{"gene":"ADK","run_date":"2026-06-09T22:02:42","timeline":{"discoveries":[{"year":2009,"finding":"The long isoform of adenosine kinase (ADK-long) localizes to the nucleus, while the short isoform localizes to the cytoplasm. The extra 20-21 amino acid N-terminal sequence (NTS) of ADK-long contains a nuclear localization signal (NLS) with the cluster PKPKKLKVE; mutation of KK to AA or AD abolished nuclear localization. Nuclear ADK is proposed to sustain methylation reactions.","method":"Immunofluorescence labeling, C-terminal c-myc epitope fusion constructs, GFP fusion with NTS, site-directed mutagenesis of NLS","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (immunofluorescence, fusion constructs, mutagenesis) in a single study, functional consequence (nuclear methylation) proposed","pmids":["19635462"],"is_preprint":false},{"year":2009,"finding":"ADK astrogliosis-driven upregulation contributes to seizure generation. In transgenic Adk-tg mice where the endogenous Adk gene was deleted and replaced by a ubiquitously expressed transgene, astrogliosis could be uncoupled from ADK upregulation; astrogliosis without ADK upregulation did not produce seizures, whereas astrogliosis with ADK upregulation did, demonstrating that ADK expression levels (not astrogliosis per se) drive seizure generation.","method":"Transgenic mouse model (endogenous Adk deleted, ubiquitous transgene), targeted CA3 injury, electrophysiological and histological readouts","journal":"Neuron glia biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with transgenic model, specific molecular uncoupling of ADK from astrogliosis with defined seizure phenotype readout","pmids":["19674507"],"is_preprint":false},{"year":2018,"finding":"ADK in myeloid/macrophage cells regulates intracellular adenosine levels; myeloid-specific ADK deletion increases intracellular adenosine, reduces DNA methylation of the ABCG1 gene promoter, upregulates ABCG1 expression, enhances cholesterol efflux, and reduces foam cell formation, suppressing atherosclerosis in ApoE-/- mice.","method":"Cre-LoxP myeloid-specific ADK knockout (LysM-Cre × ADKF/F × ApoE-/-), in vitro ADK inhibition, cholesterol efflux assay, DNA methylation (methylation-specific assays), atherosclerotic plaque quantification","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional knockout with multiple orthogonal mechanistic readouts (methylation, ABCG1 expression, cholesterol efflux, plaque size) in a single rigorous study","pmids":["30571174"],"is_preprint":false},{"year":2004,"finding":"ADK (adenosine kinase) activity is stimulated by pentavalent ions (phosphate, arsenate, vanadate) and phosphorylated compounds (e.g., phosphoribosyl pyrophosphate, phosphoenol pyruvate, creatine phosphate) that lower the Km for adenosine; structurally related compounds (phosphonoacetic acid, 2-carboxyethyl phosphonic acid) competitively inhibit AK. The mechanism proposed is that a bound phosphate forms a transient pentavalent intermediate with the β-phosphate of ATP, facilitating γ-phosphate transfer to adenosine.","method":"In vitro enzyme activity assays with a panel of phosphorylated compounds, Km determination, competitive inhibition analysis","journal":"The protein journal","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro enzymatic characterization with structure-activity analysis, but mechanistic model is interpretive and from a single lab","pmids":["15106882"],"is_preprint":false},{"year":2011,"finding":"Overexpression of ADK in astrocytes within astrocytic brain tumors and peritumoral tissue is associated with tumor-associated epilepsy; ADK activity was significantly elevated in astrocytoma WHO grade III and peritumoral tissue compared to normal cortex, consistent with ADK acting as a negative regulator of extracellular adenosine to promote seizures.","method":"Immunohistochemistry, Western blot, ADK enzymatic activity assay in surgical specimens","journal":"Epilepsia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct enzymatic activity measurement combined with protein expression data in human tissue, replicated across multiple sample types","pmids":["22092111"],"is_preprint":false},{"year":2021,"finding":"NLRP3 inflammasome activation upregulates ADK expression in astrocytes via the CREB/REST/SP1 signaling pathway: CREB and REST positively regulate ADK expression while SP1 negatively regulates it; knockdown of NLRP3 or Caspase-1 rescues the KA-induced changes, and CREB or REST silencing reduces ADK expression in KA-treated astrocytes.","method":"SE mouse model (kainic acid), siRNA knockdown (NLRP3, Caspase-1, CREB, REST, SP1), Western blot, ELISA, immunofluorescence staining; pharmacological inhibition (MCC950, Z-YVAD-FMK)","journal":"Neurochemical research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple siRNA targets with specific pathway epistasis tested, but single lab study","pmids":["34797502"],"is_preprint":false},{"year":2021,"finding":"In the mussel Mytilopsis sallei, adenosine kinase (ADK) is the molecular target of adenosine; ATP-dependent phosphorylation of adenosine by ADK activates the downstream AMPK-FoxO signaling pathway, inducing larval settlement and metamorphosis.","method":"Transcriptomic analysis, pharmacological assays, temporal/spatial gene expression analysis, siRNA interference","journal":"ACS chemical biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA epistasis plus pharmacological validation in a marine invertebrate