 Metabolism 3 R-HSA-168256 Immune System 3 R-HSA-73894 DNA Repair 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-9612973 Autophagy 2
Partners
ATG14FBI-1GSTP1NEDD4NNOSSP1

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1992 ADH5 (chi-ADH/FDH) gene structure was characterized: it is composed of nine exons and eight introns, has a CpG-island promoter lacking TATA and CAAT boxes (consistent with ubiquitous expression), and a 1.5-kb upstream fragment drives reporter transcription in CV-1 cells. Two major transcription start points were identified by primer extension. Genomic cloning, primer extension, reporter (CAT) assay Gene Medium 1446828
1999 ADH5/FDH transcription is driven by Sp1 binding to two core cis-elements (−22 bp to +22 bp) in the minimal promoter; Sp3 and Sp4 repress transcription by competing with Sp1 for these same elements without activating transcription themselves. Mutagenesis of cis-elements, electrophoretic mobility shift assay (EMSA), transient transfection/luciferase reporter in Drosophila SL2 cells (lacking endogenous Sp1) The Journal of biological chemistry High 9867805
2002 The POZ domain transcription factor FBI-1 represses ADH5/FDH transcription by directly interacting (via its POZ domain) with the zinc-finger DNA-binding domain of Sp1, preventing Sp1 binding to GC boxes of the ADH5 promoter. EMSA, chromatin immunoprecipitation (ChIP), GST pulldown, DNase I footprinting, Gal4 fusion reporter assay The Journal of biological chemistry High 12004059
2010 GSNOR deficiency leads to S-nitrosylation and proteasomal degradation of the DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT/MGMT), impairing repair of carcinogenic O6-alkylguanines and promoting hepatocarcinogenesis; these effects are abolished in GSNOR/iNOS double-knockout mice, placing iNOS upstream of GSNOR-regulated S-nitrosylation. GSNOR-knockout mouse model, iNOS/GSNOR double-knockout epistasis, immunoblot for AGT, O6-alkylguanine DNA adduct measurement, carcinogen (DEN) challenge Science translational medicine High 20371487
2011 Hepatocyte-specific (not hematopoietic-cell) deletion of GSNOR is sufficient to cause AGT depletion and increased DNA double-strand breaks (γH2AX) upon inflammatory stimulation, and increases DEN-induced mortality in an iNOS-dependent manner. Conditional (hepatocyte-specific) GSNOR knockout mice, hematopoietic-cell GSNOR knockout mice (negative control), immunoblot for AGT, γH2AX staining, iNOS/GSNOR double-knockout rescue Carcinogenesis High 21385828
2013 Pharmacological inhibition of iNOS (with 1400W) blocks AGT depletion and restores O6-ethyldeoxyguanosine repair in GSNOR-deficient livers, and short-term iNOS inhibition after DEN treatment reduces HCC multiplicity and burden in GSNOR-knockout mice to wild-type levels. GSNOR-knockout mice, iNOS inhibitor (1400W) treatment, immunoblot for AGT, O6-ethyldeoxyguanosine measurement, tumor counting Cancer research High 23440427
2013 GSNOR deficiency in mesenchymal stem cells (MSCs) impairs vasculogenesis in vitro and in vivo, associated with downregulation of PDGFRα; pharmacologic NO synthase inhibition (L-NAME) or GHRH agonists restore tube formation by normalizing VEGF-A/PDGFRα signaling. GSNOR-knockout MSCs, Matrigel tube-formation assay, in vivo vasculogenesis model, PDGFR antagonist, L-NAME treatment, GHRH agonists Proceedings of the National Academy of Sciences of the United States of America Medium 23288904
2016 GSNOR is itself subject to inhibitory S-nitrosation at conserved non-zinc-coordinating cysteine residues; nitrosation reduces catalytic activity (reversible by DTT), promotes thermal aggregation and increased polydispersity, and alters the shape of substrate/coenzyme binding pockets as shown by HDX-MS. Site-directed mutagenesis of specific cysteines reduces sensitivity to nitrosating agents. In vitro enzyme activity assays with nitrosating agents and DTT reversal, mass spectrometry (nitrosation site identification), site-directed mutagenesis, tryptophan fluorescence, thermal aggregation, hydrogen-deuterium exchange MS (HDX-MS); human, plant, and yeast GSNORs tested Biochemistry High 27064847
