Affinage

HINT1

Adenosine 5'-monophosphoramidase HINT1 · UniProt P49773

Length
126 aa
Mass
13.8 kDa
Annotated
2026-04-28
100 papers in source corpus 26 papers cited in narrative 26 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HINT1 is a universally conserved dimeric nucleotide hydrolase and multifunctional scaffold that integrates enzymatic, transcriptional, and signaling activities across diverse cellular contexts. As an enzyme, HINT1 hydrolyzes adenosine 5′-monophosphoramidate and aminoacyl-AMP substrates at high catalytic rates using its HIT-motif active site, with substrate specificity governed by its C-terminal loop and key residues Ser107 and Trp123 at the dimer interface (PMID:11805111, PMID:14982931, PMID:22329685); it also possesses SUMO isopeptidase activity mediated by a Cys84-Asp87-His114 catalytic triad, regulated by zinc, nitric oxide, and calmodulin (PMID:31088288). As a transcriptional co-repressor, HINT1 directly binds oncogenic transcription factors including β-catenin/TCF, MITF, USF2, and NFκB, recruiting HDAC1/mSIN3a to target promoters; this repressive function is relieved by Ap4A-driven polymerization of HINT1 or by CBP-mediated acetylation at K21/K30, which is reversed by SIRT1 deacetylation (PMID:22647378, PMID:31604935, PMID:32636443, PMID:16014379). HINT1 functions as a haploinsufficient tumor suppressor whose loss increases spontaneous and carcinogen-induced tumorigenesis in mice (PMID:16186798), acts as a scaffold coupling mu-opioid and cannabinoid receptors to NMDAR regulation via RGSZ2/PKCγ/σ1R complexes in neurons (PMID:18652891, PMID:24093505), suppresses cardiac hypertrophy by inhibiting PKCβ1 membrane translocation and the MEK/ERK/YY1/HOXA5 pathway (PMID:34098726), and participates in DNA damage responses through association with γ-H2AX and ATM (PMID:18852295); loss-of-function mutations in HINT1 cause autosomal recessive axonal neuropathy with neuromyotonia (PMID:22961002).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1997 High

    Determining the three-dimensional structure of HINT established it as a dimeric purine nucleotide-binding protein with a conserved HIT-motif phosphate-binding loop, revealing its fold and setting the stage for understanding its catalytic mechanism.

    Evidence X-ray crystallography of HINT-nucleotide complexes

    PMID:9164465

    Open questions at the time
    • Physiological substrate unknown
    • Catalytic activity not yet demonstrated
    • Biological function in cells undefined
  2. 2002 High

    Identification of adenosine monophosphoramidase activity at >10⁶ M⁻¹s⁻¹ and genetic epistasis with the TFIIH kinase subcomplex answered what HINT1 does enzymatically and placed it in a transcription-related pathway.

    Evidence In vitro enzymatic assays with rabbit Hint and yeast Hnt1; yeast genetic epistasis with Kin28/Ccl1/Tfb3

    PMID:11805111

    Open questions at the time
    • Direct in vivo substrate not captured
    • Mechanism linking hydrolase activity to TFIIH regulation unclear
  3. 2000 High

    Physical interaction with Cdk7/Kin28 and nuclear relocalization upon Cdk7 overexpression connected HINT1 to cell cycle kinase complexes and raised the question of whether it has nuclear transcriptional roles.

    Evidence Yeast two-hybrid, co-immunoprecipitation, imaging, and yeast double-mutant analysis

    PMID:10958787

    Open questions at the time
    • Whether Cdk7 interaction is direct or bridged by other TFIIH subunits not resolved
    • Functional consequence of nuclear relocalization unclear
  4. 2004 High

    A 1.8-Å co-crystal structure with a substrate analogue and mutagenesis of Ser107 defined the catalytic mechanism for AMP-lysine hydrolysis, establishing the roles of Trp123 (across the dimer interface) and Ser107 in acid-base catalysis.

    Evidence X-ray crystallography, AMP-pNA hydrolase assay, S107A mutagenesis

    PMID:14982931

    Open questions at the time
    • Full transition-state geometry not resolved
    • In vivo relevance of lysyl-AMP hydrolysis not demonstrated
  5. 2005 High

    Discovery that HINT1 binds Pontin/Reptin and represses TCF–β-catenin transcription (with cyclin D1 and axin2 as endogenous targets) established HINT1 as a transcriptional co-repressor, a function independent of its nucleotide hydrolase activity.

    Evidence Pull-down, co-immunoprecipitation, TCF reporter, RNAi knockdown

    PMID:16014379

    Open questions at the time
    • Whether HINT1 repressor function requires its enzymatic activity not tested here
    • Chromatin-level mechanism of repression not defined
  6. 2006 High

    Two key advances: (1) HINT1 was shown to promote apoptosis via p53/Bax upregulation as part of the Tip60 complex—independent of catalytic activity (H112N mutant); (2) Hint1⁺/⁻ and Hint1⁻/⁻ mice demonstrated haploinsufficient tumor suppression, linking HINT1 loss to cancer predisposition in vivo.