ortholog context, multiple methods, single lab","pmids":["34254778"],"is_preprint":false},{"year":2024,"finding":"Hyperibone J binds ADK at the ASN-312 site, reducing ADK protein stability and expression in microglia. Reduced ADK attenuates the ATP/P2X7R/Caspase-1-mediated maturation and release of IL-1β, and inhibits TLR4/NF-κB-driven transcription of Nlrp3, Il-1b, Tnf, and Il-6, producing antidepressant and anti-neuroinflammatory effects.","method":"Network pharmacology, molecular docking, RNA-seq, Western blot, qPCR, ELISA; in vitro LPS-induced BV-2 microglia model, in vivo depression models","journal":"Journal of advanced research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — binding site identification is computational/molecular biology, but downstream pathway effects validated by multiple biochemical readouts; single lab","pmids":["39019111"],"is_preprint":false},{"year":2024,"finding":"Berberine promotes ADK expression, increasing AMP levels and the AMP/ATP ratio, which activates AMPK and downstream Nrf2 signaling; siADK knockdown abolishes the hepatoprotective effects of berberine in hepatocytes, placing ADK upstream of AMPK/Nrf2 in a pathway mediating anti-inflammatory and antioxidant hepatic protection.","method":"siRNA knockdown of ADK in HepG2 and BRL-3A cells, AMP/ATP measurement, Western blot (p-AMPK, Nrf2, HO-1), ROS and MDA assays; in vivo rat fructose model","journal":"Biomedicine & pharmacotherapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA epistasis places ADK upstream of AMPK/Nrf2, orthogonal metabolic and protein readouts, single lab","pmids":["39243432"],"is_preprint":false},{"year":2019,"finding":"A homozygous missense mutation in ADK (c.427T>C, p.Cys143Arg) causes adenosine kinase deficiency leading to hypermethioninemia and severe intellectual disability in humans, establishing that ADK function is required for normal methionine metabolism.","method":"Whole exome sequencing, clinical phenotyping","journal":"Gene","confidence":"Low","confidence_rationale":"Tier 3 / Weak — genetic discovery via sequencing; mechanistic inference (ADK required for methionine cycle) is indirect from loss-of-function phenotype, no biochemical rescue","pmids":["30771478"],"is_preprint":false},{"year":1999,"finding":"A nonsense mutation in AK-1 (Arg107Stop) results in a truncated 107-amino acid protein with completely absent adenylate kinase activity and causes chronic haemolytic anaemia with elevated 2,3-DPG in erythrocytes, demonstrating that AK-1 enzymatic activity is required for normal red cell energy metabolism.","method":"cDNA sequencing, enzyme activity assay in red cell lysates, clinical phenotyping","journal":"British journal of haematology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — loss-of-function mutation with enzyme activity readout in human patients; no biochemical rescue experiment","pmids":["10233365"],"is_preprint":false},{"year":1983,"finding":"An adenylate kinase-associated protein (Mr ~34,000) co-purifies with both wild-type and temperature-sensitive mutant E. coli adenylate kinase through multiple purification steps, and alters the thermolability of the mutant enzyme in a concentration-dependent manner, indicating this protein can regulate adenylate kinase activity.","method":"Protein purification, SDS-PAGE, thermolability assay at 40°C, co-purification","journal":"The Journal of biological chemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — co-purification and thermolability effect shown in E. coli, single lab, no molecular identity of the associated protein established","pmids":["6313692"],"is_preprint":false}],"current_model":"ADK (adenosine kinase) phosphorylates adenosine to AMP using ATP as phosphate donor, with activity stimulated by pentavalent ions that facilitate γ-phosphate transfer; the long isoform localizes to the nucleus via a specific NLS and sustains methylation reactions, while the short isoform is cytoplasmic; astrocytic ADK is a key negative regulator of extracellular adenosine homeostasis in the brain (controlling seizure threshold), regulates intracellular adenosine levels in myeloid cells to epigenetically control cholesterol trafficking via ABCG1 DNA methylation, and is transcriptionally regulated by the NLRP3/Caspase-1/CREB/REST/SP1 axis during epileptogenesis."},"narrative":{"mechanistic_narrative":"ADK (adenosine kinase) is the ATP-dependent kinase that phosphorylates adenosine to AMP, serving as the principal metabolic regulator of intracellular and extracellular adenosine and thereby controlling adenosine-dependent signaling and methylation reactions [PMID:15106882]. Catalysis is stimulated by pentavalent ions (phosphate, arsenate, vanadate) and phosphorylated compounds that lower the Km for adenosine, with the proposed mechanism being formation of a transient pentavalent phosphate intermediate at the β-phosphate of ATP that facilitates γ-phosphate transfer [PMID:15106882]. The enzyme exists as two isoforms with distinct localization: the long isoform carries an N-terminal nuclear localization signal (cluster PKPKKLKVE) directing it to the nucleus where it sustains methylation reactions, while the short isoform is cytoplasmic [PMID:19635462]. In the brain, astrocytic ADK acts as a negative regulator of extracellular adenosine: ADK upregulation, rather than astrogliosis itself, drives seizure generation [PMID:19674507], and elevated ADK accompanies tumor-associated epilepsy in human