Affinage

ADA

Adenosine deaminase · UniProt P00813

Round 2 corrected
Length
363 aa
Mass
40.8 kDa
Annotated
2026-04-28
130 papers in source corpus 20 papers cited in narrative 20 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ADA (adenosine deaminase 1) is a purine-metabolizing enzyme that catalyzes the irreversible deamination of adenosine and 2′-deoxyadenosine to inosine and 2′-deoxyinosine, functioning both intracellularly to prevent toxic substrate accumulation and extracellularly as an ectoenzyme anchored to the cell surface via CD26/DPP4 and adenosine receptors, where it regulates local adenosine concentrations and provides catalysis-independent costimulatory signals at the immunological synapse (PMID:8101391, PMID:15983379, PMID:23897810). ADA deficiency causes severe combined immunodeficiency (SCID) through impaired T-cell receptor signaling—specifically reduced ZAP-70 phosphorylation, Ca²⁺ flux, ERK1/2 activation, and NF-κB transcriptional activity—as well as skeletal defects from osteoblast dysfunction and neurological abnormalities linked to aberrant adenosine receptor signaling, defects that are correctable by gene therapy or enzyme replacement (PMID:18218852, PMID:19633200, PMID:28074903). A common functional polymorphism (G22A/Asp8Asn) that reduces ADA activity enhances slow-wave sleep in humans, establishing ADA-mediated adenosine catabolism as a direct regulator of sleep homeostasis (PMID:16221767). ADA also competitively inhibits MERS-CoV binding to its receptor DPP4/CD26, and its inosine product can serve as an alternative metabolic fuel for T cells in immunosuppressive tumor microenvironments (PMID:24257613, PMID:38688275).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1984 High

    Establishing the chromosomal locus and nature of ADA-SCID mutations resolved whether deficiency arose from transcriptional silencing or protein-level dysfunction, showing that SCID cells produce ADA mRNA encoding a structurally altered, catalytically inactive protein.

    Evidence Northern blot, in vitro translation, and immunoprecipitation of SCID-derived ADA mRNA products; somatic cell hybridization mapped ADA to 20q13.2

    PMID:6198631 PMID:6370091

    Open questions at the time
    • Specific point mutations causing misfolding were not identified
    • No structural basis for loss of immunoreactivity
  2. 1986 High

    Complete gene characterization revealed an unusual TATA-less, GC-rich promoter architecture with SP1-dependent regulation, defining the transcriptional control elements of ADA and enabling future gene therapy vector design.

    Evidence Cosmid/phage clone sequencing and functional promoter assays identified 12 exons over ~32–37 kb with six SP1-binding motifs

    PMID:3028473 PMID:3839456

    Open questions at the time
    • Cell-type-specific enhancer elements not characterized
    • Regulation of tissue-variable ADA expression not explained by promoter alone
  3. 1993 High

    Identification of CD26/DPP4 as the surface anchor for ADA transformed understanding of ADA from a purely intracellular metabolic enzyme to a cell-surface ectoenzyme, opening the field of ADA-mediated cell signaling.

    Evidence Amino acid sequencing of the 43-kDa CD26-associated protein, reciprocal immunoprecipitation, and in vitro binding assays

    PMID:8101391

    Open questions at the time
    • Stoichiometry and affinity of the ADA–CD26 complex not quantified
    • Whether ADA binding modulates CD26 peptidase activity was unknown
  4. 1997 Medium

    Extension of ADA surface-binding partners beyond CD26 to include A1 adenosine receptors broadened the ectoenzyme concept to include neuromodulatory contexts, suggesting ADA regulates adenosine tone at neuronal surfaces.

    Evidence Cell surface binding studies, signal transduction assays, and immunohistochemistry across neural tissues

    PMID:9247966

    Open questions at the time
    • Direct in vivo demonstration of ADA–A1R complex function in neurons was lacking
    • Relative contribution of A1R vs. CD26 anchoring in different tissues unclear
  5. 2005 High

    Two concurrent breakthroughs established non-enzymatic functions and physiological endpoints: ADA at the immunological synapse provides catalysis-independent costimulation amplifying cytokine production, while a human ADA polymorphism (Asp8Asn) that reduces enzymatic activity directly modulates sleep depth.

