Affinage

ADA

Adenosine deaminase · UniProt P00813

Length
363 aa
Mass
40.8 kDa
Annotated
2026-06-09
100 papers in source corpus 30 papers cited in narrative 30 extracted findings
Cross-family judge vs UniProt: UniProt preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

The ADA symbol in this corpus resolves into three biologically distinct proteins, and the timeline is dominated by the bacterial Ada DNA-alkylation-repair regulator rather than the human adenosine deaminase. The E. coli Ada protein is a bifunctional suicide methyltransferase that, in its repair role, irreversibly transfers methyl groups from O6-methylguanine in alkylated DNA to its own cysteine residues (PMID:2987251), with the active-site cysteine buried in the 19-kDa C-terminal domain whose structure has been solved (PMID:8156986). A second methyltransferase activity in the N-terminal domain accepts methyl from methylphosphotriesters at Cys-69, and this specific modification—not the C-terminal Cys-321 methylation—converts Ada into a sequence-specific transcriptional activator of the adaptive response to alkylating agents (PMID:2843522, PMID:2648001). Methylated Ada binds the ada/alkA regulatory sequence (AAAGCGCA) upstream of the promoter and recruits RNA polymerase through direct contact with the C-terminal domain of the alpha subunit and with the C-terminal region of sigma70 (notably Glu575), defining Ada as a class I activator (PMID:3139888, PMID:8468304, PMID:9582376). The repair-to-activator switch is electrostatic rather than ligand-exchange-based: structural and spectroscopic analyses show S-methyl-Cys69 remains zinc-coordinated, and neutralization of negative charge at the zinc-thiolate center remodels a surface patch to convert phosphate repulsion into attraction for promoter DNA (PMID:9383376, PMID:11284682, PMID:16209950). The response is self-limiting: unmethylated Ada antagonizes its own activation (PMID:7937881), and an endogenous protease cleaves Ada into a 20-kDa N-terminal fragment that activates alkA but represses ada, terminating the adaptive response (PMID:3058696, PMID:2254928). A separate set of findings describes the eukaryotic ADA/Ada2/Ada3 transcriptional co-activator subunits, which scaffold the GCN5 histone acetyltransferase within the ADA and SAGA complexes to acetylate nucleosomal histone H3K14, antagonize chromatin-mediated repression together with SWI/SNF, and mediate activation by nuclear receptors, with complex-specific ADA2 isoforms (ATAC ADA2a vs SAGA ADA2b) differentially stimulating GCN5 (PMID:9224714, PMID:9343382, PMID:26468280). A third set addresses human ADA enzymatic activity, whose deficiency causes toxic purine accumulation impairing TCR signaling (PMID:18218852), Treg suppressive function via the CD39/CD73/adenosine axis (PMID:22184407), bone homeostasis via RANKL/OPG imbalance (PMID:19633200), and brain adenosine receptor signaling (PMID:28074903). These three groups describe unrelated proteins sharing the ADA/Ada symbol.

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1982 Medium

    Established that Ada is a regulatory locus required for the inducible adaptive response, not merely the repair enzyme itself, since ada mutants retain basal methyltransferase but cannot upregulate it.

    Evidence In vitro enzyme assay on radiolabeled DNA comparing wild-type and ada mutant E. coli strains

    PMID:6749819

    Open questions at the time
    • Did not define the molecular activity of the Ada gene product
    • Single genetic study without biochemical mechanism
  2. 1985 High

    Defined Ada as a suicidal methyltransferase that transfers methyl from O6-methylguanine to its own cysteines, identifying the repair chemistry and protein.

    Evidence Protein purification, in vitro methyltransferase assay, DNA sequencing and S1 mapping in E. coli

    PMID:2987251 PMID:3929077

    Open questions at the time
    • Did not resolve which cysteine accepts which methyl group
    • Mechanism linking methylation to transcription not established
  3. 1988 High

    Showed that methylation of Cys-69 by methylphosphotriester transfer—reproducible with chemical methylating agents—converts Ada into a transcriptional activator, mechanistically coupling DNA damage sensing to gene induction.

    Evidence In vitro transcription reconstitution and promoter mutagenesis with purified methylated/unmethylated Ada

    PMID:2843522 PMID:3139888

    Open questions at the time
    • Direct DNA binding by methylated Ada not yet demonstrated
    • RNA polymerase contacts undefined
  4. 1989 High

    Demonstrated that methylated Ada binds the ada promoter regulatory sequence and facilitates RNA polymerase binding, and that Cys-69 (not Cys-321) methylation is specifically required, separating the repair and regulatory functions.

    Evidence DNase I footprinting and in vitro transcription with Cys69Ala/Cys321Ala site-directed mutants

    PMID:2648001

    Open questions at the time
    • Biophysical nature of DNA binding not quantified
    • Specific RNA polymerase subunit contacts not mapped
  5. 1990 High

    Established the self-limiting architecture of the response: proteolytic cleavage removes the ada activator and generates a 20-kDa fragment that activates alkA but represses ada, terminating the adaptive response; DNA binding was also characterized biophysically.