astrocytoma tissue [PMID:22092111]. ADK expression in astrocytes is transcriptionally controlled by an NLRP3 inflammasome/Caspase-1 axis acting through CREB and REST (positive) and SP1 (negative) regulators [PMID:34797502]. In myeloid cells, ADK governs intracellular adenosine to set DNA methylation of the ABCG1 promoter, with ADK deletion raising adenosine, reducing ABCG1 methylation, enhancing cholesterol efflux, and suppressing atherosclerosis [PMID:30571174]. Loss-of-function evidence links ADK to one-carbon metabolism: a homozygous p.Cys143Arg mutation causes adenosine kinase deficiency with hypermethioninemia and severe intellectual disability [PMID:30771478].","teleology":[{"year":2004,"claim":"Established the catalytic logic of ADK by defining how phosphate transfer to adenosine is achieved, answering how the enzyme couples ATP hydrolysis to adenosine phosphorylation.","evidence":"In vitro enzyme assays with a panel of phosphorylated compounds, Km determination and competitive inhibition analysis","pmids":["15106882"],"confidence":"Medium","gaps":["Pentavalent intermediate model is interpretive without a crystallographic transition-state structure","Single lab characterization"]},{"year":2009,"claim":"Resolved why ADK has dual subcellular roles by showing isoform-specific localization, linking the nuclear long isoform to methylation and the cytoplasmic short isoform to bulk adenosine metabolism.","evidence":"Immunofluorescence, c-myc and GFP fusion constructs, and site-directed mutagenesis of the NLS in cells","pmids":["19635462"],"confidence":"High","gaps":["The nuclear methylation role is proposed rather than directly demonstrated by a methylation readout in this study","Functional separation of isoform substrate preferences not established"]},{"year":2009,"claim":"Demonstrated causality between ADK expression and epilepsy by genetically uncoupling ADK upregulation from astrogliosis, showing ADK level itself drives seizures.","evidence":"Transgenic mouse with endogenous Adk deleted and a ubiquitous transgene, targeted CA3 injury, electrophysiology and histology","pmids":["19674507"],"confidence":"High","gaps":["Does not define the transcriptional drivers of astrocytic ADK upregulation","Extracellular adenosine measurements inferred rather than directly tracked"]},{"year":2011,"claim":"Extended the ADK-seizure model to human pathology by showing elevated ADK in astrocytoma and peritumoral tissue associated with tumor-associated epilepsy.","evidence":"Immunohistochemistry, Western blot and ADK enzymatic activity assays in human surgical specimens","pmids":["22092111"],"confidence":"Medium","gaps":["Correlative human tissue data without genetic manipulation","Causal contribution of ADK to tumor epileptogenesis not directly tested"]},{"year":2018,"claim":"Revealed an epigenetic output of ADK metabolism by linking myeloid intracellular adenosine to ABCG1 promoter methylation and cholesterol efflux, establishing ADK as a regulator of foam cell formation and atherosclerosis.","evidence":"Myeloid-specific Cre-LoxP ADK knockout in ApoE-/- mice, cholesterol efflux assay, methylation-specific assays, plaque quantification","pmids":["30571174"],"confidence":"High","gaps":["Mechanistic link from adenosine to DNA methyltransferase activity (via SAH) inferred rather than directly demonstrated","Specific methyltransferase responsible not identified"]},{"year":2021,"claim":"Identified the transcriptional control circuit driving astrocytic ADK during epileptogenesis, placing NLRP3/Caspase-1 upstream of CREB/REST/SP1 regulation of ADK.","evidence":"Kainic acid status epilepticus mouse model, siRNA knockdown of NLRP3, Caspase-1, CREB, REST and SP1, with pharmacological inflammasome inhibition","pmids":["34797502"],"confidence":"Medium","gaps":["Direct promoter occupancy of CREB/REST/SP1 on the ADK gene not shown","Single lab study"]},{"year":2021,"claim":"Showed ADK functions as a signaling node beyond metabolism in an invertebrate, acting as the adenosine target that activates AMPK-FoxO to drive larval settlement.","evidence":"Transcriptomics, pharmacological assays and siRNA interference in the mussel Mytilopsis sallei","pmids":["34254778"],"confidence":"Medium","gaps":["Ortholog context may not transfer to mammalian ADK signaling","Direct biochemical link from ADK product to AMPK not dissected"]},{"year":2024,"claim":"Connected ADK to AMPK-dependent stress responses by showing its product can drive the AMP/ATP ratio, placing ADK upstream of AMPK/Nrf2 hepatoprotective signaling.","evidence":"siRNA knockdown of ADK in HepG2 and BRL-3A cells, AMP/ATP and ROS measurements, in vivo rat fructose model","pmids":["39243432"],"confidence":"Medium","gaps":["Single lab; direction of ADK effect (increasing AMP) contrasts with its canonical adenosine-consuming role and is not reconciled","Tissue specificity unclear"]},{"year":2024,"claim":"Defined a druggable site on ADK (ASN-312) whose engagement destabilizes the protein and dampens microglial neuroinflammation, providing a chemical handle on ADK function.","evidence":"Network pharmacology, molecular docking, RNA-seq, biochemical readouts in LPS-induced BV-2 microglia and in vivo depression models","pmids":["39019111"],"confidence":"Medium","gaps":["Binding site identification is largely computational without co-crystal structure","Mechanism of protein destabilization not biochemically resolved"]},{"year":2019,"claim":"Provided human genetic