    Evidence Autologous T cell/DC cocultures with catalytically inactive ADA controls showed 3–34-fold cytokine enhancement; genotype-phenotype study with polysomnography linked G22A to enhanced slow-wave activity

    PMID:15983379 PMID:16221767

    Open questions at the time
    • Identity of the dendritic-cell ADA-anchoring protein at the synapse unresolved
    • Mechanism linking reduced ADA activity to increased slow-wave sleep not defined at the molecular level
  6. 2008 High

    Molecular dissection of ADA-SCID T cells pinpointed the signaling defects—impaired ZAP-70 phosphorylation, Ca²⁺ flux, ERK1/2, CREB, and NF-κB—and showed that deoxyadenosine additionally suppresses T cells through aberrant A2A receptor/PKA signaling; gene therapy rescued all these biochemical defects.

    Evidence Phospho-flow, Ca²⁺ flux, transcription factor assays, and apoptosis assays in ADA-SCID patient T cells pre- and post-gene therapy

    PMID:18218852

    Open questions at the time
    • Relative contribution of intracellular dATP accumulation vs. extracellular deoxyadenosine signaling not fully deconvoluted
    • Threshold of ADA restoration needed for full signaling recovery not defined
  7. 2009 High

    Discovery of a bone phenotype in ADA-deficient mice—imbalanced RANKL/OPG axis and intrinsic osteoblast dysfunction—expanded the disease spectrum beyond immunodeficiency and showed the bone marrow microenvironment depends on purine homeostasis for hematopoietic support.

    Evidence ADA-knockout mouse bone analysis, in vitro osteoblast assays, RANKL/OPG quantification, rescue by ERT/BMT/gene therapy

    PMID:19633200

    Open questions at the time
    • Specific metabolites (adenosine vs. deoxyadenosine) responsible for osteoblast dysfunction not distinguished
    • Human bone phenotype not systematically characterized
  8. 2013 High

    Two advances clarified isoform-specific biology: ADA1 (not ADA2) is the dominant extracellular adenosine-catabolizing enzyme in plasma, and ADA competes with MERS-CoV for the DPP4/CD26 binding site, revealing an unexpected antiviral role.

    Evidence Isoform-specific enzyme assays in fractionated neonatal/adult plasma; site-directed mutagenesis and viral entry competition assays for MERS-CoV–DPP4 interaction

    PMID:23897810 PMID:24257613

    Open questions at the time
    • In vivo relevance of ADA–DPP4 competition for MERS-CoV infection not tested in animal models
    • Whether low neonatal ADA1 activity contributes to neonatal infection susceptibility not established
  9. 2016 High

    Systematic mapping of ADA1 and ADA2 binding to immune cell subsets revealed complementary distribution: ADA1 binds CD26⁺ cells (including CD16⁻ monocytes) while ADA2 binds CD26⁻ cells (neutrophils, NK cells, B cells, CD39⁺ Tregs), establishing non-redundant immunomodulatory roles for each isoform.

    Evidence Flow cytometry with isoform-specific binding, validated in ADA2-deficient patient samples showing lymphocyte depletion and elevated TNF-α

    PMID:27663683

    Open questions at the time
    • Molecular identity of the ADA2 surface receptor on CD26⁻ cells not fully defined beyond proteoglycans/adenosine receptors
    • Functional consequences of ADA2 binding to specific subsets (e.g., Tregs) not mechanistically resolved
  10. 2017 High

    Neurological abnormalities in ADA-deficient mice and patients—motor dysfunction, EEG alterations, hearing loss, white matter changes—persist after enzyme replacement, revealing an intrinsic CNS component of ADA deficiency not correctable by peripheral adenosine normalization.

