{"gene":"AK1","run_date":"2026-06-09T22:02:43","timeline":{"discoveries":[{"year":2000,"finding":"AK1 knockout hearts show 94% reduction in total AK activity and 36% reduction in beta-phosphoryl transfer; under hypoxia, AK1-deficient hearts exhibit blunted AK-catalyzed phosphotransfer response, lowered intracellular ATP levels, increased Pi/ATP ratio, and suppressed adenosine generation, demonstrating AK1 is essential for maintaining myocardial energetic homeostasis under metabolic stress.","method":"[18O]phosphoryl oxygen analysis, 31P NMR, mass spectrometry in AK1 knockout mice hearts","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (18O labeling, 31P NMR, mass spectrometry) in knockout model with well-defined phenotypic readouts; replicated in subsequent studies","pmids":["11006295"],"is_preprint":false},{"year":2002,"finding":"AK1 knockout hearts display accelerated loss of contractile force at ischemia onset and reduced nucleotide salvage on reperfusion (lower ATP, GTP, ADP, GDP); remaining ~40% beta-phosphoryl turnover is maintained via upregulation of other AK isoforms, creatine kinase flux, and glycolytic phosphotransfer, allowing postischemic contractile recovery to match wild-type levels.","method":"31P NMR, 18O phosphoryl labeling, metabolite assays in AK1 knockout mouse hearts under ischemia-reperfusion","journal":"American journal of physiology. Heart and circulatory physiology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods in defined knockout model, specific metabolic and contractile phenotype readouts","pmids":["12124227"],"is_preprint":false},{"year":2003,"finding":"Simultaneous disruption of cytosolic M-CK and AK1 isoenzymes in double-knockout mice severely reduces intracellular phosphotransfer communication and total ATP turnover under muscle load; in vitro actomyosin complex analysis showed hampered phosphoryl delivery to actomyosin ATPase, resulting in loss of contractile performance.","method":"18O labeling of Pi and ATP, actomyosin complex in vitro assay, metabolite ratio measurements in M-CK/AK1 double-knockout skeletal muscle","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro reconstitution of actomyosin ATPase combined with 18O labeling and genetic knockout, multiple orthogonal methods","pmids":["12730234"],"is_preprint":false},{"year":2004,"finding":"The AK1 gene produces two structurally distinct protein isoforms via alternative promoters and polyadenylation: cytosolic AK1 and membrane-bound AK1beta differing at the N-terminus. AK1beta localizes to the cellular membrane in transfected COS-1 and N2a cells, catalyzes ADP phosphorylation in vitro, and mediates AMP-induced activation of recombinant ATP-sensitive potassium channels in the presence of ATP.","method":"Northern analysis, immunohistochemistry, transfection in COS-1/N2a cells, in vitro phosphorylation assay, patch-clamp of recombinant KATP channels","journal":"Molecular and cellular biochemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods (localization, in vitro enzymatic assay, electrophysiology) in a single study","pmids":["14977170"],"is_preprint":false},{"year":2005,"finding":"In AK1 knockout skeletal muscle during fatiguing tetanic contractions, free ADP accumulates to ~1.7 mM (directly measured by 31P NMR spectroscopy), a concentration severalfold greater than previously estimated; despite this large ADP accumulation and energy decline, AK1-/- and wild-type muscles exhibited similar fatigue profiles.","method":"31P NMR spectroscopy of in situ contracting gastrocnemius muscle in AK1 knockout mice","journal":"American journal of physiology. Cell physiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vivo NMR measurement in defined knockout, first direct observation of free ADP in contracting muscle","pmids":["15689408"],"is_preprint":false},{"year":2007,"finding":"AK1 knockout disrupts synchrony between Pi turnover at ATP-consuming sites and gamma-ATP exchange at synthesis sites; AK1 deletion blunts vascular AK phosphotransfer, compromises the contractility-coronary flow relationship, and precipitates inadequate coronary reflow post-ischemia. The sarcolemma-associated splice variant AK1beta facilitates adenosine production—a function lost in AK1 null mice—and adenosine treatment rescues post-ischemic coronary flow to wild-type levels.","method":"18O-assisted 31P NMR in AK1 knockout hearts, coronary flow measurements, adenosine rescue experiment","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (18O NMR, flow physiology, pharmacological rescue), mechanistic pathway established through genetic and chemical epistasis","pmids":["17704060"],"is_preprint":false},{"year":1988,"finding":"In yeast Saccharomyces cerevisiae, disruption of the ADK1 (AK1 ortholog) gene is needed for normal cell proliferation but is not essential for viability; extracts of disrupted cells retain ~10% wild-type AK enzymatic activity, indicating existence of additional AK isozymes. 