evidence that ADK is required for normal one-carbon/methionine metabolism, with loss of function causing hypermethioninemia and neurodevelopmental disease.","evidence":"Whole exome sequencing and clinical phenotyping identifying homozygous p.Cys143Arg","pmids":["30771478"],"confidence":"Low","gaps":["No biochemical rescue or enzymatic characterization of the mutant","Mechanistic link to methylation cycle inferred from phenotype only"]},{"year":null,"claim":"How the nuclear vs cytoplasmic ADK isoforms differentially partition adenosine flux to control DNA/protein methylation across cell types remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No direct demonstration that nuclear ADK controls a specific methylation reaction","No structural model of substrate-bound human ADK in the corpus","Isoform-specific knockouts not reported"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[3,0]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[3]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[3,9]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[2]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[8,6]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P55263","full_name":"Adenosine kinase","aliases":["Adenosine 5'-phosphotransferase","N6,N6-dimethyladenosine kinase","N6-isopentenyladenosine kinase","N6-methyladenosine kinase"],"length_aa":362,"mass_kda":40.5,"function":"Adenosine kinase that mediates the phosphorylation of the purine nucleoside adenosine at the 5' position in an ATP-dependent manner: catalyzes phosphorylation of both unmodified and modified adenosines (PubMed:21963049, PubMed:40840445, PubMed:6246102, PubMed:8577746, PubMed:9070863). Plays a key role in the detoxification of modified adenosines containing N(6)-methylated adenine (m6A) post-transcriptional modification (PubMed:40840445). Modified nucleosides are derived from the degradation of RNAs (mRNAs, rRNAs and tRNAs) and possess intrinsic cytotoxicity and must be cleared to prevent metabolic dysfunction (PubMed:40840445). Catalyzes the phosphorylation of the free cytosolic methylated adenosine nucleotides N(6)-methyladenosine (m6A), N(6),N(6)-dimethyladenosine (m6,6A) and N(6)-isopentenyladenosine (i6A) into adenosine monophosphate (AMP) intermediates that are further detoxified by MAPDA/ADAL (PubMed:40840445)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P55263/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ADK","classification":"Not Classified","n_dependent_lines":11,"n_total_lines":1208,"dependency_fraction":0.009105960264900662},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ADK","total_profiled":1310},"omim":[{"mim_id":"614300","title":"HYPERMETHIONINEMIA DUE TO ADENOSINE KINASE DEFICIENCY","url":"https://www.omim.org/entry/614300"},{"mim_id":"610172","title":"SPERM FLAGELLAR PROTEIN 2; SPEF2","url":"https://www.omim.org/entry/610172"},{"mim_id":"607840","title":"N-ACETYLGLUCOSAMINE-1-PHOSPHOTRANSFERASE, ALPHA/BETA SUBUNITS; GNPTAB","url":"https://www.omim.org/entry/607840"},{"mim_id":"602330","title":"ACTIN-BINDING LIM PROTEIN FAMILY, MEMBER 1; ABLIM1","url":"https://www.omim.org/entry/602330"},{"mim_id":"252600","title":"MUCOLIPIDOSIS III ALPHA/BETA","url":"https://www.omim.org/entry/252600"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"liver","ntpm":141.2}],"url":"https://www.proteinatlas.org/search/ADK"},"hgnc":{"alias_symbol":["AK"],"prev_symbol":[]},"alphafold":{"accession":"P55263","domains":[{"cath_id":"3.40.1190.20","chopping":"27-34_81-136_157-349","consensus_level":"high","plddt":96.6881,"start":27,"end":349}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P55263","model_url":"https://alphafold.ebi.ac.uk/files/AF-P55263-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P55263-F1-predicted_aligned_error_v6.png","plddt_mean":93.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ADK","jax_strain_url":"https://www.jax.org/strain/search?query=ADK"},"sequence":{"accession":"P55263","fasta_url":"https://rest.uniprot.org/uniprotkb/P55263.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P55263/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P55263"}},"corpus_meta":[{"pmid":"6976317","id":"PMC_6976317","title":"Clonal analysis of B- and T-cell responses to Ia antigens. I. Topology of epitope regions on I-Ak and I-Ek molecules analyzed with 35 monoclonal alloantibodies.","date":"1981","source":"Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/6976317","citation_count":251,"is_preprint":false},{"pmid":"2984283","id":"PMC_2984283","title":"Generation of activated killer (AK) cells by recombinant interleukin 2 (rIL 2) in collaboration with interferon-gamma (IFN-gamma).","date":"1985","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/2984283","citation_count":206,"is_preprint":false},{"pmid":"25428612","id":"PMC_25428612","title":"Actinic keratosis with atypical basal cells (AK I) is the most common lesion associated with invasive squamous cell carcinoma of the skin.","date":"2014","source":"Journal of the European Academy of Dermatology and Venereology : JEADV","url":"https://pubmed.ncbi.nlm.nih.gov/25428612","citation_count":195,"is_preprint":false},{"pmid":"1972779","id":"PMC_1972779","title":"Prevention of diabetes in non-obese diabetic I-Ak transgenic mice.","date":"1990","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/1972779","citation_count":191,"is_preprint":false},{"pmid":"23200855","id":"PMC_23200855","title":"The sirtuin 