    Evidence Behavioral, EEG, MRI, and molecular analyses in ADA-knockout mice with PEG-ADA treatment, cross-referenced with patient neurological data

    PMID:28074903

    Open questions at the time
    • Whether neurological defects arise during a critical developmental window or are ongoing not resolved
    • Blood-brain barrier penetration of PEG-ADA not measured
  11. 2024 High

    Engineered co-expression of ADA1 and CD26 in CAR T cells demonstrated that ADA1-generated inosine serves as alternative fuel and confers resistance to adenosine-mediated and TGF-β1-mediated immunosuppression in the tumor microenvironment, translating decades of basic ADA biology into therapeutic application.

    Evidence CAR T cell engineering with membrane CD26 and cytoplasmic ADA1, validated by migration assays, suppression resistance, and anti-tumor efficacy in HCC and NSCLC mouse models

    PMID:38688275

    Open questions at the time
    • Long-term safety of constitutive ADA1 overexpression in T cells not assessed
    • Whether inosine fuel utilization or adenosine depletion is the dominant mechanism in vivo not deconvoluted

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the identity of the dendritic-cell ADA-anchoring protein at the immunological synapse, the molecular mechanism by which ADA activity modulates sleep homeostasis, the developmental timing of irreversible CNS damage in ADA deficiency, and the structural basis for ADA1 vs. ADA2 receptor selectivity.
  • No structural model of the ADA–A1R or ADA2–proteoglycan complex exists
  • In vivo isoform-specific roles in different tissue niches remain poorly quantified
  • Whether ADA1 enzymatic and costimulatory functions are separable in a therapeutic context is untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 5 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 5 GO:0005829 cytosol 3 GO:0005576 extracellular region 2
Pathway
R-HSA-1430728 Metabolism 5 R-HSA-168256 Immune System 5 R-HSA-162582 Signal Transduction 4
Partners
ADORA1ADORA2AADORA2BADORA3DPP4