31P NMR of mutant cells shows a significant decrease in nucleoside triphosphate levels.","method":"Gene disruption, immunological assay, 31P NMR of yeast cell suspensions","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — gene disruption with enzymatic and NMR functional readouts; ortholog study in budding yeast consistent with mammalian AK1 function","pmids":["2848829"],"is_preprint":false},{"year":1997,"finding":"A homozygous A→G substitution at codon 164 (Tyr→Cys) of the human AK1 gene results in spectrophotometrically undetectable erythrocyte adenylate kinase activity and is associated with congenital chronic hemolytic anemia, establishing this residue as critical for AK1 enzymatic function.","method":"PCR-SSCP, Sanger sequencing of AK1 gene, spectrophotometric AK activity assay in patient red blood cells","journal":"British journal of haematology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — natural loss-of-function mutation with enzymatic activity measurement and sequencing; single family but two orthogonal methods","pmids":["9432020"],"is_preprint":false},{"year":1999,"finding":"A nonsense homozygous mutation at codon 107 (Arg→Stop, CGA→TGA) in the AK1 gene produces a truncated 107-amino-acid protein with complete loss of AK activity, causing chronic hemolytic anemia and psychomotor impairment, defining Arg107 as essential for functional AK1 protein.","method":"cDNA sequencing of AK1, functional AK activity assays in patient erythrocytes","journal":"British journal of haematology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — natural loss-of-function allele with activity confirmation; two orthogonal methods (sequencing + enzyme assay), single family","pmids":["10233365"],"is_preprint":false},{"year":1990,"finding":"AK1 isoenzyme localizes to the cytosol of bovine skeletal muscle, heart, aorta, and brain (isoelectric focusing pI ≥ 9 and 8.6), distinct from mitochondrial AK2 (pI 7.9 and 7.1 in liver/kidney), as confirmed by immunostaining with anti-AK1 monoclonal antibody. Partial purification established apparent Mr of 23.5 kDa for cytosolic AK1.","method":"Isoelectric focusing, immunostaining with monoclonal antibody, chromatofocusing, partial protein purification","journal":"Enzyme","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — multiple methods (IEF, immunostaining, chromatofocusing) in a single study establishing subcellular distribution","pmids":["2261892"],"is_preprint":false},{"year":2023,"finding":"ODF4 co-immunoprecipitates with AK1 and AK2 in mouse spermatozoa; in Odf4-/- sperm, AK1 and AK2 are reduced and flagellar shape is abnormal (hairpin flagellum with large cytoplasmic droplet), causing male infertility. Restoration of Odf4 rescues the abnormalities, establishing ODF4 as a binding partner required for proper AK1 localization/retention in sperm flagella.","method":"Co-immunoprecipitation, Odf4 knockout and rescue mouse model, immunolocalization, fertility assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus genetic knockout with rescue, single lab","pmids":["36804949"],"is_preprint":false},{"year":2024,"finding":"Dinucleoside polyphosphate derivatives inhibit human AK1 catalytic activity in vitro; Ap5A shows the strongest inhibition (IC50 < 1 µM). Molecular docking maps binding of these compounds to hAK1, and QSAR modeling predicts inhibitory potency based on structural features.","method":"In vitro enzymatic inhibition assays with purified human AK1, molecular docking, QSAR analysis","journal":"Bioorganic chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay with multiple compounds and molecular docking, single lab without mutagenesis validation","pmids":["38744169"],"is_preprint":false},{"year":2022,"finding":"DARTS technology combined with LC-MS identified AK1 as a brain protein target of ginsenosides; biolayer interferometry confirmed direct binding of protopanaxadiol (PPD) to His-AK1 fusion protein (KD ≈ 8.52×10−5 mol/L), and molecular docking showed hydrogen bond interactions at the AK1 binding site.","method":"DARTS/LC-MS screening, biolayer interferometry with purified His-AK1 fusion protein, molecular docking","journal":"Zhongguo Zhong yao za zhi","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, binding confirmed by BLI but no functional/mutagenesis validation; docking is computational","pmids":["35343162"],"is_preprint":false}],"current_model":"AK1 (adenylate kinase 1) is a cytosolic phosphotransferase that catalyzes the reversible reaction 2ADP ⇌ ATP + AMP; it is essential for intracellular energy communication and nucleotide homeostasis, particularly under metabolic stress (hypoxia, ischemia), where it maintains ATP levels, generates AMP/adenosine signals for cardioprotection and coronary vasodilatation, and supports actomyosin ATPase function in muscle; a membrane-targeted splice variant (AK1beta) additionally activates ATP-sensitive potassium channels and facilitates adenosine production at the sarcolemma, while loss-of-function mutations in the AK1 gene abolish erythrocyte AK activity and cause congenital hemolytic anemia."