2 inhibitor AK-7 is neuroprotective in Huntington's disease mouse models.","date":"2012","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/23200855","citation_count":162,"is_preprint":false},{"pmid":"2997739","id":"PMC_2997739","title":"Cloning and sequencing of the adenylate kinase gene (adk) of Escherichia coli.","date":"1985","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/2997739","citation_count":121,"is_preprint":false},{"pmid":"184030","id":"PMC_184030","title":"Localisation of the human ABO: Np-1: AK-1 linkage group by regional assignment of AK-1 to 9q34.","date":"1976","source":"Human 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Production and characterization of syngeneic anti-idiotypic mAb against an anti-I-Ak mAb.","date":"1984","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/6434633","citation_count":13,"is_preprint":false},{"pmid":"1969873","id":"PMC_1969873","title":"Functional consequences of overexpressed Ia antigens in AK alpha/AK beta transgenic mice.","date":"1990","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/1969873","citation_count":13,"is_preprint":false},{"pmid":"34299327","id":"PMC_34299327","title":"Genome-Wide Identification and Expression Analysis of Tomato ADK Gene Family during Development and Stress.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34299327","citation_count":12,"is_preprint":false},{"pmid":"30616888","id":"PMC_30616888","title":"The SIRT2 inhibitor AK-7 decreases cochlear cell apoptosis and attenuates noise-induced hearing loss.","date":"2019","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/30616888","citation_count":12,"is_preprint":false},{"pmid":"6290847","id":"PMC_6290847","title":"The Escherichia coli dnaW mutation is an allele of the adk gene.","date":"1982","source":"Molecular & general genetics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/6290847","citation_count":12,"is_preprint":false},{"pmid":"21365689","id":"PMC_21365689","title":"Identification of functional motions in the adenylate kinase (ADK) protein family by computational hybrid approaches.","date":"2011","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/21365689","citation_count":12,"is_preprint":false},{"pmid":"7536636","id":"PMC_7536636","title":"Differential requirement of protein tyrosine kinase and protein kinase C in the generation of IL-2-induced LAK cell and alpha CD3-induced CD3-AK cell responses.","date":"1995","source":"Cellular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/7536636","citation_count":12,"is_preprint":false},{"pmid":"28585686","id":"PMC_28585686","title":"Neutralization of Lipopolysaccharide by Heat Shock Protein in Pediococcus pentosaceus AK-23.","date":"2017","source":"Journal of food science","url":"https://pubmed.ncbi.nlm.nih.gov/28585686","citation_count":12,"is_preprint":false},{"pmid":"25470719","id":"PMC_25470719","title":"Lmax and imiquimod 3.75%: the new standard in AK management.","date":"2015","source":"Journal of the European Academy of Dermatology and Venereology : JEADV","url":"https://pubmed.ncbi.nlm.nih.gov/25470719","citation_count":11,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49211,"output_tokens":3186,"usd":0.097712,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10724,"output_tokens":3623,"usd":0.072097,"stage2_stop_reason":"end_turn"},"total_usd":0.169809,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2009,\n      \"finding\": \"The long isoform of adenosine kinase (ADK-long) localizes to the nucleus, while the short isoform localizes to the cytoplasm. The extra 20-21 amino acid N-terminal sequence (NTS) of ADK-long contains a nuclear localization signal (NLS) with the cluster PKPKKLKVE; mutation of KK to AA or AD abolished nuclear localization. Nuclear ADK is proposed to sustain methylation reactions.\",\n      \"method\": \"Immunofluorescence labeling, C-terminal c-myc epitope fusion constructs, GFP fusion with NTS, site-directed mutagenesis of NLS\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (immunofluorescence, fusion constructs, mutagenesis) in a single study, functional consequence (nuclear methylation) proposed\",\n      \"pmids\": [\"19635462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ADK astrogliosis-driven upregulation contributes to seizure generation. In transgenic Adk-tg mice where the endogenous Adk gene was deleted and replaced by a ubiquitously expressed transgene, astrogliosis could be uncoupled from ADK upregulation; astrogliosis without ADK upregulation did not produce seizures, whereas astrogliosis with ADK upregulation did, demonstrating that ADK expression levels (not astrogliosis per se) drive seizure generation.\",\n      \"method\": \"Transgenic mouse model (endogenous Adk deleted, ubiquitous transgene), targeted CA3 injury, electrophysiological and histological readouts\",\n      \"journal\": \"Neuron glia biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with transgenic model, specific molecular uncoupling of ADK from astrogliosis with defined seizure phenotype readout\",\n      \"pmids\": [\"19674507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ADK in myeloid/macrophage cells regulates intracellular adenosine levels; myeloid-specific ADK deletion increases intracellular adenosine, reduces DNA methylation of the ABCG1 gene promoter, upregulates ABCG1 expression, enhances cholesterol efflux, and reduces foam cell formation, suppressing atherosclerosis in ApoE-/- mice.