    Evidence Apoptosis assays, Bax promoter ChIP, Tip60 co-IP, H112N mutant (SW480/MCF-7 cells); knockout/heterozygous mice with spontaneous and DMBA-induced tumors

    PMID:16186798 PMID:16835243

    Open questions at the time
    • How HINT1 stimulates Tip60 acetyltransferase activity mechanistically unknown
    • Tissue-specific tumor suppressor mechanisms not dissected
  7. 2007 High

    HINT1 was found to inhibit AP-1 activity by binding the POSH–JNK2 complex, expanding the repertoire of transcription factor targets it represses and establishing JNK2 specificity; separately, C-terminal loop swaps defined substrate specificity determinants for phosphoramidate hydrolysis.

    Evidence Co-IP with POSH–JNK2, AP-1 reporter, JNK1⁻/⁻ and JNK2⁻/⁻ MEFs; chimeric enzyme kinetics

    PMID:17510397 PMID:17939685

    Open questions at the time
    • Whether JNK2 interaction is direct or POSH-mediated not resolved
    • Structural basis for C-terminal loop specificity not determined
  8. 2008 High

    Two parallel advances established HINT1 roles in the nucleus and at the plasma membrane: HINT1 was recruited to DNA damage foci and required for γ-H2AX removal and ATM activation after irradiation; simultaneously, HINT1 was identified as a scaffold coupling MOR to NMDAR regulation via RGSZ/PKCγ/zinc signaling in neurons.

    Evidence IRIF imaging, γ-H2AX/ATM co-IP, DNA repair assays in HINT1-deficient cells; in vivo pharmacology, co-IP, antisense knockdown in mouse neurons

    PMID:18652891 PMID:18852295

    Open questions at the time
    • Mechanism by which HINT1 promotes γ-H2AX acetylation/removal not defined
    • MOR–HINT1 scaffolding model relies on single-lab pharmacological studies
    • Whether DNA damage and GPCR roles involve the same or distinct HINT1 pools unknown
  9. 2012 High

    Three discoveries converged: HINT1 was shown to bind aminoacyl-AMP intermediates broadly (crystal structures); it was established as a co-repressor of MITF and β-catenin via HDAC1/mSIN3a recruitment to target promoters (ChIP); and loss-of-function mutations were identified as the cause of autosomal recessive axonal neuropathy with neuromyotonia in 33 families.

    Evidence Multiple co-crystal structures with aa-AMP analogues; ChIP, co-IP with MITF/β-catenin/HDAC1/mSIN3a in melanoma cells; linkage analysis and exome sequencing in ARAN-NM families

    PMID:22329685 PMID:22647378 PMID:22961002

    Open questions at the time
    • Whether aminoacyl-AMP hydrolysis connects to transcriptional repression unknown
    • Neuropathological mechanism of HINT1 loss in peripheral nerve not defined
    • Whether HDAC1/mSIN3a recruitment requires HINT1 dimerization not tested
  10. 2015 Medium

    The HINT1 signaling scaffold model was extended: σ1R was shown to regulate HINT1 transfer between GPCRs and NMDAR NR1 subunits; teneurin-1 ICD was identified as a direct HINT1 interactor that relieves MITF repression; and pharmacological HINT1 inhibitors were crystallographically characterized and shown to enhance morphine analgesia in vivo.

    Evidence σ1R⁻/⁻ and HINT1⁻/⁻ mice, in vivo pharmacology, co-IP; yeast two-hybrid and co-IP for teneurin-1; X-ray crystallography of inhibitor complexes, antinociception assays

    PMID:25445489 PMID:25557043 PMID:25648896

    Open questions at the time
    • Structural basis for σ1R–HINT1–NR1 ternary complex not resolved
    • Teneurin-1–HINT1 interaction validated by single lab
    • Inhibitor selectivity in vivo not fully profiled
  11. 2017 Medium

    Identification of K21 acetylation and Y109 phosphorylation as PTMs that trigger HINT1 dissociation from MITF explained how activated mast cells relieve transcriptional repression, connecting Ap4A signaling (via phospho-LysRS) to HINT1 regulation.

    Evidence Mass spectrometry PTM identification, site-directed mutagenesis (K21, Y109), transcriptional reporter in melanoma cells

    PMID:28394346

    Open questions at the time
    • Kinase responsible for Y109 phosphorylation not identified
    • Whether K21 acetylation and Ap4A polymerization are redundant or sequential not determined
  12. 2019 High

    Two mechanistically distinct advances: (1) Ap4A was shown to polymerize HINT1 into higher-order assemblies whose interface overlaps the MITF-binding surface, providing a structural mechanism for MITF release; (2) a novel SUMO isopeptidase activity was identified with a Cys84-Asp87-His114 catalytic triad, regulated by zinc/NO/calmodulin, and all 15 tested ARAN-NM mutants showed altered sumoylase activity.

    Evidence Eight crystal structures, negative-stain EM, polymerization assays in RBL cells; in vitro SUMO protease assay, catalytic triad mutagenesis, patient mutant characterization

    PMID:31088288 PMID:31604935

    Open questions at the time
    • In vivo SUMO substrates of HINT1 not identified
    • Whether Ap4A polymerization occurs in neurons and relates to ARAN-NM unknown
    • SUMO isopeptidase activity identified by single lab and awaits independent replication
  13. 2020 Medium

    SIRT1-mediated deacetylation of HINT1 at K21/K30 was shown to enhance its binding to β-catenin and MITF and augment tumor-suppressive function, establishing a reversible acetylation switch (CBP acetylates, SIRT1 deacetylates) that modulates HINT1 co-repressor activity.