},"narrative":{"mechanistic_narrative":"AK1 is a cytosolic phosphotransferase that sustains intracellular energy communication and nucleotide homeostasis, functioning as a critical node in the high-energy phosphoryl relay between ATP-producing and ATP-consuming sites [PMID:11006295, PMID:2261892]. In the heart, AK1-catalyzed beta-phosphoryl transfer maintains myocardial energetic homeostasis under metabolic stress: its loss lowers intracellular ATP, raises the Pi/ATP ratio, suppresses adenosine generation, and accelerates contractile failure at the onset of ischemia, with residual phosphotransfer compensated by other AK isoforms, creatine kinase, and glycolytic flux [PMID:11006295, PMID:12124227]. AK1 phosphotransfer also synchronizes Pi turnover at ATP-consuming sites with gamma-ATP exchange at synthesis sites and couples cardiac contractility to coronary flow, with a sarcolemma-associated splice variant AK1beta facilitating adenosine production that rescues post-ischemic coronary reflow [PMID:17704060]. In skeletal muscle, AK1 contributes to phosphoryl delivery to the actomyosin ATPase, and its combined disruption with cytosolic creatine kinase severely curtails total ATP turnover and contractile performance [PMID:12730234]. The AK1 gene generates two isoforms via alternative promoters and polyadenylation—cytosolic AK1 and N-terminally distinct membrane-bound AK1beta, which localizes to the plasma membrane and mediates AMP-induced activation of ATP-sensitive potassium channels [PMID:14977170]. Human loss-of-function mutations abolishing erythrocyte AK activity cause congenital chronic hemolytic anemia, identifying Tyr164 and Arg107 as residues essential for enzymatic function [PMID:9432020, PMID:10233365].","teleology":[{"year":1988,"claim":"Establishing whether the adenylate kinase gene is essential and whether redundant isozymes exist was answered first in yeast, where disruption impaired proliferation but not viability and left residual AK activity.","evidence":"ADK1 gene disruption with immunological assay and 31P NMR in S. cerevisiae","pmids":["2848829"],"confidence":"High","gaps":["Does not address mammalian isoform organization","Identity of the compensating isozymes not defined"]},{"year":1990,"claim":"Defining where AK1 acts and distinguishing it from mitochondrial AK2 established AK1 as the cytosolic isoenzyme across multiple tissues.","evidence":"Isoelectric focusing, monoclonal antibody immunostaining, and partial purification from bovine tissues","pmids":["2261892"],"confidence":"Medium","gaps":["Subcellular distribution inferred biochemically, not by live imaging","Functional consequence of cytosolic localization not tested"]},{"year":1997,"claim":"Linking AK1 to human disease, a Tyr164Cys substitution abolishing erythrocyte AK activity established the residue as functionally critical and tied AK1 loss to hemolytic anemia.","evidence":"PCR-SSCP, Sanger sequencing, and spectrophotometric AK assay in patient red cells","pmids":["9432020"],"confidence":"Medium","gaps":["Single family","Mechanism linking enzyme loss to hemolysis not resolved"]},{"year":1999,"claim":"A nonsense Arg107Stop allele producing a truncated inactive protein confirmed the genotype-phenotype link and extended it to psychomotor impairment.","evidence":"cDNA sequencing and erythrocyte AK activity assay in patients","pmids":["10233365"],"confidence":"Medium","gaps":["Single family","Basis of neurological involvement not established"]},{"year":2000,"claim":"Determining AK1's quantitative role in cardiac energetics, a knockout showing near-total loss of AK phosphotransfer with collapse of ATP buffering and adenosine signaling under hypoxia established AK1 as essential for myocardial energetic homeostasis under stress.","evidence":"[18O] phosphoryl analysis, 31P NMR, and mass spectrometry in AK1 knockout mouse hearts","pmids":["11006295"],"confidence":"High","gaps":["Compensating pathways not yet quantified","Does not address membrane-bound isoform"]},{"year":2002,"claim":"Resolving how hearts survive AK1 loss, ischemia-reperfusion studies showed compensatory creatine kinase, glycolytic, and AK-isoform flux restores postischemic recovery despite acute contractile vulnerability.","evidence":"31P NMR, 18O labeling, and metabolite assays in AK1 knockout hearts under ischemia-reperfusion","pmids":["12124227"],"confidence":"High","gaps":["Identity and regulation of upregulated AK isoforms not detailed"]},{"year":2003,"claim":"Testing AK1's contribution to muscle ATPase fueling, double knockout with M-CK demonstrated that AK1 phosphotransfer supports phosphoryl delivery to the actomyosin ATPase and total ATP turnover under load.","evidence":"18O labeling, in vitro actomyosin complex assay, and metabolite measurements in M-CK/AK1 double-knockout skeletal muscle","pmids":["12730234"],"confidence":"High","gaps":["Relative contribution of AK1 alone versus M-CK not separated","Mechanism of phosphoryl channeling to ATPase not structurally defined"]},{"year":2004,"claim":"Characterizing the gene's two products, alternative promoter/polyadenylation usage was shown to yield cytosolic AK1 and membrane-bound AK1beta, the latter activating KATP channels, linking AK1 phosphotransfer to membrane excitability.","evidence":"Northern analysis, transfection localization, in vitro phosphorylation, and patch-clamp of recombinant KATP channels","pmids":["14977170"],"confidence":"High","gaps":["Endogenous tissue distribution of AK1beta not mapped","Direct channel interaction versus local nucleotide effect not distinguished"]},{"year":2005,"claim":"Directly measuring the metabolic cost of AK1 loss in muscle revealed large free ADP accumulation during fatiguing contractions, yet fatigue profiles were unchanged, indicating redundancy in energetic buffering.","evidence":"31P NMR of in situ contracting gastrocnemius in AK1 knockout mice","pmids":["15689408"],"confidence":"High","gaps":["Compensating buffering systems not identified in this assay"]},{"year":2007,"claim":"Connecting AK1 to vascular function, knockout studies showed AK1 deletion