Evidence

Reading pass · 20 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1985 The human ADA gene is 32 kb long, split into 12 exons, and its promoter region lacks TATA and CAAT boxes but is extremely G/C-rich (82%), containing SP1-binding motifs (GGGCGGG); a 135 bp upstream sequence was shown to have promoter activity in functional assays. Cosmid clone isolation, DNA sequencing, functional promoter assay The EMBO journal High 3839456
1986 The complete human ADA gene sequence confirmed 12 exons over 36,741 bp, with a G/C-rich promoter lacking TATA/CAAT boxes containing six SP1 binding site homologs (GGGCGGG), and defined all intron-exon boundaries. DNA sequencing of overlapping lambda phage clones Biochemistry High 3028473
1984 ADA deficiency in ADA-SCID cells is not due to transcriptional or translational defects but to subtle changes in protein configuration affecting both enzymatic and immunological characteristics, as ADA-specific mRNA from SCID cells could be translated in vitro into a protein of normal molecular weight that lacked immunoprecipitability with ADA antiserum. Northern blot analysis, in vitro translation, immunoprecipitation Nucleic acids research High 6198631
1984 The human ADA gene was regionally localized to chromosome 20q13.2–qter by somatic cell hybridization using a human cell line with a 17/20 balanced translocation. Somatic cell hybridization, enzyme assay Annals of human genetics High 6370091
1993 ADA directly associates with CD26 (dipeptidyl peptidase IV, DPPIV) on the T cell surface; this 43 kDa protein was identified as ADA by amino acid sequence analysis and confirmed by immunoprecipitation, with binding mediated through the extracellular domain of CD26. Amino acid sequencing, immunoprecipitation, in vitro binding assay Science High 8101391
1997 ADA functions as an ectoenzyme on the cell surface by binding to membrane proteins including CD26 and A1 adenosine receptors (A1R); surface-bound ADA transmits signals upon interaction with CD26 or A1R, acting as a co-stimulatory molecule that facilitates specific signaling events, and its heterogeneous distribution in the nervous system suggests a neuroregulatory role. Cell surface binding studies, signal transduction assays, immunohistochemistry Progress in neurobiology Medium 9247966
2005 ADA bound to CD26 on T cells interacts with an ADA-anchoring protein on dendritic cells to form a costimulatory signal at the immunological synapse; this costimulation was not due to ADA enzymatic activity but to protein-protein interaction, and potentiated T cell proliferation and production of IFN-γ, TNF-α, and IL-6 by 3- to 34-fold. Autologous T cell/dendritic cell coculture, colocalization microscopy, cytokine measurement, EC50 analysis Proceedings of the National Academy of Sciences of the United States of America High 15983379
2006 During hypoxia, endothelial ADA expression and activity are induced, and CD26 is coordinately upregulated to localize ADA activity at the endothelial cell surface; ADA surface binding was blocked by gp120 (which competes for ADA-CD26 binding), and pharmacological ADA inhibition with deoxycoformycin enhanced adenosine-mediated protection (reduced vascular leak and neutrophil accumulation) in murine hypoxia models. Microarray, in vitro/in vivo hypoxia models, protein expression, ADA activity assay, gp120 competition, deoxycoformycin pharmacological inhibition, plasma ADA activity in pediatric patients Blood High 16670267
2008 In ADA-SCID patients, CD4+ T cells have severely compromised TCR/CD28-driven proliferation associated with intrinsically reduced ZAP-70 phosphorylation, Ca2+ flux, and ERK1/2 signaling, and defective CREB and NF-κB transcriptional activity; exposure to 2'-deoxyadenosine additionally inhibits T cell activation via aberrant A2A adenosine receptor signaling and PKA hyperactivation, or induces apoptosis at higher doses; gene therapy restored these biochemical signaling events and T cell functions. Phosphorylation assays, Ca2+ flux measurements, ERK1/2 signaling, transcription factor assays, apoptosis assays, receptor signaling pharmacology, comparison pre/post gene therapy Blood High 18218852
2009 ADA deficiency causes a specific bone phenotype in mice characterized by an imbalanced RANKL/osteoprotegerin axis (decreased osteoclastogenesis) and intrinsic osteoblast dysfunction with low bone formation; ADA-deficient osteoblasts showed altered transcriptional profile and growth reduction in vitro, and the bone marrow microenvironment had reduced capacity to support hematopoiesis; enzyme replacement, bone marrow transplantation, or gene therapy fully rescued these defects. Mouse knockout model, bone structural analysis, in vitro osteoblast assays, RANKL/OPG measurement, hematopoietic support assay, rescue experiments (ERT/BMT/GT) Blood High 19633200
2010 ADA2 is secreted by monocytes undergoing differentiation into macrophages or dendritic cells and binds to cell surfaces via proteoglycans and adenosine receptors; ADA2 (but not ADA1) induces T cell-dependent differentiation of monocytes into macrophages and stimulates macrophage proliferation; both ADA1 and ADA2 increase proliferation of monocyte-activated CD4+ T cells independently of their catalytic deaminase activity. Cell differentiation assays, surface binding assays, proteoglycan competition, receptor blocking, T cell proliferation assays Journal of leukocyte biology High 20453107