    Evidence Truncated Ada overexpression, in vitro transcription, in vivo reporters, and fluorescence anisotropy DNA-binding analysis

    PMID:2254928 PMID:2354146

    Open questions at the time
    • Identity and regulation of the endogenous protease not fully defined
    • Structural basis of differential ada vs alkA promoter behavior unresolved
  6. 1994 High

    Refined the regulatory logic by showing unmethylated Ada antagonizes methylated-Ada activation of ada (requiring the C-terminal 67 residues), establishing Ada as both positive and negative modulator of its own expression.

    Evidence In vitro and in vivo transcription assays with C-terminal deletion mutants of Ada

    PMID:7937881

    Open questions at the time
    • Structural basis of the inhibitory interaction not defined
    • Promoter-specificity of inhibition mechanism unexplained
  7. 1993 High

    Identified Ada as a class I transcription factor requiring the RNA polymerase alpha C-terminal domain, then mapped a direct activating contact with the sigma70 C-terminal region (Glu575), defining the activation interface.

    Evidence In vitro transcription with alpha- and sigma-subunit deletion and point mutants

    PMID:8468304 PMID:9582376

    Open questions at the time
    • Atomic structure of the Ada–RNA polymerase contact not solved
    • Stoichiometry of the activation complex unknown
  8. 1994 High

    Resolved the switch mechanism structurally, showing methylated Cys-69 remains zinc-coordinated and that ligand exchange at zinc is not the switch, and solved the C-terminal repair domain structure revealing a buried active-site cysteine.

    Evidence Isotope-edited NMR of 13C-methyl-Cys69, Zn/Cd substitution, and X-ray crystallography of Ada-C

    PMID:8156986 PMID:9383376

    Open questions at the time
    • How surface remodeling enables DNA binding not yet visualized
    • Conformational change enabling repair-domain DNA access only proposed
  9. 1997 High

    Characterized the repair domain's substrate determinants, showing active-site steric mutations (A316P, W336A) expand reactivity toward O6-benzylguanine and that DNA binding activates Ada-C.

    Evidence Active-site site-directed mutagenesis and in vitro alkyltransferase assays with defined substrates

    PMID:9079656

    Open questions at the time
    • Physiological relevance of expanded substrate range unaddressed
    • Coupling of DNA binding to catalysis not structurally resolved
  10. 2005 High

    Provided the definitive electrostatic-switch model: structures of methylated N-Ada bound to DNA show Cys69 methylation neutralizes negative charge at the zinc center, converting phosphate repulsion to attraction and unifying repair and transcriptional functions.

    Evidence X-ray and NMR structures of methylated N-Ada–DNA complex with EXAFS/XANES and functional validation

    PMID:11284682 PMID:16209950

    Open questions at the time
    • Full-length Ada–promoter–RNA polymerase assembly structure not determined
    • Dynamics of the surface remodeling not characterized
  11. 1999 High

    Established that eukaryotic Ada2/Ada3 subunits scaffold GCN5 into distinct nucleosome-acetylating complexes (ADA and SAGA), conferring nucleosomal HAT activity absent in free GCN5 and revealing ADA as a bona fide separate complex via the Ahc1 subunit.

    Evidence Biochemical fractionation, nucleosomal HAT assays, MS identification, and deletion analysis in yeast

    PMID:10490601 PMID:9224714

    Open questions at the time
    • These findings concern a distinct protein from bacterial Ada sharing the symbol
    • Mechanism by which Ada subunits stimulate GCN5 not defined here
  12. 2000 Medium

    Linked the ADA/GCN5 co-activator subunits to chromatin antagonism with SWI/SNF and to nuclear receptor activation (glucocorticoid and thyroid hormone receptors) through direct Ada2/GCN5 contacts.

    Evidence Yeast genetic epistasis, GST pulldowns with purified proteins, and HAT assays

    PMID:10809234 PMID:9154805 PMID:9343382

    Open questions at the time
    • Direct receptor-Ada2 interactions shown in single labs
    • Concerns the eukaryotic ADA co-activator, distinct from bacterial Ada and human adenosine deaminase
  13. 2015 High

    Defined how metazoan complex context tunes GCN5: ATAC (ADA2a) and SAGA (ADA2b) both target H3K14 but ADA2b stimulates GCN5 more strongly, and holo-complex incorporation further boosts activity, with SAGA architecture mapped structurally.

    Evidence In vitro HAT assays with reconstituted modules/holo-complexes and cryo-EM plus cross-linking MS

    PMID:25713136 PMID:26468280

    Open questions at the time
    • Mechanism of differential ADA2a vs ADA2b stimulation not structurally resolved
    • Distinct protein from the human adenosine deaminase ADA
  14. 2017 Medium

    Established the physiological consequences of human ADA enzymatic deficiency across systems—T-cell receptor signaling, Treg suppressive function, bone homeostasis, and brain adenosine signaling—via toxic purine/adenosine accumulation.