uncouples contractility from coronary flow and that AK1beta-facilitated adenosine production, restorable pharmacologically, drives post-ischemic coronary reflow.","evidence":"18O-assisted 31P NMR, coronary flow measurement, and adenosine rescue in AK1 knockout hearts","pmids":["17704060"],"confidence":"High","gaps":["Step linking AK1beta to adenosine-producing enzymes not defined","AK1beta-specific genetic ablation not performed"]},{"year":2023,"claim":"Identifying a context-specific binding partner, ODF4 was shown to co-IP with AK1 and be required for AK1 retention in sperm flagella, linking AK1 localization to flagellar morphology and male fertility.","evidence":"Reciprocal Co-IP, Odf4 knockout/rescue mouse model, immunolocalization, and fertility assays","pmids":["36804949"],"confidence":"Medium","gaps":["Single lab","Whether ODF4 binds AK1 directly versus within a complex not resolved","Functional role of flagellar AK1 not directly tested"]},{"year":2024,"claim":"Defining pharmacological modulation, dinucleoside polyphosphates including Ap5A were shown to potently inhibit human AK1 in vitro, providing chemical tools and structural binding models.","evidence":"In vitro enzymatic inhibition with purified hAK1, molecular docking, and QSAR analysis","pmids":["38744169"],"confidence":"Medium","gaps":["No mutagenesis validation of docked binding mode","Cellular efficacy not tested"]},{"year":null,"claim":"How AK1beta is physically coupled to KATP channels and adenosine-generating enzymes at the sarcolemma, and whether the cytosolic and membrane isoforms have separable in vivo roles, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No isoform-specific knockout reported","No structure of AK1beta-channel assembly","Direct adenosine-generation enzyme partner not identified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,3,7,8,11]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3,9]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,1,2]},{"term_id":"R-HSA-397014","term_label":"Muscle contraction","supporting_discovery_ids":[2,4]}],"complexes":[],"partners":["ODF4","AK2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P00568","full_name":"Adenylate kinase isoenzyme 1","aliases":["ATP-AMP transphosphorylase 1","ATP:AMP phosphotransferase","Adenylate monophosphate kinase","Myokinase"],"length_aa":194,"mass_kda":21.6,"function":"Catalyzes the reversible transfer of the terminal phosphate group between ATP and AMP. Also displays broad nucleoside diphosphate kinase activity. Plays an important role in cellular energy homeostasis and in adenine nucleotide metabolism (By similarity) (PubMed:21080915, PubMed:23416111, PubMed:2542324). Also catalyzes at a very low rate the synthesis of thiamine triphosphate (ThTP) from thiamine diphosphate (ThDP) and ADP (By similarity)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P00568/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/AK1","classification":"Not Classified","n_dependent_lines":29,"n_total_lines":1208,"dependency_fraction":0.024006622516556293},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"SAR1B","stoichiometry":0.2},{"gene":"VAMP8","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/AK1","total_profiled":1310},"omim":[{"mim_id":"615365","title":"ADENYLATE KINASE 8; AK8","url":"https://www.omim.org/entry/615365"},{"mim_id":"615364","title":"ADENYLATE KINASE 7; AK7","url":"https://www.omim.org/entry/615364"},{"mim_id":"614982","title":"STRUCTURAL MAINTENANCE OF CHROMOSOMES FLEXIBLE HINGE DOMAIN-CONTAINING PROTEIN 1; SMCHD1","url":"https://www.omim.org/entry/614982"},{"mim_id":"613441","title":"TRANSCOBALAMIN II; TCN2","url":"https://www.omim.org/entry/613441"},{"mim_id":"612631","title":"ANEMIA, CONGENITAL, NONSPHEROCYTIC HEMOLYTIC, 3; CNSHA3","url":"https://www.omim.org/entry/612631"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"},{"location":"Annulus","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"choroid plexus","ntpm":522.7},{"tissue":"skeletal muscle","ntpm":1262.8},{"tissue":"tongue","ntpm":730.8}],"url":"https://www.proteinatlas.org/search/AK1"},"hgnc":{"alias_symbol":["ADK","Adk1"],"prev_symbol":[]},"alphafold":{"accession":"P00568","domains":[{"cath_id":"3.40.50.300","chopping":"1-194","consensus_level":"medium","plddt":95.9317,"start":1,"end":194}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P00568","model_url":"https://alphafold.ebi.ac.uk/files/AF-P00568-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P00568-F1-predicted_aligned_error_v6.png","plddt_mean":95.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=AK1","jax_strain_url":"https://www.jax.org/strain/search?query=AK1"},"sequence":{"accession":"P00568","fasta_url":"https://rest.uniprot.org/uniprotkb/P00568.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P00568/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P00568"}},"corpus_meta":[{"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 genetics","url":"https://pubmed.ncbi.nlm.nih.gov/184030","citation_count":105,"is_preprint":false},{"pmid":"11006295","id":"PMC_11006295","title":"Compromised energetics in the adenylate kinase AK1 gene knockout heart under metabolic stress.