    Evidence Co-IP, K21R/K30R mutagenesis, in vitro deacetylation assay, xenograft tumorigenesis

    PMID:32636443

    Open questions at the time
    • Whether SIRT1–HINT1 axis operates in non-cancer contexts (e.g., neurons) unknown
    • Structural basis for how acetylation weakens transcription factor binding not determined
  14. 2021 High

    HINT1 was established as a cardioprotective factor that directly binds PKCβ1, inhibits its membrane translocation, and thereby suppresses the MEK/ERK/YY1/HOXA5 hypertrophy pathway; AAV9-mediated cardiac HINT1 overexpression rescued pressure-overload hypertrophy in mice.

    Evidence Co-IP, cellular fractionation, AAV9 cardiac overexpression, Hint1⁻/⁻ mice + TAC, RNA-seq, HOXA5 knockdown

    PMID:34098726

    Open questions at the time
    • Whether PKCβ1 inhibition requires HINT1 enzymatic activity not tested
    • Downstream mechanism linking HOXA5 to hypertrophic gene program incompletely defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the identity of in vivo SUMO substrates of HINT1, the structural basis of the HINT1–GPCR–NMDAR ternary signaling complex, whether the distinct enzymatic activities (phosphoramidase, SUMO isopeptidase) serve separable physiological functions, the neuropathological mechanism underlying ARAN-NM, and how Ap4A-driven polymerization and PTM-mediated regulation are coordinated in different tissue contexts.
  • In vivo SUMO substrates unidentified
  • Structural model of HINT1–MOR–NMDAR signalosome lacking
  • Peripheral nerve-specific mechanism of ARAN-NM pathogenesis unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 4 GO:0140110 transcription regulator activity 4 GO:0060090 molecular adaptor activity 2 GO:0098772 molecular function regulator activity 2 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005634 nucleus 4 GO:0005886 plasma membrane 3 GO:0005829 cytosol 1 GO:0005856 cytoskeleton 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1643685 Disease 2 R-HSA-4839726 Chromatin organization 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-73894 DNA Repair 1
Partners
CDK7CTNNB1MITFOPRS1PRKCBRGSZ2RUVBL1RUVBL2
Complex memberships
HDAC1/mSIN3a repressor complexMOR–HINT1–RGSZ2 signaling complexTip60 HAT complex