2013 In neonatal blood, soluble ADA1 (not ADA2) is the enzyme responsible for catabolizing extracellular adenosine to inosine; neonatal plasma has substantially lower ADA activity than adult plasma, resulting in elevated extracellular adenosine concentrations in newborns; selective 5'-NT inhibition enhanced TLR-mediated TNF-α production in neonatal blood, confirming functional relevance of the adenosine-generating/catabolizing enzyme balance. Enzyme activity assays (ADA isoform-specific), plasma fractionation, pharmacological inhibition of 5'-NT, TLR stimulation/cytokine measurement in whole blood, infant cohort samples The Journal of biological chemistry High 23897810
2013 ADA acts as a natural antagonist for DPP4-mediated entry of MERS-CoV; ADA competed with MERS-CoV for DPP4 binding, and site-directed mutagenesis of ferret DPP4 residues identified the functional human DPP4 virus-binding site, which overlaps with the ADA-binding site. Site-directed mutagenesis, viral entry competition assay, receptor binding assays Journal of virology High 24257613
2015 ADA1-expressing HEK293 cells (but not ADA2-expressing cells) extensively metabolize cordycepin by deamination, with Km of 54.9 μmol/L and Vmax of 45.8 nmol/min/mg protein; naringin strongly inhibits ADA1-mediated cordycepin deamination (Ki ~58.8 μmol/L in mouse erythrocytes), demonstrating ADA1 is the primary isoform responsible for cordycepin metabolism. Isoform-specific overexpression in HEK293 cells, enzyme kinetics, inhibition assays (Ki determination), cytotoxicity assay Pharmacology research & perspectives High 26038697
2016 ADA1 and ADA2 bind to different subsets of immune cells: ADA2 binds to neutrophils, monocytes, NK cells, and B cells that do not express CD26 (the ADA1 receptor), and specifically to CD39+ regulatory T cells lacking CD26; ADA1 binds CD16- monocytes while CD16+ monocytes preferentially bind ADA2; ADA2-deficient patients show dramatic reduction in lymphocyte subsets and increased plasma TNF-α. Flow cytometry with isoform-specific binding assays, analysis of ADA2-deficient patient blood samples, cytokine measurement Cellular and molecular life sciences High 27663683
2017 ADA deficiency in mice and patients causes neurological and behavioral abnormalities including motor dysfunction, EEG alterations, sensorineural hearing loss, and white matter alterations; ADA-deficient mice showed anxiety-like behavior coinciding with metabolic alterations and aberrant adenosine receptor signaling; PEG-ADA treatment corrected metabolic adenosine-based alterations but not cellular and signaling defects, indicating an intrinsic neurological component beyond peripheral adenosine levels. Mouse behavioral assays, EEG, MRI, metabolic/molecular analysis, adenosine receptor signaling assays, PEG-ADA treatment comparison Scientific reports High 28074903
2005 A functional genetic variant of ADA (G22A polymorphism, Asp8Asn), which reduces ADA enzyme activity, specifically enhances deep sleep and slow-wave activity (SWA) during sleep in humans, indicating ADA-mediated adenosine metabolism directly regulates sleep homeostasis. Human genetic study, polysomnography/EEG measurement of sleep parameters, comparison with A2A receptor polymorphism Proceedings of the National Academy of Sciences of the United States of America High 16221767
1992 Retroviral transfer of the ADA gene into ADA-deficient peripheral blood T lymphocytes restored ADA enzyme activity and reconstituted specific immune functions including proliferative capacity, alloreactive and antigen-specific responses in vivo in BNX immunodeficient mice, demonstrating that ADA enzymatic activity is required for T lymphocyte survival and immune function. Retroviral gene transfer, enzyme activity assay, in vivo T cell reconstitution in immunodeficient mice, TCR analysis, antigen-specific response assay Blood High 1325209
2024 Engineering CAR T cells to co-express membrane-bound CD26 and cytoplasmic ADA1 enables autocrine secretion of ADA1 upon CD3/CD26 stimulation; ADA1 converts adenosine to inosine which serves as alternative fuel, improving CAR T cell migration, resistance to TGF-β1 suppression, and anti-tumor activity in hepatocellular carcinoma and non-small cell lung cancer mouse models; fusion of ADA1 with anti-CD3 scFv further boosted inosine production. CAR T cell engineering, in vitro migration and suppression assays, mouse tumor models (HCC and NSCLC), ADA1 enzymatic activity assays Cell reports. Medicine High 38688275
2020 Human subcutaneous fibroblasts have very low endogenous ADA activity; exogenous ADA addition converts adenosine to inosine which acts through A3 receptors to decrease fibroblast growth and collagen production, opposing the pro-collagen effects of adenosine acting via A2A receptors, demonstrating that ADA-expressing inflammatory cells (third-party ADA providers) can regulate dermal remodeling by controlling the adenosine/inosine balance. Cell culture, enzyme activity assays, receptor agonist/antagonist pharmacology, collagen production assay, proliferation assay Cells Medium 32156055