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11006295","citation_count":69,"is_preprint":false},{"pmid":"32004812","id":"PMC_32004812","title":"Cultivating Chlorella sorokiniana AK-1 with swine wastewater for simultaneous wastewater treatment and algal biomass production.","date":"2020","source":"Bioresource technology","url":"https://pubmed.ncbi.nlm.nih.gov/32004812","citation_count":64,"is_preprint":false},{"pmid":"16349542","id":"PMC_16349542","title":"Effect of Temperature on Adhesion of Vibrio Strain AK-1 to Oculina patagonica and on Coral Bleaching.","date":"1998","source":"Applied and environmental microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/16349542","citation_count":61,"is_preprint":false},{"pmid":"25312940","id":"PMC_25312940","title":"AK-1, a specific SIRT2 inhibitor, induces cell cycle arrest by downregulating Snail in HCT116 human colon carcinoma cells.","date":"2014","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/25312940","citation_count":60,"is_preprint":false},{"pmid":"12124227","id":"PMC_12124227","title":"Adenylate kinase AK1 knockout heart: energetics and functional performance under ischemia-reperfusion.","date":"2002","source":"American journal of physiology. 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Genetic and structural evidence for the conservation of mammalian autosomal synteny.","date":"1982","source":"The Journal of heredity","url":"https://pubmed.ncbi.nlm.nih.gov/7153494","citation_count":24,"is_preprint":false},{"pmid":"14977170","id":"PMC_14977170","title":"Two structurally distinct and spatially compartmentalized adenylate kinases are expressed from the AK1 gene in mouse brain.","date":"2004","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/14977170","citation_count":23,"is_preprint":false},{"pmid":"33548816","id":"PMC_33548816","title":"Semi-batch cultivation of Chlorella sorokiniana AK-1 with dual carriers for the effective treatment of full strength piggery wastewater treatment.","date":"2021","source":"Bioresource technology","url":"https://pubmed.ncbi.nlm.nih.gov/33548816","citation_count":23,"is_preprint":false},{"pmid":"28830944","id":"PMC_28830944","title":"Genome-Wide Mutation Rate Response to pH Change in the Coral Reef 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Jingyuan Chickens.","date":"2020","source":"Animals : an open access journal from MDPI","url":"https://pubmed.ncbi.nlm.nih.gov/32155715","citation_count":19,"is_preprint":false},{"pmid":"26808575","id":"PMC_26808575","title":"AK-1, a SIRT2 inhibitor, destabilizes HIF-1α and diminishes its transcriptional activity during hypoxia.","date":"2016","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/26808575","citation_count":19,"is_preprint":false},{"pmid":"29992154","id":"PMC_29992154","title":"Insights into Brevibacillus borstelensis AK1 through Whole Genome Sequencing: A Thermophilic Bacterium Isolated from a Hot Spring in Saudi Arabia.","date":"2018","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/29992154","citation_count":15,"is_preprint":false},{"pmid":"8088777","id":"PMC_8088777","title":"Genetic linkage analysis of the Ak1, Col5a1, Epb7.2, Fpgs, Grp78, Pbx3, and Notch1 genes in the region of mouse chromosome 2 homologous to human 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AK1.","date":"1990","source":"Enzyme","url":"https://pubmed.ncbi.nlm.nih.gov/2261892","citation_count":6,"is_preprint":false},{"pmid":"17937492","id":"PMC_17937492","title":"Homology model of a novel thermostable xylanase from Bacillus subtilis-AK1.","date":"2007","source":"Journal of biomolecular structure & dynamics","url":"https://pubmed.ncbi.nlm.nih.gov/17937492","citation_count":6,"is_preprint":false},{"pmid":"34321014","id":"PMC_34321014","title":"Rare hereditary nonspherocytic hemolytic anemia caused by a novel homozygous mutation, c.301C > A, (Q101K), in the AK1 gene in an Indian family.","date":"2021","source":"BMC medical genomics","url":"https://pubmed.ncbi.nlm.nih.gov/34321014","citation_count":5,"is_preprint":false},{"pmid":"23146316","id":"PMC_23146316","title":"Ak(1) genetic polymorphism and season of conception.","date":"2012","source":"European journal of obstetrics, gynecology, and reproductive 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AK1 and AK9.","date":"2024","source":"International journal of radiation biology","url":"https://pubmed.ncbi.nlm.nih.gov/38657135","citation_count":2,"is_preprint":false},{"pmid":"31615674","id":"PMC_31615674","title":"Genomic comparison of anoxybacillus flavithermus AK1, a thermophilic bacteria, with other strains.","date":"2019","source":"Enzyme and microbial technology","url":"https://pubmed.ncbi.nlm.nih.gov/31615674","citation_count":2,"is_preprint":false},{"pmid":"1647290","id":"PMC_1647290","title":"Mapping of silver fox genes: chromosomal localization of the genes for GOT2, AK1, ALDOC, ACP1, ITPA, PGP, and BLVR.","date":"1991","source":"Cytogenetics and cell genetics","url":"https://pubmed.ncbi.nlm.nih.gov/1647290","citation_count":2,"is_preprint":false},{"pmid":"1673557","id":"PMC_1673557","title":"PCR-based detection of polymorphic DdeI and KpnI sites in intron 5 of the adenylate kinase (AK1) gene.","date":"1991","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/1673557","citation_count":2,"is_preprint":false},{"pmid":"38744169","id":"PMC_38744169","title":"Synthesis, kinetic studies, and QSAR of dinucleoside polyphosphate derivatives as human AK1 inhibitors.","date":"2024","source":"Bioorganic chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/38744169","citation_count":1,"is_preprint":false},{"pmid":"19048477","id":"PMC_19048477","title":"Pig KALRN, MYH1, MLC2V, SNX13, AK1, and PPIA loci RH mapping and chromosome position refining.","date":"2008","source":"Genetics and molecular research : GMR","url":"https://pubmed.ncbi.nlm.nih.gov/19048477","citation_count":1,"is_preprint":false},{"pmid":"2074010","id":"PMC_2074010","title":"[Mapping of the silver fox genome. III. Determination of the chromosomal localization of the GOT2, AK1, ALDOC, ACP1, ITPA, PGP and BLVR genes].","date":"1990","source":"Genetika","url":"https://pubmed.ncbi.nlm.nih.gov/2074010","citation_count":1,"is_preprint":false},{"pmid":"35343162","id":"PMC_35343162","title":"[Discovery and confirmation of protein action site AK1 of ginsenosides in brain based on DARTS technology].","date":"2022","source":"Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica","url":"https://pubmed.ncbi.nlm.nih.gov/35343162","citation_count":0,"is_preprint":false},{"pmid":"40016400","id":"PMC_40016400","title":"Novel AK-1 gene variants combined with thalassemia causing rare hereditary non-spherocytic hemolytic anemia in a Chinese family.","date":"2025","source":"Annals of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/40016400","citation_count":0,"is_preprint":false},{"pmid":"210969","id":"PMC_210969","title":"[Rare electrophoretic variants of the proteins adenylate kinase 1, phosphoglucomutase 1 and 2, and transferrin (AK1, PGM1, PGM2, Tf) in two populations of French Guiana].","date":"1978","source":"Comptes rendus hebdomadaires des seances de l'Academie des sciences. Serie D: Sciences naturelles","url":"https://pubmed.ncbi.nlm.nih.gov/210969","citation_count":0,"is_preprint":false},{"pmid":"42240388","id":"PMC_42240388","title":"Complete genome sequence of Thermus scotoductus AK-1 isolated from an Arctic hydrothermal site in Alaska.","date":"2026","source":"Microbiology resource announcements","url":"https://pubmed.ncbi.nlm.nih.gov/42240388","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.11.09.622791","title":"Isolation, Characterization, and Identification of Nitrogen Fixing Bacteria from Rhizosphere of  <i>Sonneratia apetala</i>  Collected from Sundarbans","date":"2024-11-09","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.09.622791","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":22651,"output_tokens":3378,"usd":0.059312,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10979,"output_tokens":3687,"usd":0.073535,"stage2_stop_reason":"end_turn"},"total_usd":0.132847,"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\": 2000,\n      \"finding\": \"AK1 knockout hearts show 94% reduction in total AK activity and 36% reduction in beta-phosphoryl transfer; under hypoxia, AK1-deficient hearts exhibit blunted AK-catalyzed phosphotransfer response, lowered intracellular ATP levels, increased Pi/ATP ratio, and suppressed adenosine generation, demonstrating AK1 is essential for maintaining myocardial energetic homeostasis under metabolic stress.\",\n      \"method\": \"[18O]phosphoryl oxygen analysis, 31P NMR, mass spectrometry in AK1 knockout mice hearts\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (18O labeling, 31P NMR, mass spectrometry) in knockout model with well-defined phenotypic readouts; replicated in subsequent studies\",\n      \"pmids\": [\"11006295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"AK1 knockout hearts display accelerated loss of contractile force at ischemia onset and reduced nucleotide salvage on reperfusion (lower ATP, GTP, ADP, GDP); remaining ~40% beta-phosphoryl turnover is maintained via upregulation of other AK isoforms, creatine kinase flux, and glycolytic phosphotransfer, allowing postischemic contractile recovery to match wild-type levels.\",\n      \"method\": \"31P NMR, 18O phosphoryl labeling, metabolite assays in AK1 knockout mouse hearts under ischemia-reperfusion\",\n      \"journal\": \"American journal of physiology. Heart and circulatory physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods in defined knockout model, specific metabolic and contractile phenotype readouts\",\n      \"pmids\": [\"12124227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Simultaneous disruption of cytosolic M-CK and AK1 isoenzymes in double-knockout mice severely reduces intracellular phosphotransfer communication and total ATP turnover under muscle load; in vitro actomyosin complex analysis showed hampered phosphoryl delivery to actomyosin ATPase, resulting in loss of contractile performance.\",\n      \"method\": \"18O labeling of Pi and ATP, actomyosin complex in vitro assay, metabolite ratio measurements in M-CK/AK1 double-knockout skeletal muscle\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro reconstitution of actomyosin ATPase combined with 18O labeling and genetic knockout, multiple orthogonal methods\",\n      \"pmids\": [\"12730234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The AK1 gene produces two structurally distinct protein isoforms via alternative promoters and polyadenylation: cytosolic AK1 and membrane-bound AK1beta differing at the N-terminus. AK1beta localizes to the cellular membrane in transfected COS-1 and N2a cells, catalyzes ADP phosphorylation in vitro, and mediates AMP-induced activation of recombinant ATP-sensitive potassium channels in the presence of ATP.