2017 Increased GSNOR expression in the hippocampus during aging decreases S-nitrosation of CaMKIIα at Cys280/Cys289, reducing its synaptosomal accumulation and downstream p(S831)-GluR1 phosphorylation, causing LTP defects and cognitive impairment; GSNOR knockout rescues these age-related deficits. GSNOR transgenic (neuron-specific overexpression) and knockout mice, Morris water maze/fear conditioning/Y-maze behavioral tests, LTP electrophysiology, synaptosomal fractionation, biotin-switch assay for S-nitrosation, CaMKIIα C280/C289 site-directed mutagenesis The Journal of neuroscience High 28883020
2018 GSNOR depletion increases S-nitrosylation of Akt at Cys224, which reduces Akt phosphorylation at Ser473 and suppresses T-cell activation; GSNOR knockout in ApoE-/- mice reduces T-cell-driven atherosclerosis under hyperhomocysteinemia conditions. GSNOR-knockout/ApoE-double-knockout mice, adoptive T-cell transfer, site-directed mutagenesis (Akt C224), biotin-switch for S-nitrosylation, flow cytometry, immunoblot Redox biology High 29860106
2019 GSNOR allosteric activation by its own substrate GSNO was demonstrated kinetically (Hill coefficient ~1.75); an allosteric GSNO-binding site comprising residues Asn185, Lys188, Gly321, and Lys323 was identified by docking, molecular dynamics, and HDX-MS; K188A and K323A mutations abolish allosteric behavior. Enzyme kinetics (Hill-Langmuir equation), molecular docking, molecular dynamics simulation, HDX-MS, site-directed mutagenesis (K188A, K323A) Antioxidants (Basel, Switzerland) High 31766125
2019 nNOS and GSNOR co-localize at the sarcolemma and co-immunoprecipitate in C2C12 myotubes and myofibers; GSNOR expression decreases in mouse models of muscular dystrophy, aging, and ALS, indicating a physical and functional interaction relevant to skeletal muscle homeostasis. Co-immunoprecipitation, immunofluorescence co-localization, expression analysis in dystrophic/ALS/aged muscle, C2C12 differentiation model Cell death & disease Medium 31043586
2020 GSNOR translation is induced by hydrogen peroxide and mitochondrial ROS via a signaling cascade: redox activation of ATM → phosphorylation of CHK2 and p53 → increased GSNOR protein levels; this ATM/GSNOR axis sustains mitophagy and influences T-cell activation. siRNA knockdown, selective pharmacological inhibitors of ATM/CHK2, immunoblot, flow cytometry (mitophagy markers), redox-insensitive ATM mutant expression EMBO reports Medium 33245190
2020 Combined deficiency of ADH5 (formaldehyde dehydrogenase) and ALDH2 causes AMeD syndrome; cellular studies showed decreased formaldehyde tolerance underlies loss of hematopoietic stem cell differentiation/proliferation capacity; Adh5 E506K/E506K mice recapitulated dwarfism, short lifespan, and hematopoietic failure. Patient-derived cellular studies, ADH5/ALDH2 double-knockout/knock-in mouse model, hematopoietic stem cell functional assays, formaldehyde exposure experiments Science advances High 33355142
2021 ADH5 is the primary cellular defense against formaldehyde (ALDH2 is a backup); ADH5/ALDH2-deficient iPSCs show drastically defective hematopoietic differentiation with increased DNA damage when stimulated, partially reversed by ALDH2 agonist C1; lymphocytes from patients show elevated sister chromatid exchanges reflecting homologous recombination repair of formaldehyde damage. Patient-derived iPSCs, disease model cell lines, hematopoietic differentiation assays, SCE assay, DNA damage markers, ALDH2 agonist (C1) rescue Blood High 33512438
2021 ADH5-mediated denitrosylation regulates brown adipose tissue (BAT) thermogenesis: loss of ADH5 in BAT impairs cold-induced UCP1-dependent thermogenesis and worsens obesity-associated metabolic dysfunction; ADH5 expression in BAT is induced by transcription factor HSF1, and HSF1 activator administration increases ADH5 expression and improves UCP1-mediated respiration. BAT-specific ADH5 knockout mice, cold exposure challenge, UCP1-dependent respiration assay, HSF1 activator pharmacology, ChIP/reporter for HSF1→Adh5 transcription Cell reports Medium 34788615