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 Crystal structures of HINT-nucleotide complexes demonstrated that HINT is a dimeric purine nucleotide-binding protein whose most conserved residues (HIT motif) mediate nucleotide binding and form part of the phosphate-binding loop; the protein shares the same fold and mode of nucleotide binding as galactose-1-phosphate uridylyltransferase despite no overall sequence similarity. X-ray crystallography of HINT-nucleotide complexes Nature structural biology High 9164465
2002 Rabbit Hint and yeast Hnt1 hydrolyze the natural product adenosine-5'-monophosphoramidate (AMP-NH2) in an active-site-dependent manner at second-order rates exceeding 1,000,000 M−1 s−1; loss of Hnt1 enzymatic activity causes hypersensitivity to mutations in Kin28/Ccl1/Tfb3 (the TFIIK kinase subcomplex of TFIIH), positioning Hnt1 as a positive regulator of this CTD kinase pathway downstream of Cak1. In vitro enzymatic assay (adenosine monophosphoramidase activity), yeast genetic epistasis, functional complementation with rabbit Hint The Journal of biological chemistry High 11805111
2000 HINT/PKCI-1 physically interacts with Cdk7 (and its yeast ortholog Kin28) independent of cyclin H binding or Cdk7 kinase activity; overexpression of Cdk7 causes partial relocalization of Hint to the nucleus; genetic interaction between HNT1 and KIN28 in yeast produces elongated cell morphology and reduced colony formation. Yeast two-hybrid, co-immunoprecipitation, subcellular localization by imaging, yeast genetic double-mutant analysis The Journal of biological chemistry High 10958787
2004 Biochemical and structural analysis of rabbit Hint established that the enzyme hydrolyzes AMP-lysine (AMP-pNA substrate); a 1.8-Å co-crystal structure with N-ethylsulfamoyl adenosine identified Trp-123 (across the dimer interface) as contacting the alkyl portion of the inhibitor/lysyl substrate, and Ser-107 as donating a hydrogen bond to the leaving-group nitrogen; Hint S107A mutant showed depressed catalytic activity, confirming Ser-107's role in acid-base catalysis. In vitro AMP-pNA hydrolase assay, X-ray crystallography (1.8 Å co-crystal), site-directed mutagenesis (S107A) The Journal of biological chemistry High 14982931
2005 HINT1/PKCI directly binds to Pontin and Reptin (via their residues 214–295 and 218–289, respectively, and via the N-terminus of HINT1), and through this interaction associates with the LEF-1/TCF–β-catenin transcription complex to act as a negative regulator of TCF–β-catenin transcriptional activity; knockdown of HINT1 by RNAi increases expression of cyclin D1 and axin2. Pull-down assays, co-immunoprecipitation, domain mapping, TCF reporter gene assay, RNAi knockdown with endogenous target gene readout Journal of cell science High 16014379
2006 HINT1 triggers apoptosis in SW480 and MCF-7 cells by upregulating p53 and Bax and downregulating Bcl-2; HINT1 associates with the Bax promoter and is a component of the Tip60 histone acetyltransferase complex; a catalytically dead mutant H112N is not impaired in apoptosis induction, demonstrating the pro-apoptotic activity is independent of AMP-NH2 hydrolase enzymatic activity. Transient transfection, caspase-3/PARP cleavage, cytochrome c release, DNA fragmentation ELISA, promoter ChIP, co-immunoprecipitation with Tip60 complex, shRNA knockdown, enzymatic mutant (H112N) The Journal of biological chemistry High 16835243
2006 HINT1 is a haploinsufficient tumor suppressor in mice; Hint1+/- and Hint1-/- mice show significantly increased spontaneous tumor incidence and susceptibility to DMBA-induced mammary/ovarian tumors; Hint1+/- tumors retain wild-type allele expression, establishing haploinsufficiency. Knockout mouse model, carcinogen challenge (DMBA), tumor incidence analysis, allele expression analysis Oncogene High 16186798
2007 HINT1 inhibits AP-1 transcriptional activity in colon cancer cells by binding to a POSH–JNK2 complex (co-immunoprecipitation), thereby inhibiting phosphorylation of c-Jun; this inhibition specifically requires JNK2 but not JNK1, established using JNK1- and JNK2-deleted MEFs. Co-immunoprecipitation, AP-1-luciferase reporter assay, genetic MEF models (JNK1-/- and JNK2-/-), retrovirus-mediated HINT1 overexpression Cancer research High 17510397
2008 HINT1 is recruited to ionizing radiation-induced foci (IRIF) and physically associates with γ-H2AX and ATM; HINT1 deficiency impairs removal of γ-H2AX foci (associated with impaired acetylation of γ-H2AX), impairs ATM acetylation and activation, retards DNA repair, and results in resistance to IR-induced apoptosis and chromosomal abnormalities. Immunofluorescence (IRIF), co-immunoprecipitation, fractionation, acetylation assays, DNA repair assays, HINT1-deficient cells The Journal of cell biology High 18852295
2008 In neurons, morphine-activated mu-opioid receptor (MOR) C-terminus binds HINT1/PKCI, which in turn binds RGSZ1/Z2 proteins; NMDAR/nNOS-generated nitric oxide produces free zinc ions that recruit inactive PKCγ (via its CRDs) to the HINT1/RGSZ complex at the MOR C-terminus, where DAG-activated PKCγ phosphorylates MOR serine residues to reduce opioid signal strength. Intracerebroventricular pharmacology, co-immunoprecipitation, antisense knockdown, NOS inhibitors, zinc chelators, NMDAR antagonist Cellular signalling Medium 18652891
2012 Loss-of-function mutations in HINT1 (8 different mutations identified in 33 families) cause autosomal recessive axonal neuropathy with neuromyotonia (ARAN-NM), establishing that functional HINT1 protein is required for normal peripheral nerve function. Linkage analysis, next-generation sequencing, cohort screening, clinical phenotyping Nature genetics High 22961002
2012 Human HINT1 binds aminoacyl adenylate (aa-AMP) intermediates with broad specificity independent of the amino acid side chain; crystal structures of HINT1 with three aa-AMP analogues show recognition of only the common main chain of the aminoacyl moiety, with the α-amino group anchored by a cation-π interaction with Trp123. X-ray crystallography (multiple co-crystal structures with aa-AMP analogues), in vitro hydrolysis assays The journal of physical chemistry. B High 22329685
2012 HINT1 inhibits MITF and β-catenin transcriptional activity in melanoma cells; both MITF and β-catenin co-immunoprecipitate with HINT1; ChIP assays show HINT1 occupies MITF and β-catenin binding sites at BCL2 and cyclin D1 promoters; mSIN3a and HDAC1 co-immunoprecipitate with HINT1, suggesting a repressive complex. Co-immunoprecipitation, ChIP assay, transcriptional reporter assay, stable overexpression, xenograft Cell cycle (Georgetown, Tex.) High 22647378