\",\n      \"method\": \"Northern analysis, immunohistochemistry, transfection in COS-1/N2a cells, in vitro phosphorylation assay, patch-clamp of recombinant KATP channels\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods (localization, in vitro enzymatic assay, electrophysiology) in a single study\",\n      \"pmids\": [\"14977170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"In AK1 knockout skeletal muscle during fatiguing tetanic contractions, free ADP accumulates to ~1.7 mM (directly measured by 31P NMR spectroscopy), a concentration severalfold greater than previously estimated; despite this large ADP accumulation and energy decline, AK1-/- and wild-type muscles exhibited similar fatigue profiles.\",\n      \"method\": \"31P NMR spectroscopy of in situ contracting gastrocnemius muscle in AK1 knockout mice\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vivo NMR measurement in defined knockout, first direct observation of free ADP in contracting muscle\",\n      \"pmids\": [\"15689408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"AK1 knockout disrupts synchrony between Pi turnover at ATP-consuming sites and gamma-ATP exchange at synthesis sites; AK1 deletion blunts vascular AK phosphotransfer, compromises the contractility-coronary flow relationship, and precipitates inadequate coronary reflow post-ischemia. The sarcolemma-associated splice variant AK1beta facilitates adenosine production—a function lost in AK1 null mice—and adenosine treatment rescues post-ischemic coronary flow to wild-type levels.\",\n      \"method\": \"18O-assisted 31P NMR in AK1 knockout hearts, coronary flow measurements, adenosine rescue experiment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (18O NMR, flow physiology, pharmacological rescue), mechanistic pathway established through genetic and chemical epistasis\",\n      \"pmids\": [\"17704060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"In yeast Saccharomyces cerevisiae, disruption of the ADK1 (AK1 ortholog) gene is needed for normal cell proliferation but is not essential for viability; extracts of disrupted cells retain ~10% wild-type AK enzymatic activity, indicating existence of additional AK isozymes. 31P NMR of mutant cells shows a significant decrease in nucleoside triphosphate levels.\",\n      \"method\": \"Gene disruption, immunological assay, 31P NMR of yeast cell suspensions\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — gene disruption with enzymatic and NMR functional readouts; ortholog study in budding yeast consistent with mammalian AK1 function\",\n      \"pmids\": [\"2848829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"A homozygous A→G substitution at codon 164 (Tyr→Cys) of the human AK1 gene results in spectrophotometrically undetectable erythrocyte adenylate kinase activity and is associated with congenital chronic hemolytic anemia, establishing this residue as critical for AK1 enzymatic function.\",\n      \"method\": \"PCR-SSCP, Sanger sequencing of AK1 gene, spectrophotometric AK activity assay in patient red blood cells\",\n      \"journal\": \"British journal of haematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — natural loss-of-function mutation with enzymatic activity measurement and sequencing; single family but two orthogonal methods\",\n      \"pmids\": [\"9432020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"A nonsense homozygous mutation at codon 107 (Arg→Stop, CGA→TGA) in the AK1 gene produces a truncated 107-amino-acid protein with complete loss of AK activity, causing chronic hemolytic anemia and psychomotor impairment, defining Arg107 as essential for functional AK1 protein.\",\n      \"method\": \"cDNA sequencing of AK1, functional AK activity assays in patient erythrocytes\",\n      \"journal\": \"British journal of haematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — natural loss-of-function allele with activity confirmation; two orthogonal methods (sequencing + enzyme assay), single family\",\n      \"pmids\": [\"10233365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"AK1 isoenzyme localizes to the cytosol of bovine skeletal muscle, heart, aorta, and brain (isoelectric focusing pI ≥ 9 and 8.6), distinct from mitochondrial AK2 (pI 7.9 and 7.1 in liver/kidney), as confirmed by immunostaining with anti-AK1 monoclonal antibody. Partial purification established apparent Mr of 23.5 kDa for cytosolic AK1.\",\n      \"method\": \"Isoelectric focusing, immunostaining with monoclonal antibody, chromatofocusing, partial protein purification\",\n      \"journal\": \"Enzyme\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — multiple methods (IEF, immunostaining, chromatofocusing) in a single study establishing subcellular distribution\",\n      \"pmids\": [\"2261892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ODF4 co-immunoprecipitates with AK1 and AK2 in mouse spermatozoa; in Odf4-/- sperm, AK1 and AK2 are reduced and flagellar shape is abnormal (hairpin flagellum with large cytoplasmic droplet), causing male infertility. Restoration of Odf4 rescues the abnormalities, establishing ODF4 as a binding partner required for proper AK1 localization/retention in sperm flagella.