2021 GSNOR deficiency increases S-nitrosylation of TANK-binding kinase 1 (TBK1) at Cys423, inhibiting TBK1 kinase activity and reducing interferon production, thereby impairing antiviral innate immune responses; GSNOR-deficient mice show higher mortality upon HSV-1 infection. GSNOR-knockout MEFs and macrophages, viral infection assays (HSV-1, VSV), biotin-switch for TBK1 S-nitrosation at Cys423, kinase activity assay, N6022 GSNOR inhibitor, interferon ELISA Redox biology High 34678655
2022 ADH5/GSNOR deficiency impairs STING-dependent innate immune responses; GSNO (whose catabolism is mediated by ADH5) induces S-nitrosylation of STING at Cys257, inhibiting its binding to cGAMP; ADH5 facilitates STING activation by maintaining low cellular SNO levels. Adh5-knockout mice, viral/bacterial infection models (HSV-1, Listeria), biotin-switch for STING S-nitrosylation at Cys257, cGAMP-binding assay, interferon production measurement Nature communications High 38409248
2022 GSNOR deficiency induces S-nitrosylation of MAPK14 (p38) at Cys211, increasing MAPK14 kinase activity and promoting NLRP3 inflammasome transcription (Nlrp3, Il-1β); Gsnor-/-Nlrp3-/- double-knockout mice have reduced disease severity in LPS-induced septic shock and DSS-induced colitis models. GSNOR-knockout macrophages, GSNOR/NLRP3 double-knockout mice, biotin-switch for MAPK14 S-nitrosation at Cys211, MAPK14 kinase activity assay, LPS septic shock and DSS colitis in vivo models Cellular & molecular immunology High 38570588
2023 GSNOR deficiency induces S-nitrosylation of focal adhesion kinase 1 (FAK1) at Cys658, enhancing FAK1 autophosphorylation and enabling cancer cells to survive in suspension (anoikis resistance); GSNOR-deficient tumor models are susceptible to FAK1 inhibitors. GSNOR-deficient tumor cell lines and mouse models, biotin-switch/MS for FAK1 S-nitrosation at C658, FAK1 autophosphorylation assay, anoikis resistance assay, FAK1 inhibitor treatment Cell reports High 36656716
2023 GSNOR is localized in mitochondria (in addition to cytoplasm); mitochondrial GSNOR denitrosylates ANT1 at Cys160, maintaining mitochondrial membrane potential and mitophagy; cardiac-specific GSNOR knockout worsens heart failure, and restoration of mitochondrial GSNOR improves mitochondrial function and cardiac performance. Cellular fractionation, immunofluorescence, colloidal gold staining (electron microscopy), cardiac-specific GSNOR KO mice, AAV9-mitochondria-targeting GSNOR overexpression, biotin-switch + LC-MS/MS for ANT1 S-nitrosation at Cys160, ANT1 C160A mutant, mitochondrial membrane potential assay, transverse aortic constriction HF model Circulation research High 37377022
2022 CDK5 S-nitrosation at Cys83 (increased by GSNOR deficiency) inhibits CDK5 kinase activity and CDK5-mediated autophagy; in an MPTP-induced Parkinson's disease mouse model, GSNOR knockout or N6022 inhibitor treatment alleviates CDK5-mediated autophagy and neurotoxicity. GSNOR-knockout mice, MPTP PD model, N6022 GSNOR inhibitor, biotin-switch for CDK5 S-nitrosation at Cys83, CDK5 kinase activity assay, behavioral tests, dopaminergic neuron counting Free radical biology & medicine Medium 35918012
2025 NEDD4 E3 ubiquitin ligase ubiquitinates and degrades GSNOR under cardiac hypertrophy conditions; NEDD4 expression is elevated in hypertrophic myocardium while GSNOR mRNA remains unchanged; enzyme-dead NEDD4 mutant or non-ubiquitylatable GSNOR mutant decrease GSNOR ubiquitination and inhibit hypertrophic growth; NEDD4-specific inhibitors suppress this axis. Mass spectrometry identification of NEDD4 as E3 ligase, NEDD4 cardiomyocyte-specific KO mice, ubiquitination assays, NEDD4 enzyme-dead mutant and GSNOR non-ubiquitylatable mutant, protein synthesis/degradation inhibitors, in vivo transverse aortic constriction, clinical samples Circulation research High 39846173
2021 S-nitrosylation of GSK3β (increased in GSNOR-deficient iPSCs) reduces GSK3β expression and promotes cardiomyocyte differentiation and maturation from iPSCs; GSNO treatment of wild-type iPSCs phenocopies this effect. GSNOR-knockout iPSCs, directed cardiomyocyte differentiation assay, biotin-switch for GSK3β S-nitrosylation, GSNO treatment, Nkx2.5/Brachyury/GATA4 expression markers The journal of cardiovascular aging Medium 34790975