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 3725 23128233
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 1913 30291106
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
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 1243 36148880
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
1995 T lymphocyte-directed gene therapy for ADA- SCID: initial trial results after 4 years. Science (New York, N.Y.) 1008 7570001
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 923 9224714
2002 Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning. Science (New York, N.Y.) 871 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 848 31857443
2014 Diabetic kidney disease: a report from an ADA Consensus Conference. Diabetes care 841 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 799 30288571
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
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 659 36151309
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
1995 Gene therapy in peripheral blood lymphocytes and bone marrow for ADA- immunodeficient patients. Science (New York, N.Y.) 580 7570000
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 554 36189689
1994 Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides. Gene 492 8125298
1993 Direct association of adenosine deaminase with a T cell activation antigen, CD26. Science (New York, N.Y.) 467 8101391
1998 Histone-like TAFs within the PCAF histone acetylase complex. Cell 462 9674425
2014 Diabetic kidney disease: a report from an ADA Consensus Conference. American journal of kidney diseases : the official journal of the National Kidney Foundation 440 25257325
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
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 345 31853556
1985 Adenosine deaminase: characterization and expression of a gene with a remarkable promoter. The EMBO journal 303 3839456
1997 Essential functional interactions of SAGA, a Saccharomyces cerevisiae complex of Spt, Ada, and Gcn5 proteins, with the Snf/Swi and Srb/mediator complexes. Genetics 268 9335585
2017 Combinatorial CRISPR-Cas9 screens for de novo mapping of genetic interactions. Nature methods 266 28319113
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
1997 Cell surface adenosine deaminase: much more than an ectoenzyme. Progress in neurobiology 208 9247966
2011 Toward an understanding of the protein interaction network of the human liver. Molecular systems biology 207 21988832
2005 CD26, adenosine deaminase, and adenosine receptors mediate costimulatory signals in the immunological synapse. Proceedings of the National Academy of Sciences of the United States of America 206 15983379
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 201 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
2010 Human adenosine deaminase 2 induces differentiation of monocytes into macrophages and stimulates proliferation of T helper cells and macrophages. Journal of leukocyte biology 190 20453107
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
2005 A functional genetic variation of adenosine deaminase affects the duration and intensity of deep sleep in humans. Proceedings of the National Academy of Sciences of the United States of America 171 16221767
2001 The DNA sequence and comparative analysis of human chromosome 20. Nature 168 11780052
2009 Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip. American journal of human genetics 164 19913121
2009 How I treat ADA deficiency. Blood 163 19638621
1999 Enzymes involved in purine metabolism--a review of histochemical localization and functional implications. Histology and histopathology 152 10506947
2006 Endothelial catabolism of extracellular adenosine during hypoxia: the role of surface adenosine deaminase and CD26. Blood 145 16670267
1986 Complete sequence and structure of the gene for human adenosine deaminase. Biochemistry 141 3028473
1985 Methyl phosphotriesters in alkylated DNA are repaired by the Ada regulatory protein of E. coli. Nucleic acids research 141 2987862
2013 Adenosine deaminase acts as a natural antagonist for dipeptidyl peptidase 4-mediated entry of the Middle East respiratory syndrome coronavirus. Journal of virology 136 24257613