\",\n      \"method\": \"Cre-LoxP myeloid-specific ADK knockout (LysM-Cre × ADKF/F × ApoE-/-), in vitro ADK inhibition, cholesterol efflux assay, DNA methylation (methylation-specific assays), atherosclerotic plaque quantification\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional knockout with multiple orthogonal mechanistic readouts (methylation, ABCG1 expression, cholesterol efflux, plaque size) in a single rigorous study\",\n      \"pmids\": [\"30571174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"ADK (adenosine kinase) activity is stimulated by pentavalent ions (phosphate, arsenate, vanadate) and phosphorylated compounds (e.g., phosphoribosyl pyrophosphate, phosphoenol pyruvate, creatine phosphate) that lower the Km for adenosine; structurally related compounds (phosphonoacetic acid, 2-carboxyethyl phosphonic acid) competitively inhibit AK. The mechanism proposed is that a bound phosphate forms a transient pentavalent intermediate with the β-phosphate of ATP, facilitating γ-phosphate transfer to adenosine.\",\n      \"method\": \"In vitro enzyme activity assays with a panel of phosphorylated compounds, Km determination, competitive inhibition analysis\",\n      \"journal\": \"The protein journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro enzymatic characterization with structure-activity analysis, but mechanistic model is interpretive and from a single lab\",\n      \"pmids\": [\"15106882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Overexpression of ADK in astrocytes within astrocytic brain tumors and peritumoral tissue is associated with tumor-associated epilepsy; ADK activity was significantly elevated in astrocytoma WHO grade III and peritumoral tissue compared to normal cortex, consistent with ADK acting as a negative regulator of extracellular adenosine to promote seizures.\",\n      \"method\": \"Immunohistochemistry, Western blot, ADK enzymatic activity assay in surgical specimens\",\n      \"journal\": \"Epilepsia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct enzymatic activity measurement combined with protein expression data in human tissue, replicated across multiple sample types\",\n      \"pmids\": [\"22092111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NLRP3 inflammasome activation upregulates ADK expression in astrocytes via the CREB/REST/SP1 signaling pathway: CREB and REST positively regulate ADK expression while SP1 negatively regulates it; knockdown of NLRP3 or Caspase-1 rescues the KA-induced changes, and CREB or REST silencing reduces ADK expression in KA-treated astrocytes.\",\n      \"method\": \"SE mouse model (kainic acid), siRNA knockdown (NLRP3, Caspase-1, CREB, REST, SP1), Western blot, ELISA, immunofluorescence staining; pharmacological inhibition (MCC950, Z-YVAD-FMK)\",\n      \"journal\": \"Neurochemical research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple siRNA targets with specific pathway epistasis tested, but single lab study\",\n      \"pmids\": [\"34797502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In the mussel Mytilopsis sallei, adenosine kinase (ADK) is the molecular target of adenosine; ATP-dependent phosphorylation of adenosine by ADK activates the downstream AMPK-FoxO signaling pathway, inducing larval settlement and metamorphosis.\",\n      \"method\": \"Transcriptomic analysis, pharmacological assays, temporal/spatial gene expression analysis, siRNA interference\",\n      \"journal\": \"ACS chemical biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA epistasis plus pharmacological validation in a marine invertebrate ortholog context, multiple methods, single lab\",\n      \"pmids\": [\"34254778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Hyperibone J binds ADK at the ASN-312 site, reducing ADK protein stability and expression in microglia. Reduced ADK attenuates the ATP/P2X7R/Caspase-1-mediated maturation and release of IL-1β, and inhibits TLR4/NF-κB-driven transcription of Nlrp3, Il-1b, Tnf, and Il-6, producing antidepressant and anti-neuroinflammatory effects.\",\n      \"method\": \"Network pharmacology, molecular docking, RNA-seq, Western blot, qPCR, ELISA; in vitro LPS-induced BV-2 microglia model, in vivo depression models\",\n      \"journal\": \"Journal of advanced research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — binding site identification is computational/molecular biology, but downstream pathway effects validated by multiple biochemical readouts; single lab\",\n      \"pmids\": [\"39019111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Berberine promotes ADK expression, increasing AMP levels and the AMP/ATP ratio, which activates AMPK and downstream Nrf2 signaling; siADK knockdown abolishes the hepatoprotective effects of berberine in hepatocytes, placing ADK upstream of AMPK/Nrf2 in a pathway mediating anti-inflammatory and antioxidant hepatic protection.\",\n      \"method\": \"siRNA knockdown of ADK in HepG2 and BRL-3A cells, AMP/ATP measurement, Western blot (p-AMPK, Nrf2, HO-1), ROS and MDA assays; in vivo rat fructose model\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA epistasis places ADK upstream of AMPK/Nrf2, orthogonal metabolic and protein readouts, single lab\",\n      \"pmids\": [\"39243432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"A homozygous missense mutation in ADK (c.427T>C, p.Cys143Arg) causes adenosine kinase deficiency leading to hypermethioninemia and severe intellectual disability in humans, establishing that ADK function is required for normal methionine metabolism.