2014 NF-κB binds the GSNOR promoter (−88 bp to −73 bp) in response to NGF/TrkA/MEK1-2 signaling, activating GSNOR transcription; in PC12 cells, GSNOR negatively regulates neurite outgrowth—overexpression decreases and knockdown promotes neuronal differentiation. Luciferase reporter assay, EMSA, ChIP, TrkA/MEK inhibitors, GSNOR overexpression and knockdown in PC12 cells, neurite morphometry Free radical research Medium 24654711
2026 GSNOR denitrosates Beclin-1 at Cys351; S-nitrosation of Beclin-1 at this site enhances its interaction with ATG14 and increases autophagy, promoting beige-to-white adipocyte conversion during aging; adipose-specific GSNOR overexpression promotes adipose whitening and metabolic decline. GSNOR adipose-specific knock-in and knockout mice, aging cohorts, biotin-switch for Beclin-1 S-nitrosation at Cys351, Beclin-1 C351A mutant, Beclin-1/ATG14 co-immunoprecipitation, mitochondrial content and beige adipocyte quantification Nature communications High 41730881
2033 N6022 (GSNOR inhibitor) interferes with the interaction between GSNOR and GSTP1, boosting GSTP1 antioxidant activity and attenuating microglia ferroptosis; GSNOR inhibition also promotes Nrf2 nuclear translocation in cerebral ischemia/reperfusion injury models. OGD/R cell model and MCAO/R mouse model, co-immunoprecipitation (GSNOR–GSTP1 interaction), Nrf2 nuclear fractionation, SLC7A11-GPX4 pathway analysis, infarct volume measurement European journal of pharmacology Medium 38574838
2025 ADH5 loss in FANCA-deficient keratinocytes causes synthetic lethality and elevates formaldehyde levels and DNA damage markers; ADH5 is the primary formaldehyde defense in keratinocytes, cooperating with ALDH2 and DNA polymerase theta (Polθ); genetic or pharmacological targeting of ADH5 enhances Polθ-inhibitor efficacy in leukemic cells. Systematic CRISPR inactivation of ADH/ALDH genes in FANCA-deficient keratinocyte cell lines, formaldehyde level measurement, DNA damage marker assays, NAC rescue experiment, Polθ inhibitor combination studies bioRxivpreprint Medium bio_10.1101_2025.11.13.688345

Source papers

Stage 0 corpus · 95 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 112 28393572
2011 Function of S-nitrosoglutathione reductase (GSNOR) in plant development and under biotic/abiotic stress. Plant signaling & behavior 108 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 89 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
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 73 33355142
2019 GSNOR provides plant tolerance to iron toxicity via preventing iron-dependent nitrosative and oxidative cytotoxicity. Nature communications 71 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
2009 Genetic variants of GSNOR and ADRB2 influence response to albuterol in African-American children with severe asthma. Pediatric pulmonology 51 19514054
2020 The Emerging Role of GSNOR in Oxidative Stress Regulation. Trends in plant science 50 33004257
2020 Redox activation of ATM enhances GSNOR translation to sustain mitophagy and tolerance to oxidative stress. EMBO reports 50 33245190
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
2023 Mitochondrial GSNOR Alleviates Cardiac Dysfunction via ANT1 Denitrosylation. Circulation research 47 37377022
1992 Cloning and characterization of the ADH5 gene encoding human alcohol dehydrogenase 5, formaldehyde dehydrogenase. Gene 46 1446828
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
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 37 28883020
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
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 32 32514323
2021 Analysis of disease model iPSCs derived from patients with a novel Fanconi anemia-like IBMFS ADH5/ALDH2 deficiency. Blood 31 33512438
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 27 29860106
2018 Denitrosylate and live longer: how ADH5/GSNOR links mitophagy to aging. Autophagy 25 30029585
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 21 38574838
2021 ADH5-mediated NO bioactivity maintains metabolic homeostasis in brown adipose tissue. Cell reports 21 34788615
2018 S-nitrosoglutathione reductase (GSNOR) inhibitor as an immune modulator in experimental autoimmune encephalomyelitis. Free radical biology & medicine 19 29694854