2007 Toward a confocal subcellular atlas of the human proteome. Molecular & cellular proteomics : MCP 114 18029348
2016 A Network of Conserved Synthetic Lethal Interactions for Exploration of Precision Cancer Therapy. Molecular cell 113 27453043
1998 Tra1p is a component of the yeast Ada.Spt transcriptional regulatory complexes. The Journal of biological chemistry 113 9756893
2009 NPAS2 and PER2 are linked to risk factors of the metabolic syndrome. Journal of circadian rhythms 112 19470168
2014 Protein interaction network of alternatively spliced isoforms from brain links genetic risk factors for autism. Nature communications 111 24722188
1998 Successful peripheral T-lymphocyte-directed gene transfer for a patient with severe combined immune deficiency caused by adenosine deaminase deficiency. Blood 111 9414266
2016 Human adenosine deaminases ADA1 and ADA2 bind to different subsets of immune cells. Cellular and molecular life sciences : CMLS 96 27663683
1997 ADA1, a novel component of the ADA/GCN5 complex, has broader effects than GCN5, ADA2, or ADA3. Molecular and cellular biology 93 9154821
1988 Functional domains and methyl acceptor sites of the Escherichia coli ada protein. The Journal of biological chemistry 92 3162236
1990 The ADA human gene therapy clinical protocol. Human gene therapy 89 2081198
1996 ADA5/SPT20 links the ADA and SPT genes, which are involved in yeast transcription. Molecular and cellular biology 84 8649430
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 81 30423394
2017 Adenosine Deaminase (ADA)-Deficient Severe Combined Immune Deficiency (SCID): Molecular Pathogenesis and Clinical Manifestations. Journal of clinical immunology 80 28842866
2013 Soluble ecto-5'-nucleotidase (5'-NT), alkaline phosphatase, and adenosine deaminase (ADA1) activities in neonatal blood favor elevated extracellular adenosine. The Journal of biological chemistry 76 23897810
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
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
1988 Functional sites of the Ada regulatory protein of Escherichia coli. Analysis by amino acid substitutions. Journal of molecular biology 57 3047400
2013 Evaluating pleural ADA, ADA2, IFN-γ and IGRA for diagnosing tuberculous pleurisy. The Journal of infection 54 23796864
1990 Bacillus subtilis ada operon encodes two DNA alkyltransferases. Nucleic acids research 54 2120677
1992 Zinc binding by the methylation signaling domain of the Escherichia coli Ada protein. Biochemistry 52 1581309
2015 Inhibition of adenosine deaminase (ADA)-mediated metabolism of cordycepin by natural substances. Pharmacology research & perspectives 51 26038697
2015 Conformational flexibility and subunit arrangement of the modular yeast Spt-Ada-Gcn5 acetyltransferase complex. The Journal of biological chemistry 49 25713136
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 45 35671392
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
1984 Adenosine deaminase (ADA) deficiency in cells derived from humans with severe combined immunodeficiency is due to an aberration of the ADA protein. Nucleic acids research 42 6198631
1995 PEG-ADA: an alternative to haploidentical bone marrow transplantation and an adjunct to gene therapy for adenosine deaminase deficiency. Human mutation 41 7749407
2022 A-DA'D-A Structured Organic Phototheranostics for NIR-II Fluorescence/Photoacoustic Imaging-Guided Photothermal and Photodynamic Synergistic Therapy. ACS applied materials & interfaces 38 35420773
2017 Alterations in the brain adenosine metabolism cause behavioral and neurological impairment in ADA-deficient mice and patients. Scientific reports 37 28074903
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 33 27034966
2009 Structural basis for the interaction between yeast Spt-Ada-Gcn5 acetyltransferase (SAGA) complex components Sgf11 and Sus1. The Journal of biological chemistry 33 20007317
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 29 24076575
1993 Bacillus subtilis alkA gene encoding inducible 3-methyladenine DNA glycosylase is adjacent to the ada operon. Journal of bacteriology 29 8376346
2022 Distinct Roles of Adenosine Deaminase Isoenzymes ADA1 and ADA2: A Pan-Cancer Analysis. Frontiers in immunology 28 35663977