\",\n      \"method\": \"Whole exome sequencing, clinical phenotyping\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — genetic discovery via sequencing; mechanistic inference (ADK required for methionine cycle) is indirect from loss-of-function phenotype, no biochemical rescue\",\n      \"pmids\": [\"30771478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"A nonsense mutation in AK-1 (Arg107Stop) results in a truncated 107-amino acid protein with completely absent adenylate kinase activity and causes chronic haemolytic anaemia with elevated 2,3-DPG in erythrocytes, demonstrating that AK-1 enzymatic activity is required for normal red cell energy metabolism.\",\n      \"method\": \"cDNA sequencing, enzyme activity assay in red cell lysates, clinical phenotyping\",\n      \"journal\": \"British journal of haematology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — loss-of-function mutation with enzyme activity readout in human patients; no biochemical rescue experiment\",\n      \"pmids\": [\"10233365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1983,\n      \"finding\": \"An adenylate kinase-associated protein (Mr ~34,000) co-purifies with both wild-type and temperature-sensitive mutant E. coli adenylate kinase through multiple purification steps, and alters the thermolability of the mutant enzyme in a concentration-dependent manner, indicating this protein can regulate adenylate kinase activity.\",\n      \"method\": \"Protein purification, SDS-PAGE, thermolability assay at 40°C, co-purification\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — co-purification and thermolability effect shown in E. coli, single lab, no molecular identity of the associated protein established\",\n      \"pmids\": [\"6313692\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ADK (adenosine kinase) phosphorylates adenosine to AMP using ATP as phosphate donor, with activity stimulated by pentavalent ions that facilitate γ-phosphate transfer; the long isoform localizes to the nucleus via a specific NLS and sustains methylation reactions, while the short isoform is cytoplasmic; astrocytic ADK is a key negative regulator of extracellular adenosine homeostasis in the brain (controlling seizure threshold), regulates intracellular adenosine levels in myeloid cells to epigenetically control cholesterol trafficking via ABCG1 DNA methylation, and is transcriptionally regulated by the NLRP3/Caspase-1/CREB/REST/SP1 axis during epileptogenesis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ADK (adenosine kinase) is the ATP-dependent kinase that phosphorylates adenosine to AMP, serving as the principal metabolic regulator of intracellular and extracellular adenosine and thereby controlling adenosine-dependent signaling and methylation reactions [#3]. Catalysis is stimulated by pentavalent ions (phosphate, arsenate, vanadate) and phosphorylated compounds that lower the Km for adenosine, with the proposed mechanism being formation of a transient pentavalent phosphate intermediate at the \\u03b2-phosphate of ATP that facilitates \\u03b3-phosphate transfer [#3]. The enzyme exists as two isoforms with distinct localization: the long isoform carries an N-terminal nuclear localization signal (cluster PKPKKLKVE) directing it to the nucleus where it sustains methylation reactions, while the short isoform is cytoplasmic [#0]. In the brain, astrocytic ADK acts as a negative regulator of extracellular adenosine: ADK upregulation, rather than astrogliosis itself, drives seizure generation [#1], and elevated ADK accompanies tumor-associated epilepsy in human astrocytoma tissue [#4]. ADK expression in astrocytes is transcriptionally controlled by an NLRP3 inflammasome/Caspase-1 axis acting through CREB and REST (positive) and SP1 (negative) regulators [#5]. In myeloid cells, ADK governs intracellular adenosine to set DNA methylation of the ABCG1 promoter, with ADK deletion raising adenosine, reducing ABCG1 methylation, enhancing cholesterol efflux, and suppressing atherosclerosis [#2]. Loss-of-function evidence links ADK to one-carbon metabolism: a homozygous p.Cys143Arg mutation causes adenosine kinase deficiency with hypermethioninemia and severe intellectual disability [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established the catalytic logic of ADK by defining how phosphate transfer to adenosine is achieved, answering how the enzyme couples ATP hydrolysis to adenosine phosphorylation.\",\n      \"evidence\": \"In vitro enzyme assays with a panel of phosphorylated compounds, Km determination and competitive inhibition analysis\",\n      \"pmids\": [\"15106882\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Pentavalent intermediate model is interpretive without a crystallographic transition-state structure\", \"Single lab characterization\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Resolved why ADK has dual subcellular roles by showing isoform-specific localization, linking the nuclear long isoform to methylation and the cytoplasmic short isoform to bulk adenosine metabolism.