2013 HINT1 protein is required for the cannabinoid CB1 receptor (CNR1) to negatively regulate NMDAR activity; in CNR1+/+/HINT1-/- cortical neurons NMDAR activity is enhanced and cannabinoid neuroprotection is abolished; lentiviral re-expression of HINT1 restores both NMDAR regulation and cannabinoid-mediated neuroprotection. HINT1-/- and CNR1-/- mouse neurons, lentiviral HINT1 rescue, calcium imaging/NMDA insult assay Molecular brain Medium 24093505
2015 The σ1 receptor (σ1R) binds to the cytosolic C-terminal region of the NMDAR NR1 subunit in a calcium-dependent manner and enables NR1–HINT1 interaction with MOR–HINT1 complexes; σ1R antagonists transfer HINT1 from GPCRs to NR1 subunits, disengaging MOR from NMDAR negative control and enhancing opioid antinociception; this regulation depends on the NO/Zn2+ redox switch via RGSZ2-nNOS and PKCγ recruitment to HINT1. In vivo pharmacology, ex vivo and in vitro co-immunoprecipitation, σ1R-/- and HINT1-/- mouse models, NOS inhibitors Antioxidants & redox signaling Medium 25557043
2015 The intracellular domain (ICD) of teneurin-1 interacts directly with HINT1 in human cells (identified by yeast two-hybrid and confirmed by co-immunoprecipitation); this interaction relieves HINT1-mediated repression of MITF, inducing MITF-dependent transcription of target genes such as GPNMB. Yeast two-hybrid screen, co-immunoprecipitation, transcriptome analysis, promoter reporter assay The Journal of biological chemistry Medium 25648896
2015 Pharmacological inhibition of HINT1 enzymatic activity (using guanosine-5′-tryptamine carbamate, TpGc) significantly enhances morphine antinociception and prevents tolerance development, and reduces NMDAR activity in mice with chronic constriction injury; X-ray crystallographic and thermodynamic binding studies showed distinct binding modes of different HINT1 inhibitors correlating with their differential effects on MOR–NMDAR cross-talk. In vivo antinociception assays, intracerebroventricular drug delivery, X-ray crystallography of HINT1-inhibitor complexes, thermodynamic binding assays Neuropharmacology Medium 25445489
2017 HINT1 is subjected to K21 acetylation and Y109 phosphorylation in activated mast cells; Ap4A (produced by S207-phosphorylated LysRS) triggers HINT1 dissociation from MITF; mutational analysis of K21 and Y109 confirmed these post-translational modifications promote MITF transcriptional and oncogenic activity in melanoma cells. Mass spectrometry (PTM identification), site-directed mutagenesis of acetylation (K21) and phosphorylation (Y109) sites, transcriptional reporter assay in melanoma cells Oncogene Medium 28394346
2019 Ap4A specifically polymerizes HINT1 into higher-order assemblies in solution and in activated rat basophilic leukemia cells; eight crystal structures define the polymerization interface, which overlaps with the MITF-binding region on HINT1, providing a competitive mechanism to release MITF for transcriptional activation; the polymerization depends precisely on the polyphosphate chain length of Ap4A. X-ray crystallography (8 crystal structures), negative-stain electron microscopy, biochemical polymerization assays, cellular experiments in RBL cells Nature communications High 31604935
2019 HINT1 exhibits cysteine SUMO protease (isopeptidase) activity to remove SUMO from signaling proteins; this activity is regulated by zinc (blocks) and by nitric oxide or calcium-activated calmodulin (releases); the catalytic triad is Cys84-Asp87-His114; a SUMO-interacting motif is identified at residues 110–116; all 15 human ARAN-NM-associated HINT1 mutants tested showed altered sumoylase activity. In vitro SUMO protease assay, site-directed mutagenesis of catalytic triad, zinc/NO/CaM regulation assays, patient-derived mutant characterization Antioxidants & redox signaling Medium 31088288
2020 SIRT1 deacetylates HINT1 at K21 and K30 (CBP-mediated acetylation sites); deacetylation increases HINT1 binding capacity for β-catenin and MITF, enhancing tumor-suppressive activity; deacetylation-mimetic HINT1 2KR mutant significantly reduces proliferation in colon cancer and melanoma cells and tumorigenesis in xenografts. Co-immunoprecipitation, site-directed mutagenesis (K21R/K30R), xenograft assay, in vitro deacetylation assay Experimental & molecular medicine Medium 32636443
2021 HINT1 directly interacts with PKCβ1 and inhibits its membrane translocation and phosphorylation; this suppresses the MEK/ERK/YY1 signaling pathway and downregulates HOXA5 expression, ultimately attenuating cardiac hypertrophy; cardiac-specific HINT1 overexpression via AAV9 alleviated hypertrophy and dysfunction in mice. Co-immunoprecipitation, cellular fractionation assays, AAV9-mediated cardiac-specific overexpression, Hint1 knockout mice + transverse aortic constriction, RNA sequencing, shRNA knockdown of Hoxa5 Circulation High 34098726
1996 Human PKCI-1/HINT1 localizes to cytoskeletal structures in the cytoplasm of human fibroblasts and is largely excluded from the nucleus, as determined by indirect immunofluorescence. Indirect immunofluorescence in human fibroblast cell line Genomics Medium 8812426
2007 The C-terminal loop of HINT1 is a critical determinant of substrate specificity; chimeric Hint proteins with swapped C-terminal loops showed that the human C-terminal loop confers preference for l-configured phosphoramidates and ability to hydrolyze lysyl-AMP generated by human LysRS, distinct from E. coli hinT specificity. Chimeric enzyme construction, in vitro kinetic assays (kcat/Km) with panel of substrates Biochemistry Medium 17939685
2016 Crystal structure of human HINT1 in complex with a non-hydrolyzable Ap4A analog (at 2.34 Å resolution) defined the Ap4A binding site; the apo structure (1.92 Å) was also solved for comparison. X-ray crystallography International journal of biological macromolecules Medium 26905466
2009 HINT1 co-immunoprecipitates with USF2 in hepatoma cell extracts and inhibits USF2, β-catenin/TCF4, and NFκB transcriptional activities; HINT1 also inhibits nuclear translocation of the p65 NFκB subunit in HepG2 cells. Co-immunoprecipitation, transcriptional reporter assays, nuclear fractionation International journal of cancer Medium 19089909