    Evidence ADA-deficient mouse models and patient-derived T cells with signaling, suppression, bone, and metabolic readouts plus therapeutic rescue (ERT/BMT/gene therapy)

    PMID:18218852 PMID:19633200 PMID:22184407 PMID:28074903

    Open questions at the time
    • These describe human adenosine deaminase, a distinct enzyme from the bacterial/eukaryotic Ada in this corpus
    • Intrinsic versus adenosine-mediated contributions only partially separated

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how the full bacterial Ada–promoter–RNA polymerase activation complex is structurally assembled and how the surface electrostatic switch is communicated to the holoenzyme; the corpus also conflates three distinct ADA/Ada proteins.
  • No atomic structure of the activator-bound transcription initiation complex
  • Symbol collision among bacterial Ada repair regulator, eukaryotic ADA co-activator subunit, and human adenosine deaminase

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140097 catalytic activity, acting on DNA 4 GO:0140110 transcription regulator activity 4 GO:0003677 DNA binding 3 GO:0016740 transferase activity 3 GO:0140096 catalytic activity, acting on a protein 2
Pathway
R-HSA-74160 Gene expression (Transcription) 4 R-HSA-4839726 Chromatin organization 3 R-HSA-73894 DNA Repair 2
Partners
ADA2ADA3GCN5SPT7TRA1
Complex memberships
ADA complexATACSAGA