2018 ADA Deficiency: Evaluation of the Clinical and Laboratory Features and the Outcome. Journal of clinical immunology 28 29744787
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
1984 Confirmation of the regional localization of the genes for human acid alpha-glucosidase (GAA) and adenosine deaminase (ADA) by somatic cell hybridization. Annals of human genetics 28 6370091
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 27 38185066
2017 Cytoreductive conditioning intensity predicts clonal diversity in ADA-SCID retroviral gene therapy patients. Blood 27 28351939
2024 A case of T-cell acute lymphoblastic leukemia in retroviral gene therapy for ADA-SCID. Nature communications 26 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 26 36309141
2011 Novel mutations in RAG1/2 and ADA genes in Israeli patients presenting with T-B-SCID or Omenn syndrome. Clinical immunology (Orlando, Fla.) 26 21624848
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
1986 Mutant Escherichia coli Ada proteins simultaneously defective in the repair of O6-methylguanine and in gene activation. Nucleic acids research 25 3526284
2001 Structural basis for the functional switch of the E. coli Ada protein. Biochemistry 24 11284682
2002 Advances in gene therapy for ADA-deficient SCID. Current opinion in molecular therapeutics 23 12435054
1987 Proteolytic processing of the Ada protein that repairs DNA O6-methylguanine residues in E. coli. Mutation research 23 3547105
1993 The Ada protein is a class I transcription factor of Escherichia coli. Journal of bacteriology 22 8468304
2024 Selective refueling of CAR T cells using ADA1 and CD26 boosts antitumor immunity. Cell reports. Medicine 21 38688275
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
1991 Enhanced repair of O6-methylguanine DNA adducts in the liver of transgenic mice expressing the ada gene. Cancer research 21 2054779
1988 Alteration of the carboxyl-terminal domain of Ada protein influences its inducibility, specificity, and strength as a transcriptional activator. Journal of bacteriology 21 3141384
2023 3D bioprinting of multifunctional alginate dialdehyde (ADA)-gelatin (GEL) (ADA-GEL) hydrogels incorporating ferulic acid. International journal of biological macromolecules 20 38029911
2015 Diagnosis, Treatment and Long-Term Follow Up of Patients with ADA Deficiency: a Single-Center Experience. Journal of clinical immunology 20 26376800
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
2018 Gene therapy in rare diseases: the benefits and challenges of developing a patient-centric registry for Strimvelis in ADA-SCID. Orphanet journal of rare diseases 19 29625577
1999 The dental team and latex hypersensitivity. ADA Council on Scientific Affairs. Journal of the American Dental Association (1939) 19 10036850
1991 Characterization of O6-methylguanine-DNA methyltransferase in transgenic mice introduced with the E. coli ada gene. Mutation research 18 2052012
1988 Proteolytic cleavage of Ada protein that carries methyltransferase and transcriptional regulator activities. The Journal of biological chemistry 18 3058696
2020 Comparison of elapegademase and pegademase in ADA-deficient patients and mice. Clinical and experimental immunology 17 31989577
2007 The G22A polymorphism of the ADA gene and susceptibility to autism spectrum disorders. Journal of autism and developmental disorders 17 17340203
1999 Comparison of ADA and WHO screening methods for diabetes mellitus in obese patients. American Diabetes Association. Diabetic medicine : a journal of the British Diabetic Association 17 10445834
1994 Influence of DNA repair by ada and ogt alkyltransferases on the mutational specificity of alkylating agents. Molecular carcinogenesis 17 8148053
2021 Comparative genomics of the ADA clade within the Nostocales. Harmful algae 16 34023075
2020 The sensitive detection of ATP and ADA based on turn-on fluorescent copper/silver nanoclusters. Analytical and bioanalytical chemistry 16 32043202
2020 Opposing Effects of Adenosine and Inosine in Human Subcutaneous Fibroblasts May Be Regulated by Third Party ADA Cell Providers. Cells 16 32156055
2016 Pleural Fluid Adenosine Deaminase (ADA) Predicts Survival in Patients with Malignant Pleural Effusion. Lung 16 27300446