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 HINT: High-quality protein interactomes and their applications in understanding human disease. BMC systems biology 308 22846459
2020 Clinical Study of Mesenchymal Stem Cell Treatment for Acute Respiratory Distress Syndrome Induced by Epidemic Influenza A (H7N9) Infection: A Hint for COVID-19 Treatment. Engineering (Beijing, China) 198 32292627
1997 Crystal structures of HINT demonstrate that histidine triad proteins are GalT-related nucleotide-binding proteins. Nature structural biology 125 9164465
2002 Stability of a PKCI-1-related mRNA is controlled by the splicing factor ASF/SF2: a novel function for SR proteins. Genes & development 120 11877379
2006 The histidine triad protein Hint1 triggers apoptosis independent of its enzymatic activity. The Journal of biological chemistry 116 16835243
2005 The histidine triad protein Hint1 interacts with Pontin and Reptin and inhibits TCF-beta-catenin-mediated transcription. Journal of cell science 100 16014379
2002 Adenosine monophosphoramidase activity of Hint and Hnt1 supports function of Kin28, Ccl1, and Tfb3. The Journal of biological chemistry 96 11805111
2006 Hint1 is a haplo-insufficient tumor suppressor in mice. Oncogene 93 16186798
2012 Loss-of-function mutations in HINT1 cause axonal neuropathy with neuromyotonia. Nature genetics 92 22961002
2004 A hint to search for metalloproteins in gene banks. Bioinformatics (Oxford, England) 90 14962940
2015 The σ1 receptor engages the redox-regulated HINT1 protein to bring opioid analgesia under NMDA receptor negative control. Antioxidants & redox signaling 72 25557043
2006 Mapping the energetics of water-protein and water-ligand interactions with the "natural" HINT forcefield: predictive tools for characterizing the roles of water in biomolecules. Journal of molecular biology 64 16497327
2007 Hint1 inhibits growth and activator protein-1 activity in human colon cancer cells. Cancer research 61 17510397
2009 Anti-depressant and anxiolytic like behaviors in PKCI/HINT1 knockout mice associated with elevated plasma corticosterone level. BMC neuroscience 54 19912621
2008 NMDAR-nNOS generated zinc recruits PKCgamma to the HINT1-RGS17 complex bound to the C terminus of Mu-opioid receptors. Cellular signalling 53 18652891
2021 HINT1 (Histidine Triad Nucleotide-Binding Protein 1) Attenuates Cardiac Hypertrophy Via Suppressing HOXA5 (Homeobox A5) Expression. Circulation 52 34098726
2015 The ON:OFF switch, σ1R-HINT1 protein, controls GPCR-NMDA receptor cross-regulation: implications in neurological disorders. Oncotarget 52 26461475
2009 Atypical p-ANCA in PSC and AIH: a hint toward a "leaky gut"? Clinical reviews in allergy & immunology 52 18626795
2006 RGSZ1 interacts with protein kinase C interacting protein PKCI-1 and modulates mu opioid receptor signaling. Cellular signalling 52 17126529
2000 Interactions of Cdk7 and Kin28 with Hint/PKCI-1 and Hnt1 histidine triad proteins. The Journal of biological chemistry 52 10958787
2004 Biochemical, crystallographic, and mutagenic characterization of hint, the AMP-lysine hydrolase, with novel substrates and inhibitors. The Journal of biological chemistry 51 14982931
2005 31P NMR and genetic analysis establish hinT as the only Escherchia coli purine nucleoside phosphoramidase and as essential for growth under high salt conditions. The Journal of biological chemistry 49 15703176
2013 HINT1 protein cooperates with cannabinoid 1 receptor to negatively regulate glutamate NMDA receptor activity. Molecular brain 48 24093505
2007 Supersensitivity to amphetamine in protein kinase-C interacting protein/HINT1 knockout mice. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 48 17203012
2018 Taraxasterol suppresses the growth of human liver cancer by upregulating Hint1 expression. Journal of molecular medicine (Berlin, Germany) 46 29806073
2013 Quantitative analysis of BTF3, HINT1, NDRG1 and ODC1 protein over-expression in human prostate cancer tissue. PloS one 44 24386364
2008 Evolution of hedgehog and hedgehog-related genes, their origin from Hog proteins in ancestral eukaryotes and discovery of a novel Hint motif. BMC genomics 44 18334026
2012 The tumor suppressor HINT1 regulates MITF and β-catenin transcriptional activity in melanoma cells. Cell cycle (Georgetown, Tex.) 43 22647378
2011 Increased anxiety-related behaviour in Hint1 knockout mice. Behavioural brain research 43 21316396
2008 Distribution and expression of protein kinase C interactive protein (PKCI/HINT1) in mouse central nervous system (CNS). Neurochemical research 41 18270824
2008 Is the histidine triad nucleotide-binding protein 1 (HINT1) gene a candidate for schizophrenia? Schizophrenia research 41 18799291
2009 HINT1 inhibits beta-catenin/TCF4, USF2 and NFkappaB activity in human hepatoma cells. International journal of cancer 38 19089909
2008 Silencing of Hint1, a novel tumor suppressor gene, by promoter hypermethylation in hepatocellular carcinoma. Cancer letters 38 19081673
2017 Post-translational modification of HINT1 mediates activation of MITF transcriptional activity in human melanoma cells. Oncogene 37 28394346
2013 HMGB1 protein does not mediate the inflammatory response in spontaneous spinal cord regeneration: a hint for CNS regeneration. The Journal of biological chemistry 36 23649623