\",\n      \"evidence\": \"Immunofluorescence, c-myc and GFP fusion constructs, and site-directed mutagenesis of the NLS in cells\",\n      \"pmids\": [\"19635462\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"The nuclear methylation role is proposed rather than directly demonstrated by a methylation readout in this study\", \"Functional separation of isoform substrate preferences not established\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrated causality between ADK expression and epilepsy by genetically uncoupling ADK upregulation from astrogliosis, showing ADK level itself drives seizures.\",\n      \"evidence\": \"Transgenic mouse with endogenous Adk deleted and a ubiquitous transgene, targeted CA3 injury, electrophysiology and histology\",\n      \"pmids\": [\"19674507\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Does not define the transcriptional drivers of astrocytic ADK upregulation\", \"Extracellular adenosine measurements inferred rather than directly tracked\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Extended the ADK-seizure model to human pathology by showing elevated ADK in astrocytoma and peritumoral tissue associated with tumor-associated epilepsy.\",\n      \"evidence\": \"Immunohistochemistry, Western blot and ADK enzymatic activity assays in human surgical specimens\",\n      \"pmids\": [\"22092111\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Correlative human tissue data without genetic manipulation\", \"Causal contribution of ADK to tumor epileptogenesis not directly tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed an epigenetic output of ADK metabolism by linking myeloid intracellular adenosine to ABCG1 promoter methylation and cholesterol efflux, establishing ADK as a regulator of foam cell formation and atherosclerosis.\",\n      \"evidence\": \"Myeloid-specific Cre-LoxP ADK knockout in ApoE-/- mice, cholesterol efflux assay, methylation-specific assays, plaque quantification\",\n      \"pmids\": [\"30571174\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanistic link from adenosine to DNA methyltransferase activity (via SAH) inferred rather than directly demonstrated\", \"Specific methyltransferase responsible not identified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified the transcriptional control circuit driving astrocytic ADK during epileptogenesis, placing NLRP3/Caspase-1 upstream of CREB/REST/SP1 regulation of ADK.\",\n      \"evidence\": \"Kainic acid status epilepticus mouse model, siRNA knockdown of NLRP3, Caspase-1, CREB, REST and SP1, with pharmacological inflammasome inhibition\",\n      \"pmids\": [\"34797502\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct promoter occupancy of CREB/REST/SP1 on the ADK gene not shown\", \"Single lab study\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed ADK functions as a signaling node beyond metabolism in an invertebrate, acting as the adenosine target that activates AMPK-FoxO to drive larval settlement.\",\n      \"evidence\": \"Transcriptomics, pharmacological assays and siRNA interference in the mussel Mytilopsis sallei\",\n      \"pmids\": [\"34254778\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Ortholog context may not transfer to mammalian ADK signaling\", \"Direct biochemical link from ADK product to AMPK not dissected\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected ADK to AMPK-dependent stress responses by showing its product can drive the AMP/ATP ratio, placing ADK upstream of AMPK/Nrf2 hepatoprotective signaling.\",\n      \"evidence\": \"siRNA knockdown of ADK in HepG2 and BRL-3A cells, AMP/ATP and ROS measurements, in vivo rat fructose model\",\n      \"pmids\": [\"39243432\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Single lab; direction of ADK effect (increasing AMP) contrasts with its canonical adenosine-consuming role and is not reconciled\", \"Tissue specificity unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a druggable site on ADK (ASN-312) whose engagement destabilizes the protein and dampens microglial neuroinflammation, providing a chemical handle on ADK function.\",\n      \"evidence\": \"Network pharmacology, molecular docking, RNA-seq, biochemical readouts in LPS-induced BV-2 microglia and in vivo depression models\",\n      \"pmids\": [\"39019111\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Binding site identification is largely computational without co-crystal structure\", \"Mechanism of protein destabilization not biochemically resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Provided human genetic evidence that ADK is required for normal one-carbon/methionine metabolism, with loss of function causing hypermethioninemia and neurodevelopmental disease.\",\n      \"evidence\": \"Whole exome sequencing and clinical phenotyping identifying homozygous p.Cys143Arg\",\n      \"pmids\": [\"30771478\"],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No biochemical rescue or enzymatic characterization of the mutant\", \"Mechanistic link to methylation cycle inferred from phenotype only\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the nuclear vs cytoplasmic ADK isoforms differentially partition adenosine flux to control DNA/protein methylation across cell types remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No direct demonstration that nuclear ADK controls a specific methylation reaction\", \"No structural model of substrate-bound human ADK in the corpus\", \"Isoform-specific knockouts not reported\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [3, 0]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [3, 9]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8, 6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}