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1985 The E. coli Ada protein (38–39 kDa) transfers methyl groups from O6-methylguanine residues in alkylated DNA to its own cysteine residues, functioning as a suicidal methyltransferase; the protein comprises 354 amino acids and the promoter was mapped by S1 nuclease. Protein purification, in vitro methyltransferase assay, DNA sequencing, S1 nuclease mapping The Journal of biological chemistry High 2987251
1985 Ada protein acts as a positive autogenous regulator: cloned ada gene product induces expression of O6-methylguanine-DNA methyltransferase and 3-methyladenine-DNA glycosylase II even without alkylating agent treatment, and induction is strongly enhanced by methylating agents, demonstrating that the methylated Ada protein promotes transcription of its own gene. Cloning in multicopy plasmids, beta-galactosidase reporter (ada'-lacZ fusion), enzyme activity assays in vivo Mutation research High 3929077
1982 The ada mutation is in a regulatory locus controlling O6-methylguanine-DNA methyltransferase induction; ada mutants contain basal methyltransferase but cannot upregulate it upon alkylation treatment, showing Ada is required for the adaptive transcriptional response. In vitro enzyme assay with synthetic radiolabeled DNA substrate, comparison of wild-type and ada mutant strains Journal of bacteriology Medium 6749819
1988 Methylation of Ada protein at Cys-69 (by methyl phosphotriester transfer) converts Ada into a transcriptional activator; direct methylation of purified Ada protein by chemical methylating agents (methyl methanesulfonate, methyl iodide) also activates its ability to promote ada gene transcription in a reconstituted in vitro system. In vitro transcription reconstitution with purified methylated/unmethylated Ada protein The Journal of biological chemistry High 2843522
1988 Ada protein expression is controlled by an ada regulatory sequence (AAAGCGCA) located upstream of the -35 box; both -10 and -35 promoter elements and this regulatory sequence are required for controlled ada expression. Methylated Ada protein is required for in vitro ada-specific transcription. Random and site-directed mutagenesis of ada promoter, deletion analysis, in vitro transcription Journal of molecular biology High 3139888
1988 Ada protein is cleaved by an endogenous E. coli thiol protease into a 20-kDa N-terminal fragment (which retains methylphosphotriester methyltransferase activity and can promote alkA but not ada transcription when methylated) and a 19-kDa C-terminal fragment (which retains O6-methylguanine methyltransferase activity); neither fragment alone promotes ada transcription. Partial purification of Ada-specific protease, proteolysis assay, activity assays on isolated fragments The Journal of biological chemistry High 3058696
1989 Methylated Ada protein binds the ada promoter (positions -63 to -31) including the AAAGCGCA regulatory sequence; non-methylated Ada does not bind stably. Methylation of Cys-69 (not Cys-321) is specifically required for Ada binding to the ada promoter and for facilitating subsequent RNA polymerase binding. The methylated Ada protein also allows RNA polymerase to bind properly, initiating transcription. DNase I footprinting, in vitro transcription with site-specific Ada mutants (Cys69Ala, Cys321Ala), promoter mutant analysis Journal of molecular biology High 2648001
1990 The methylated 20-kDa N-terminal Ada fragment binds the alkA regulatory sequence and facilitates RNA polymerase binding to the alkA promoter, activating alkA transcription in vitro. The same methylated 20-kDa protein binds the ada promoter but does not support RNA polymerase binding there, thus acting as a repressor of ada transcription. Proteolytic cleavage of Ada terminates the adaptive response by removing the activator and generating a repressor. Overexpression of truncated Ada, in vitro transcription, in vivo reporter assays Journal of molecular biology High 2254928
1990 Ada protein binds DNA non-cooperatively; approximately 7 bp are covered per Ada monomer; binding is ionic in nature (equilibrium association constant decreases with increasing NaCl), as measured by fluorescence anisotropy. Fluorescence anisotropy of Ada protein upon DNA binding; quantitative binding analysis Biochemistry Medium 2354146
1993 Methylated Ada protein is a class I transcription factor: it requires the C-terminal domain of the RNA polymerase alpha subunit for transcriptional activation, as demonstrated by loss of Ada-dependent activation with C-terminal-deleted alpha subunit mutant RNA polymerases. In vitro transcription with mutant RNA polymerases bearing C-terminal-deleted alpha subunits Journal of bacteriology High 8468304
1994 Crystal structure of the 19-kDa C-terminal domain of E. coli Ada (Ada-C), the O6-methylguanine-DNA methyltransferase domain, shows the active-site cysteine is buried; a conformational change is proposed to allow DNA binding and methyl transfer. X-ray crystallography The EMBO journal High 8156986
1994 Unmethylated Ada at physiologically relevant concentrations specifically inhibits methylated Ada activation of ada transcription (but not alkA transcription) both in vitro and in vivo; this requires the C-terminal 67 amino acids of Ada. This establishes Ada as both a positive and negative modulator of its own expression. In vitro transcription assay, in vivo reporter assays, C-terminal deletion mutants of Ada Proceedings of the National Academy of Sciences of the United States of America High 7937881
1994 In the methylated Ada protein–DNA complex, S-methylcysteine-69 (S-Me-Cys69) remains coordinated to the zinc ion; ligand exchange at the zinc center is not the mechanism for switching Ada from repair to transcriptional activator mode. Isotope-edited NMR (13C-labeled methyl group at Cys69), comparison of Zn- and Cd-substituted forms Chemistry & biology High 9383376
1997 Ada protein-dependent transcriptional activation at the ada and aidB promoters requires direct interaction between methylated Ada and the C-terminal domain of the RNA polymerase sigma70 subunit (amino acids 574–613); several negatively charged residues in sigma70 (notably Glu575) are critical. The alpha subunit C-terminal domain allows initial RNA polymerase binding, while sigma70 interaction drives activation. Deletion mutagenesis of RNA polymerase alpha and sigma subunits, in vitro transcription, site-directed mutagenesis of sigma70 The Journal of biological chemistry High 9582376
1997 E. coli Ada-C protein can repair O6-benzylguanine in DNA, but very slowly compared to human alkyltransferase and E. coli Ogt; two active-site mutations (A316P and W336A) that enlarge the substrate-binding pocket of Ada-C greatly increase its reactivity with O6-benzylguanine, and DNA binding activates Ada-C for this reaction. Site-directed mutagenesis, in vitro alkyltransferase assay, substrate competition experiments The Journal of biological chemistry High 9079656
2001 NMR solution structure of the N-terminal 10-kDa Ada domain (N-Ada10) reveals the zinc-thiolate center; EXAFS/XANES data confirm that S-Me-Cys69 remains coordinated to zinc upon methylation. The transferred methyl group makes contacts within N-Ada but not with DNA, implying that methylation induces a conformational change that remodels the protein surface to enhance promoter DNA binding without direct methyl-DNA contact. NMR structure determination, EXAFS/XANES spectroscopy, NOESY of labeled methylated Ada–DNA complexes Biochemistry High 11284682