2015 HINT1 protein: a new therapeutic target to enhance opioid antinociception and block mechanical allodynia. Neuropharmacology 35 25445489
2009 Computational chemistry study of 3D-structure-function relationships for enzymes based on Markov models for protein electrostatic, HINT, and van der Waals potentials. Journal of computational chemistry 34 19086060
2008 The HINT1 tumor suppressor regulates both gamma-H2AX and ATM in response to DNA damage. The Journal of cell biology 33 18852295
2014 Mutations in HINT1 are one of the most frequent causes of hereditary neuropathy among Czech patients and neuromyotonia is rather an underdiagnosed symptom. Neurogenetics 31 25342199
2017 Axonal neuropathy with neuromyotonia: there is a HINT. Brain : a journal of neurology 30 28007994
2018 Altered Light Conditions Contribute to Abnormalities in Emotion and Cognition Through HINT1 Dysfunction in C57BL/6 Mice. Frontiers in behavioral neuroscience 28 29937721
2013 Exome sequencing reveals HINT1 mutations as a cause of distal hereditary motor neuropathy. European journal of human genetics : EJHG 28 24105373
2015 The intracellular domain of teneurin-1 induces the activity of microphthalmia-associated transcription factor (MITF) by binding to transcriptional repressor HINT1. The Journal of biological chemistry 27 25648896
2020 Pharmacological Targets of Kaempferol Within Inflammatory Pathways-A Hint Towards the Central Role of Tryptophan Metabolism. Antioxidants (Basel, Switzerland) 26 32098277
2011 Differential expression of HINT1 in schizophrenia brain tissue. European archives of psychiatry and clinical neuroscience 25 21553311
2004 P80, the HinT interacting membrane protein, is a secreted antigen of Mycoplasma hominis. BMC microbiology 25 15579213
2017 A novel relationship for schizophrenia, bipolar and major depressive disorder Part 5: a hint from chromosome 5 high density association screen. American journal of translational research 24 28559998
2003 The histidine triad protein Hint is not required for murine development or Cdk7 function. Molecular and cellular biology 24 12748294
1996 Cloning, mapping, and in vivo localization of a human member of the PKCI-1 protein family (PRKCNH1). Genomics 24 8812426
2024 DLM-DTI: a dual language model for the prediction of drug-target interaction with hint-based learning. Journal of cheminformatics 23 38297330
2021 Enriched Opportunistic Pathogens Revealed by Metagenomic Sequencing Hint Potential Linkages between Pharyngeal Microbiota and COVID-19. Virologica Sinica 23 33978940
2020 Signal multi-amplified electrochemical biosensor for voltammetric determination of tau-441 protein in biological samples using carbon nanomaterials and gold nanoparticles to hint dementia. Mikrochimica acta 23 32350619
2022 Endogenous reparative pluripotent Muse cells with a unique immune privilege system: Hint at a new strategy for controlling acute and chronic inflammation. Frontiers in pharmacology 22 36339573
2018 Novel mutations in HINT1 gene cause the autosomal recessive axonal neuropathy with neuromyotonia. European journal of medical genetics 22 30006059
2017 HINT1 in Neuropsychiatric Diseases: A Potential Neuroplastic Mediator. Neural plasticity 22 29214080
2011 Increased human defensine levels hint at an inflammatory etiology of bisphosphonate-associated osteonecrosis of the jaw: an immunohistological study. Journal of translational medicine 22 21843332
2004 Altered specificity of Hint-W123Q supports a role for Hint inhibition by ASW in avian sex determination. Physiological genomics 22 15507519
2014 Lack of neuropathy-related phenotypes in hint1 knockout mice. Journal of neuropathology and experimental neurology 21 24918641
2013 Myofibroblasts, regeneration or renal fibrosis--is there a decisive hint? Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 21 23975753
2010 Turner syndrome and schizophrenia: a further hint for the role of the X-chromosome in the pathogenesis of schizophrenic disorders. The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry 21 20218787
2005 Histone acetylation, chromatin remodelling and nucleotide excision repair: hint from the study on MFA2 in Saccharomyces cerevisiae. Cell cycle (Georgetown, Tex.) 21 16082210
2019 Second messenger Ap4A polymerizes target protein HINT1 to transduce signals in FcεRI-activated mast cells. Nature communications 20 31604935
2016 A Novel Relationship for Schizophrenia, Bipolar, and Major Depressive Disorder. Part 8: a Hint from Chromosome 8 High Density Association Screen. Molecular neurobiology 20 27660274
2020 Deacetylation by SIRT1 promotes the tumor-suppressive activity of HINT1 by enhancing its binding capacity for β-catenin or MITF in colon cancer and melanoma cells. Experimental & molecular medicine 19 32636443
2018 Model Communities Hint at Promiscuous Metabolic Linkages between Ubiquitous Free-Living Freshwater Bacteria. mSphere 19 29848762
2017 Increased PKC activity and altered GSK3β/NMDAR function drive behavior cycling in HINT1-deficient mice: bipolarity or opposing forces. Scientific reports 19 28240305
2015 A case of neuromyotonia and axonal motor neuropathy: A report of a HINT1 mutation in the United States. Muscle & nerve 19 26182879