2021 GSNOR facilitates antiviral innate immunity by restricting TBK1 cysteine S-nitrosation. Redox biology 18 34678655
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
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
2025 NEDD4-Mediated GSNOR Degradation Aggravates Cardiac Hypertrophy and Dysfunction. Circulation research 16 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 16 36252109
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
2024 S-nitrosothiol homeostasis maintained by ADH5 facilitates STING-dependent host defense against pathogens. Nature communications 13 38409248
2022 GABA keeps nitric oxide in balance by regulating GSNOR to enhance disease resistance of harvested tomato against Botrytis cinerea. Food chemistry 13 35640428
2023 GSNOR deficiency promotes tumor growth via FAK1 S-nitrosylation. Cell reports 12 36656716
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
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 10 38549378
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
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 The Physiological Implications of S-Nitrosoglutathione Reductase (GSNOR) Activity Mediating NO Signalling in Plant Root Structures. Antioxidants (Basel, Switzerland) 9 33266126
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
2025 Phytophthora Disrupts Plant Immunity by Manipulating Nitric Oxide Homeostasis Through GSNOR Inhibition. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 6 40539224
2018 S-Nitrosoglutathione Reductase (GSNOR) Deficiency Results in Secondary Hypogonadism. The journal of sexual medicine 6 29606625
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 5 38330777
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
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 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
2025 GSNOR deletion differentially alters age-related cardiac function in a sex-dependent manner. American journal of physiology. Heart and circulatory physiology 2 41407313
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 S-nitrosation in endothelium: different outcomes of NRF2 and GSNOR loss. Free radical biology & medicine 1 41308936
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
2026 Modulation of GSNOR activity for improved NO homeostasis and flood resilience in plants. Plant signaling & behavior 0 41542844
2026 Heterologous GSNOR expression modulates nitric oxide and glutathione redox to differentially shape plant responses to herbicides. Journal of hazardous materials 0 41604923
2026 A Coupled GSH/GSNOR System Denitrosylates TRXh5 to Allow Activation of SA Signalling by Oxidative Stress. Plant, cell & environment 0 41611640
2026 S-nitrosoglutathione reductase GSNOR drives age-related obesity by promoting adipose tissue whitening through de-nitrosation of Beclin-1. Nature communications 0 41730881
2026 Loss of erythrocyte arginase-1 impairs vasorelaxation due to endothelial GSNOR overexpression and denitrosylation of G protein subunits. Redox biology 0 42085863
2025 Assessing the association between ADH5 and ALDH1A1 genetic variants and substance use disorder risk in a Jordanian male population. BMC genomics 0 40033181
2025 Thermogenic Adipose ADH5 Counteracts Age-related Metabolic Decline. bioRxiv : the preprint server for biology 0 40631281
2025 A case of ADH5/ALDH2 deficiency combined with 3q29 microduplication syndrome. BMC pediatrics 0 41039406
2025 ADH5 inhibits proliferation but promotes EMT in non-small cell lung cancer cell through activating Smad2/Smad3. Open life sciences 0 41079602
2025 Glycolysis Inhibition Restores Immune Sensitivity in GSNOR-Deficient Colorectal Cancer. Laboratory investigation; a journal of technical methods and pathology 0 41083002
2025 GSNOR is essential for nitric oxide homeostasis and involved in aflatoxin biosynthesis and pathogenicity in Aspergillus flavus. Applied and environmental microbiology 0 41400364
2024 Cord Blood Transplantation Using Myeloablative Conditioning for Pediatric Advanced Myelodysplastic Syndrome in AMeD Syndrome With a Novel ADH5 Variant. Pediatric blood & cancer 0 39616414

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