2005 X-ray and solution structures of the methylated N-terminal Ada chemosensor domain bound to DNA reveal that methyl phosphotriester repair and methylation-dependent transcriptional activation both operate through a zinc- and methylation-dependent electrostatic switch: methylation of Cys69 neutralizes a negative charge at the zinc center, converting a repulsive to an attractive interaction with DNA phosphates, thereby switching Ada from a repair protein to a transcriptional activator. X-ray crystallography and NMR of methylated N-Ada–DNA complex; functional validation Molecular cell High 16209950
1997 In yeast, Gcn5 (which contains Ada protein homologs as subunits) functions as the catalytic histone acetyltransferase subunit in two distinct native complexes: the 0.8-MDa ADA complex and the 1.8-MDa SAGA complex. Both complexes contain Ada2 and can acetylate nucleosomal histones, unlike recombinant Gcn5 alone. The SAGA complex additionally contains Spt proteins linked to TBP function. Biochemical fractionation, histone acetyltransferase assays on free and nucleosomal histones, deletion mutant analysis Genes & development High 9224714
1997 Mutations in yeast ADA2, ADA3, and GCN5 (subunits of the Ada/histone acetyltransferase complex) cause phenotypes similar to swi/snf mutants and are required for expression of SWI/SNF-dependent genes; ada and swi1 double mutants are inviable; SIN1 mutations (chromatin component) or histone H3/H4 mutations partially suppress ada/swi defects, establishing that ADA/GCN5 and SWI/SNF complexes cooperate to antagonize chromatin-mediated repression. Yeast genetics, epistasis analysis, double mutant viability, partial purification of three GCN5-dependent acetyltransferase activities Molecular and cellular biology High 9343382
1998 Tra1p is a component of yeast Ada/Spt transcriptional regulatory complexes; its association with Ada.Spt complexes was established by tandem mass spectrometry of Ngg1p/Ada3p co-purified proteins and confirmed by reciprocal co-immunoprecipitation of Ada2p and Tra1p. Tra1p co-fractionates with Ngg1p and Spt7p; binding of Tra1p to DNA-cellulose requires Ada components. Tandem mass spectrometry, reciprocal co-immunoprecipitation, sequential chromatography The Journal of biological chemistry High 9756893
1999 The yeast ADA complex (0.8 MDa) is a distinct histone acetyltransferase complex separate from SAGA, containing Ada2, Ada3, Gcn5, and a novel unique subunit Ahc1 (product of YOR023C); deletion of AHC1 disrupts ADA complex integrity without affecting SAGA, demonstrating that ADA is not merely a SAGA subcomplex. 10-step chromatographic purification, mass spectrometry, immunoblotting, deletion mutant analysis Molecular and cellular biology High 10490601
1997 The yeast Ada adaptor complex is important for glucocorticoid receptor (GR)-mediated gene activation; Ada2 directly binds the GR tau1c transactivation domain in vitro using purified proteins and GST-pulldown, and this interaction is reduced by a mutation that reduces tau1c transactivation. Yeast genetics (ada mutant phenotype), GST pulldown with purified proteins, in vitro protein-protein interaction Molecular and cellular biology Medium 9154805
2000 In yeast, GCN5, ADA2, ADA1, and ADA3 are required for T3/GRIP1 or SRC-1 coactivator-dependent transcriptional activation by human thyroid hormone receptor beta1 (hTRbeta1); hTRbeta1 binds directly to yeast or human GCN5 and to hADA2 in vitro; T3-dependent binding of hTRbeta1 to hGCN5 is enhanced by GRIP1 or SRC-1. The HAT domain and bromodomain of GCN5 must be intact for maximal activation. Yeast genetic epistasis, in vitro protein-protein interaction (GST pulldown with purified proteins), mutagenesis of GRIP1 LXXLL motifs Molecular endocrinology (Baltimore, Md.) Medium 10809234
2015 In metazoans, GCN5 is incorporated into two distinct HAT complexes: ATAC (containing ADA2a) and SAGA (containing ADA2b). The subunit environment determines GCN5 catalytic activity: all tested GCN5-containing complexes acetylate mainly histone H3K14, but ADA2b has a stronger stimulatory influence on GCN5 activity than ADA2a. Incorporation into holo-complexes further increases GCN5 activity beyond the HAT module alone. In vitro HAT assay with purified recombinant and endogenous ATAC/SAGA HAT modules and holo-complexes using histone peptides and full-length histones The Journal of biological chemistry High 26468280
2015 The SAGA complex adopts three major conformations; the acetyltransferase module is localized in the most mobile region. Cross-linking mass spectrometry mapped comprehensive subunit interconnectivity, showing that Spt and Taf subunits form the structural core, and chromatin-binding domains cluster on one flexible face. Gradient fixation, single-particle EM (2D and 3D), EM-based subunit labeling, cross-linking mass spectrometry The Journal of biological chemistry High 25713136
2011 In ADA-deficient mice, Tregs show alterations in plasma membrane CD39/CD73 ectonucleotidase machinery and have limited suppressive activity via extracellular adenosine; ADA deficiency causes loss of Treg function contributing to autoimmunity. PEG-ADA-treated mice develop autoantibodies and hypothyroidism and have Tregs lacking suppressive activity, whereas bone marrow transplantation or gene therapy corrects Treg function. Functional Treg suppression assays, flow cytometry, mouse genetic models (ADA-/- mice), treatment comparisons (PEG-ADA, BMT, gene therapy) Blood Medium 22184407
2009 ADA deficiency in mice causes a bone phenotype resulting from RANKL/OPG axis imbalance (decreased osteoclastogenesis) and intrinsic osteoblast dysfunction (reduced bone formation); ADA-deficient osteoblasts in vitro show altered transcriptional profile and growth reduction. Treatment with ERT, BMT, or gene therapy fully rescues the bone phenotype. Mouse genetic model (ADA-/- mice), structural bone analysis, in vitro osteoblast culture, RANKL/OPG quantification, treatment rescue experiments Blood Medium 19633200
2008 In ADA-SCID patients, ADA substrate accumulation causes impaired TCR/CD28-driven T-cell proliferation and cytokine production associated with reduced ZAP-70 phosphorylation, Ca2+ flux, and ERK1/2 signaling, and defective CREB and NF-κB transcriptional activity. Exposure to 2'-deoxyadenosine further inhibits T-cell activation via A2A adenosine receptor/PKA hyperactivation. Gene therapy restores normal TCR signaling in patient T cells. Phosphoprotein analysis, calcium flux assay, cytokine measurement, patient T cells vs. gene-therapy-corrected T cells Blood Medium 18218852
2017 In ADA-deficient mice, metabolic alterations in the brain include aberrant adenosine receptor signaling; PEG-ADA corrects metabolic adenosine-based alterations but not cellular and signaling defects, indicating an intrinsic neurological component to ADA deficiency separate from circulating adenosine levels. Behavioral testing, molecular/metabolic analyses, treatment with PEG-ADA vs. untreated ADA-/- mice Scientific reports Medium 28074903
1990 The B. subtilis ada operon encodes two separate DNA alkyltransferases: AdaA (methylphosphotriester-DNA methyltransferase) functioning as a transcriptional activator of the ada operon, and AdaB (O6-methylguanine-DNA methyltransferase) functioning specifically in repair of mutagenic O6-methylguanine; the two genes overlap by 11 bp and are co-induced by MNNG. Complementation of ada mutants, gene cloning, transcript analysis, functional dissection of truncated constructs Nucleic acids research Medium 2120677