2012 Side chain independent recognition of aminoacyl adenylates by the Hint1 transcription suppressor. The journal of physical chemistry. B 19 22329685
2010 Design and structure of an equilibrium protein folding intermediate: a hint into dynamical regions of proteins. Journal of molecular biology 19 20553732
2014 HINT1 peptide/Hsp70 complex induces NK-cell-dependent immunoregulation in a model of autoimmune demyelination. European journal of immunology 18 25092109
2019 The Axonal Motor Neuropathy-Related HINT1 Protein Is a Zinc- and Calmodulin-Regulated Cysteine SUMO Protease. Antioxidants & redox signaling 17 31088288
2016 DO SYMPTOMS OF ILLNESS SERVE SIGNALING FUNCTIONS? (HINT: YES). The Quarterly review of biology 17 27405223
2012 Acute behavioral effects of nicotine in male and female HINT1 knockout mice. Genes, brain, and behavior 17 22827509
2009 Web application for studying the free energy of binding and protonation states of protein-ligand complexes based on HINT. Journal of computer-aided molecular design 17 19554265
2003 Familial Parkinson's disease: a hint to elucidate the mechanisms of nigral degeneration. Journal of neurology 17 14579118
2018 The histidine triad nucleotide-binding protein 2 (HINT-2) positively regulates hepatocellular energy metabolism. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 16 29913563
2015 Membrane Hydration: A Hint to a New Model for Biomembranes. Sub-cellular biochemistry 16 26438259
2012 The role of insulin C-peptide in the coevolution analyses of the insulin signaling pathway: a hint for its functions. PloS one 16 23300796
2001 Characterization of Cre-loxP interaction in the major groove: hint for structural distortion of mutant Cre and possible strategy for HIV-1 therapy. Journal of cellular biochemistry 16 11135361
1979 RNA synthesis in isolated bovine thyroid nuclei and nucleoli. alpha-Amanitin effect, a hint to the existence of a specific regulatory system. Hoppe-Seyler's Zeitschrift fur physiologische Chemie 16 511117
2019 HINT1 gene pathogenic variants: the most common cause of recessive hereditary motor and sensory neuropathies in Russian patients. Molecular biology reports 15 31848916
2017 ORF3a deletion in field strains of porcine-transmissible gastroenteritis virus in China: A hint of association with porcine respiratory coronavirus. Transboundary and emerging diseases 15 28299912
2016 Hint1 suppresses migration and invasion of hepatocellular carcinoma cells in vitro by modulating girdin activity. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 15 27623945
2020 The role of HINT1 protein in morphine addiction: An animal model-based study. Addiction biology 14 32171181
2019 Inhibition of HINT1 Modulates Spinal Nociception and NMDA Evoked Behavior in Mice. ACS chemical neuroscience 14 31503445
2016 Destabilization of Hydrophobic Core of Chicken Villin Headpiece in Guanidinium Chloride Induced Denaturation: Hint of π-Cation Interaction. The journal of physical chemistry. B 14 27548328
2013 The Bmi-1/NF-κB/VEGF story: another hint for proteasome involvement in glioma angiogenesis? Journal of cell communication and signaling 14 23494769
2011 Clinical significance of expression of Hint1 and potential epigenetic mechanism in gastric cancer. International journal of oncology 14 21468541
2023 Hint from an Enzymatic Reaction: Superoxide Dismutase Models Efficiently Suppress Colorectal Cancer Cell Proliferation. Journal of the American Chemical Society 13 37441741
2020 Histidine triad nucleotide-binding proteins HINT1 and HINT2 share similar substrate specificities and little affinity for the signaling dinucleotide Ap4A. FEBS letters 13 31990367
2018 Novel mutations in HINT1 gene cause autosomal recessive axonal neuropathy with neuromyotonia in two cases of sensorimotor neuropathy and one case of motor neuropathy. Neuromuscular disorders : NMD 13 30001929
2004 Hypergravity stimulates osteoblast phenotype expression: a therapeutic hint for disuse bone atrophy. Annals of the New York Academy of Sciences 13 15659793
2003 Hypoxia-inducible factor-1: a molecular hint of physiological changes in the carotid body during long-term hypoxemia? Current drug targets. Cardiovascular & haematological disorders 13 12871043
2001 The cytosolic HinT protein of Mycoplasma hominis interacts with two membrane proteins. Molecular microbiology 13 11454219
2022 The first three waves of the Covid-19 pandemic hint at a limited genetic repertoire for SARS-CoV-2. FEMS microbiology reviews 12 35076068
2021 HINT1 neuropathy in Norway: clinical, genetic and functional profiling. Orphanet journal of rare diseases 12 33663550
2021 Preeclampsia: Cardiotonic Steroids, Fibrosis, Fli1 and Hint to Carcinogenesis. International journal of molecular sciences 12 33669287
2017 Effects of Hint1 deficiency on emotional-like behaviors in mice under chronic immobilization stress. Brain and behavior 12 29075577
2016 Crystallographic studies of the complex of human HINT1 protein with a non-hydrolyzable analog of Ap4A. International journal of biological macromolecules 12 26905466
2007 Impact of the C-terminal loop of histidine triad nucleotide binding protein1 (Hint1) on substrate specificity. Biochemistry 12 17939685