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes care 1940 30291106
2022 Management of Hyperglycemia in Type 2 Diabetes, 2022. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes care 1303 36148880
1997 Yeast Gcn5 functions in two multisubunit complexes to acetylate nucleosomal histones: characterization of an Ada complex and the SAGA (Spt/Ada) complex. Genes & development 927 9224714
2002 Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning. Science (New York, N.Y.) 873 12089448
2019 2019 Update to: Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes care 858 31857443
2014 Diabetic kidney disease: a report from an ADA Consensus Conference. Diabetes care 850 25249672
2018 Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 809 30288571
2022 Management of hyperglycaemia in type 2 diabetes, 2022. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 688 36151309
2022 Diabetes Management in Chronic Kidney Disease: A Consensus Report by the American Diabetes Association (ADA) and Kidney Disease: Improving Global Outcomes (KDIGO). Diabetes care 597 36189689
1995 Gene therapy in peripheral blood lymphocytes and bone marrow for ADA- immunodeficient patients. Science (New York, N.Y.) 580 7570000
2014 Diabetic kidney disease: a report from an ADA Consensus Conference. American journal of kidney diseases : the official journal of the National Kidney Foundation 446 25257325
2020 2019 update to: Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 346 31853556
1998 T lymphocytes with a normal ADA gene accumulate after transplantation of transduced autologous umbilical cord blood CD34+ cells in ADA-deficient SCID neonates. Nature medicine 250 9662367
2022 Diabetes management in chronic kidney disease: a consensus report by the American Diabetes Association (ADA) and Kidney Disease: Improving Global Outcomes (KDIGO). Kidney international 218 36202661
2007 Multilineage hematopoietic reconstitution without clonal selection in ADA-SCID patients treated with stem cell gene therapy. The Journal of clinical investigation 198 17671653
1997 Role for ADA/GCN5 products in antagonizing chromatin-mediated transcriptional repression. Molecular and cellular biology 187 9343382
2017 Gene therapy for ADA-SCID, the first marketing approval of an ex vivo gene therapy in Europe: paving the road for the next generation of advanced therapy medicinal products. EMBO molecular medicine 184 28396566
1994 Crystal structure of a suicidal DNA repair protein: the Ada O6-methylguanine-DNA methyltransferase from E. coli. The EMBO journal 176 8156986
2009 How I treat ADA deficiency. Blood 164 19638621
1999 The ADA complex is a distinct histone acetyltransferase complex in Saccharomyces cerevisiae. Molecular and cellular biology 156 10490601
1985 Purification and structure of the intact Ada regulatory protein of Escherichia coli K12, O6-methylguanine-DNA methyltransferase. The Journal of biological chemistry 129 2987251
1998 Tra1p is a component of the yeast Ada.Spt transcriptional regulatory complexes. The Journal of biological chemistry 113 9756893
2018 Systematic Review for the 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 94 30586775
2018 Systematic Review for the 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Journal of the American College of Cardiology 89 30423394
1990 The ADA human gene therapy clinical protocol. Human gene therapy 89 2081198
2017 Adenosine Deaminase (ADA)-Deficient Severe Combined Immune Deficiency (SCID): Molecular Pathogenesis and Clinical Manifestations. Journal of clinical immunology 81 28842866
2004 Mutations in genes required for T-cell development: IL7R, CD45, IL2RG, JAK3, RAG1, RAG2, ARTEMIS, and ADA and severe combined immunodeficiency: HuGE review. Genetics in medicine : official journal of the American College of Medical Genetics 81 14726805
2011 Alterations in the adenosine metabolism and CD39/CD73 adenosinergic machinery cause loss of Treg cell function and autoimmunity in ADA-deficient SCID. Blood 79 22184407
1989 Retroviral vector-mediated high-efficiency expression of adenosine deaminase (ADA) in hematopoietic long-term cultures of ADA-deficient marrow cells. Proceedings of the National Academy of Sciences of the United States of America 76 2549545
2017 Twenty-Five Years of Gene Therapy for ADA-SCID: From Bubble Babies to an Approved Drug. Human gene therapy 70 28847159
1982 O6-methylguanine-DNA methyltransferase in wild-type and ada mutants of Escherichia coli. Journal of bacteriology 67 6749819
2005 A methylation-dependent electrostatic switch controls DNA repair and transcriptional activation by E. coli ada. Molecular cell 66 16209950
2006 Ex vivo gene therapy with lentiviral vectors rescues adenosine deaminase (ADA)-deficient mice and corrects their immune and metabolic defects. Blood 63 16835374
2009 ADA-deficient SCID is associated with a specific microenvironment and bone phenotype characterized by RANKL/OPG imbalance and osteoblast insufficiency. Blood 61 19633200
2008 Altered intracellular and extracellular signaling leads to impaired T-cell functions in ADA-SCID patients. Blood 58 18218852
1997 Role of the Ada adaptor complex in gene activation by the glucocorticoid receptor. Molecular and cellular biology 58 9154805
2013 Evaluating pleural ADA, ADA2, IFN-γ and IGRA for diagnosing tuberculous pleurisy. The Journal of infection 55 23796864
1990 Bacillus subtilis ada operon encodes two DNA alkyltransferases. Nucleic acids research 54 2120677
1991 Cloning and characterization of the Salmonella typhimurium ada gene, which encodes O6-methylguanine-DNA methyltransferase. Journal of bacteriology 51 1904855
2006 In vivo transduction by intravenous injection of a lentiviral vector expressing human ADA into neonatal ADA gene knockout mice: a novel form of enzyme replacement therapy for ADA deficiency. Molecular therapy : the journal of the American Society of Gene Therapy 50 16651028
1997 Repair of O6-benzylguanine by the Escherichia coli Ada and Ogt and the human O6-alkylguanine-DNA alkyltransferases. The Journal of biological chemistry 50 9079656
2015 Conformational flexibility and subunit arrangement of the modular yeast Spt-Ada-Gcn5 acetyltransferase complex. The Journal of biological chemistry 49 25713136
2000 GCN5 and ADA adaptor proteins regulate triiodothyronine/GRIP1 and SRC-1 coactivator-dependent gene activation by the human thyroid hormone receptor. Molecular endocrinology (Baltimore, Md.) 49 10809234
1987 DNA base changes induced following in vivo exposure of unadapted, adapted or ada- Escherichia coli to N-methyl-N'-nitro-N-nitrosoguanidine. Molecular & general genetics : MGG 49 3323828
2022 Outcomes following treatment for ADA-deficient severe combined immunodeficiency: a report from the PIDTC. Blood 48 35671392
1989 Regulation of expression of the ada gene controlling the adaptive response. Interactions with the ada promoter of the Ada protein and RNA polymerase. Journal of molecular biology 48 2648001
2015 Subunits of ADA-two-A-containing (ATAC) or Spt-Ada-Gcn5-acetyltrasferase (SAGA) Coactivator Complexes Enhance the Acetyltransferase Activity of GCN5. The Journal of biological chemistry 45 26468280
1990 Positive and negative regulation of transcription by a cleavage product of Ada protein. Journal of molecular biology 44 2254928
1995 PEG-ADA: an alternative to haploidentical bone marrow transplantation and an adjunct to gene therapy for adenosine deaminase deficiency. Human mutation 41 7749407
2020 Characterization of total adenosine deaminase activity (ADA) and its isoenzymes in saliva and serum in health and inflammatory conditions in four different species: an analytical and clinical validation pilot study. BMC veterinary research 39 33046093
2017 Alterations in the brain adenosine metabolism cause behavioral and neurological impairment in ADA-deficient mice and patients. Scientific reports 39 28074903
1993 Transfer of the ADA gene into bone marrow cells and peripheral blood lymphocytes for the treatment of patients affected by ADA-deficient SCID. Human gene therapy 39 8399494
1989 Expression of the ogt gene in wild-type and ada mutants of E. coli. Nucleic acids research 39 2682522
1988 Expression of the ada gene of Escherichia coli in response to alkylating agents. Identification of transcriptional regulatory elements. Journal of molecular biology 37 3139888
1994 The Ada protein acts as both a positive and a negative modulator of Escherichia coli's response to methylating agents. Proceedings of the National Academy of Sciences of the United States of America 36 7937881
1992 Transfer of the ADA gene into human ADA-deficient T lymphocytes reconstitutes specific immune functions. Blood 36 1325209
1985 Regulation of expression of the cloned ada gene in Escherichia coli. Mutation research 36 3929077
2017 How We Manage Adenosine Deaminase-Deficient Severe Combined Immune Deficiency (ADA SCID). Journal of clinical immunology 34 28194615
2016 Development of Immunocapture-LC/MS Assay for Simultaneous ADA Isotyping and Semiquantitation. Journal of immunology research 34 27034966
1998 Ada protein-RNA polymerase sigma subunit interaction and alpha subunit-promoter DNA interaction are necessary at different steps in transcription initiation at the Escherichia coli Ada and aidB promoters. The Journal of biological chemistry 34 9582376
1990 Interaction of Ada protein with DNA examined by fluorescence anisotropy of the protein. Biochemistry 34 2354146
2022 2021 White Paper on Recent Issues in Bioanalysis: TAb/NAb, Viral Vector CDx, Shedding Assays; CRISPR/Cas9 & CAR-T Immunogenicity; PCR & Vaccine Assay Performance; ADA Assay Comparability & Cut Point Appropriateness (Part 3 - Recommendations on Gene Therapy, Cell Therapy, Vaccine Assays; Immunogenicity of Biotherapeutics and Novel Modalities; Integrated Summary of Immunogenicity Harmonization). Bioanalysis 33 35578991
2012 Gene therapy/bone marrow transplantation in ADA-deficient mice: roles of enzyme-replacement therapy and cytoreduction. Blood 33 22833548
2017 ADA-07 Suppresses Solar Ultraviolet-Induced Skin Carcinogenesis by Directly Inhibiting TOPK. Molecular cancer therapeutics 30 28655782
2014 Ada response - a strategy for repair of alkylated DNA in bacteria. FEMS microbiology letters 30 24810496
2013 The inclusion of ADA-SCID in expanded newborn screening by tandem mass spectrometry. Journal of pharmaceutical and biomedical analysis 30 24076575
1993 Bacillus subtilis alkA gene encoding inducible 3-methyladenine DNA glycosylase is adjacent to the ada operon. Journal of bacteriology 29 8376346
2023 Use of sodium-glucose co-transporter 2 inhibitors and glucagon-like peptide-1 receptor agonists according to the 2019 ESC guidelines and the 2019 ADA/EASD consensus report in a national population of patients with type 2 diabetes. European journal of preventive cardiology 28 36582120
2023 A new andrographolide derivative ADA targeting SIRT3-FOXO3a signaling mitigates cognitive impairment by activating mitophagy and inhibiting neuroinflammation in Apoe4 mice. Phytomedicine : international journal of phytotherapy and phytopharmacology 28 38185066
2018 ADA Deficiency: Evaluation of the Clinical and Laboratory Features and the Outcome. Journal of clinical immunology 28 29744787
2007 Bacterial DNA repair genes and their eukaryotic homologues: 3. AlkB dioxygenase and Ada methyltransferase in the direct repair of alkylated DNA. Acta biochimica Polonica 28 17823664
2005 Tuberculous effusion: ADA activity correlates with CD4+ cell numbers in the fluid and the pleura. Respiration; international review of thoracic diseases 28 15824526
1989 Enhanced O6-methylguanine-DNA methyltransferase activity in transgenic mice containing an integrated E. coli ada repair gene. Mutation research 28 2530449
2024 A case of T-cell acute lymphoblastic leukemia in retroviral gene therapy for ADA-SCID. Nature communications 27 38688902
2022 Zinc normalizes hepatic lipid handling via modulation of ADA/XO/UA pathway and caspase 3 signaling in highly active antiretroviral therapy-treated Wistar rats. Chemico-biological interactions 27 36309141
2017 Cytoreductive conditioning intensity predicts clonal diversity in ADA-SCID retroviral gene therapy patients. Blood 27 28351939
1994 Metal-coordination sphere in the methylated Ada protein-DNA co-complex. Chemistry & biology 26 9383376
1988 Activation of Ada protein as a transcriptional regulator by direct alkylation with methylating agents. The Journal of biological chemistry 26 2843522
2020 Adenosine Deaminase (ADA)-Deficient Severe Combined Immune Deficiency (SCID) in the US Immunodeficiency Network (USIDNet) Registry. Journal of clinical immunology 25 32880085
2015 Spt-Ada-Gcn5-Acetyltransferase (SAGA) Complex in Plants: Genome Wide Identification, Evolutionary Conservation and Functional Determination. PloS one 25 26263547
2011 The ada operon of Mycobacterium tuberculosis encodes two DNA methyltransferases for inducible repair of DNA alkylation damage. DNA repair 25 21570366
2007 ADA*2 allele of the adenosine deaminase gene may protect against coronary artery disease. Cardiology 25 17287605
1988 Rapid, large-scale purification and characterization of 'Ada protein' (O6 methylguanine-DNA methyltransferase) of E. coli. Nucleic acids research 25 3041376
2018 2018 White Paper on Recent Issues in Bioanalysis: focus on immunogenicity assays by hybrid LBA/LCMS and regulatory feedback (Part 2 - PK, PD & ADA assays by hybrid LBA/LCMS & regulatory agencies' inputs on bioanalysis, biomarkers and immunogenicity). Bioanalysis 24 30488729
2001 Structural basis for the functional switch of the E. coli Ada protein. Biochemistry 24 11284682
1990 High level, regulated expression of the chimeric P-enolpyruvate carboxykinase (GTP)-bacterial O6-alkylguanine-DNA alkyltransferase (ada) gene in transgenic mice. Cancer research 24 2407342
1989 Cloning and expression of the Bacillus subtilis methyltransferase gene in Escherichia coli ada- cells. Mutation research 24 2505068
1985 Adenosine deaminase (ADA) in leukemia: clinical value of plasma ADA activity and characterization of leukemic cell ADA. American journal of hematology 24 3985005
2002 Advances in gene therapy for ADA-deficient SCID. Current opinion in molecular therapeutics 23 12435054
2019 Effect of quercetin on E-NTPDase/E-ADA activities and cytokine secretion of complete Freund adjuvant-induced arthritic rats. Cell biochemistry and function 22 31365139
1993 The Ada protein is a class I transcription factor of Escherichia coli. Journal of bacteriology 22 8468304
2018 Evaluation of ADA HbA1c criteria in the diagnosis of pre-diabetes and diabetes in a population of Chinese adolescents and young adults at high risk for diabetes: a cross-sectional study. BMJ open 21 30093511
2011 Analysis of serum adenosine deaminase (ADA) and ADA1 and ADA2 isoenzyme activities in HIV positive and HIV-HBV co-infected patients. Clinical biochemistry 21 21640091
1991 Enhanced repair of O6-methylguanine DNA adducts in the liver of transgenic mice expressing the ada gene. Cancer research 21 2054779
2023 3D bioprinting of multifunctional alginate dialdehyde (ADA)-gelatin (GEL) (ADA-GEL) hydrogels incorporating ferulic acid. International journal of biological macromolecules 20 38029911
2014 DNA binding by Sgf11 protein affects histone H2B deubiquitination by Spt-Ada-Gcn5-acetyltransferase (SAGA). The Journal of biological chemistry 20 24509845
2007 Pleural fluid ADA, IgA-ELISA and PCR sensitivities for the diagnosis of pleural tuberculosis. Scandinavian journal of clinical and laboratory investigation 20 17852820
2019 Dosing and Re-Administration of Lentiviral Vector for In Vivo Gene Therapy in Rhesus Monkeys and ADA-Deficient Mice. Molecular therapy. Methods & clinical development 19 31871959
1999 The dental team and latex hypersensitivity. ADA Council on Scientific Affairs. Journal of the American Dental Association (1939) 19 10036850
1988 Proteolytic cleavage of Ada protein that carries methyltransferase and transcriptional regulator activities. The Journal of biological chemistry 18 3058696

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