\",\n      \"method\": \"Co-immunoprecipitation, Odf4 knockout and rescue mouse model, immunolocalization, fertility assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus genetic knockout with rescue, single lab\",\n      \"pmids\": [\"36804949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Dinucleoside polyphosphate derivatives inhibit human AK1 catalytic activity in vitro; Ap5A shows the strongest inhibition (IC50 < 1 µM). Molecular docking maps binding of these compounds to hAK1, and QSAR modeling predicts inhibitory potency based on structural features.\",\n      \"method\": \"In vitro enzymatic inhibition assays with purified human AK1, molecular docking, QSAR analysis\",\n      \"journal\": \"Bioorganic chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay with multiple compounds and molecular docking, single lab without mutagenesis validation\",\n      \"pmids\": [\"38744169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DARTS technology combined with LC-MS identified AK1 as a brain protein target of ginsenosides; biolayer interferometry confirmed direct binding of protopanaxadiol (PPD) to His-AK1 fusion protein (KD ≈ 8.52×10−5 mol/L), and molecular docking showed hydrogen bond interactions at the AK1 binding site.\",\n      \"method\": \"DARTS/LC-MS screening, biolayer interferometry with purified His-AK1 fusion protein, molecular docking\",\n      \"journal\": \"Zhongguo Zhong yao za zhi\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, binding confirmed by BLI but no functional/mutagenesis validation; docking is computational\",\n      \"pmids\": [\"35343162\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"AK1 (adenylate kinase 1) is a cytosolic phosphotransferase that catalyzes the reversible reaction 2ADP ⇌ ATP + AMP; it is essential for intracellular energy communication and nucleotide homeostasis, particularly under metabolic stress (hypoxia, ischemia), where it maintains ATP levels, generates AMP/adenosine signals for cardioprotection and coronary vasodilatation, and supports actomyosin ATPase function in muscle; a membrane-targeted splice variant (AK1beta) additionally activates ATP-sensitive potassium channels and facilitates adenosine production at the sarcolemma, while loss-of-function mutations in the AK1 gene abolish erythrocyte AK activity and cause congenital hemolytic anemia.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"AK1 is a cytosolic phosphotransferase that sustains intracellular energy communication and nucleotide homeostasis, functioning as a critical node in the high-energy phosphoryl relay between ATP-producing and ATP-consuming sites [#0, #9]. In the heart, AK1-catalyzed beta-phosphoryl transfer maintains myocardial energetic homeostasis under metabolic stress: its loss lowers intracellular ATP, raises the Pi/ATP ratio, suppresses adenosine generation, and accelerates contractile failure at the onset of ischemia, with residual phosphotransfer compensated by other AK isoforms, creatine kinase, and glycolytic flux [#0, #1]. AK1 phosphotransfer also synchronizes Pi turnover at ATP-consuming sites with gamma-ATP exchange at synthesis sites and couples cardiac contractility to coronary flow, with a sarcolemma-associated splice variant AK1beta facilitating adenosine production that rescues post-ischemic coronary reflow [#5]. In skeletal muscle, AK1 contributes to phosphoryl delivery to the actomyosin ATPase, and its combined disruption with cytosolic creatine kinase severely curtails total ATP turnover and contractile performance [#2]. The AK1 gene generates two isoforms via alternative promoters and polyadenylation—cytosolic AK1 and N-terminally distinct membrane-bound AK1beta, which localizes to the plasma membrane and mediates AMP-induced activation of ATP-sensitive potassium channels [#3]. Human loss-of-function mutations abolishing erythrocyte AK activity cause congenital chronic hemolytic anemia, identifying Tyr164 and Arg107 as residues essential for enzymatic function [#7, #8].\",\n  \"teleology\": [\n    {\n      \"year\": 1988,\n      \"claim\": \"Establishing whether the adenylate kinase gene is essential and whether redundant isozymes exist was answered first in yeast, where disruption impaired proliferation but not viability and left residual AK activity.\",\n      \"evidence\": \"ADK1 gene disruption with immunological assay and 31P NMR in S. cerevisiae\",\n      \"pmids\": [\"2848829\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address mammalian isoform organization\", \"Identity of the compensating isozymes not defined\"]\n    },\n    {\n      \"year\": 1990,\n      \"claim\": \"Defining where AK1 acts and distinguishing it from mitochondrial AK2 established AK1 as the cytosolic isoenzyme across multiple tissues.\",\n      \"evidence\": \"Isoelectric focusing, monoclonal antibody immunostaining, and partial purification from bovine tissues\",\n      \"pmids\": [\"2261892\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Subcellular distribution inferred biochemically, not by live imaging\", \"Functional consequence of cytosolic localization not tested\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Linking AK1 to human disease, a Tyr164Cys substitution abolishing erythrocyte AK activity established the residue as functionally critical and tied AK1 loss to hemolytic anemia.\",\n      \"evidence\": \"PCR-SSCP, Sanger sequencing, and spectrophotometric AK assay in patient red cells\",\n      \"pmids\": [\"9432020\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single family\", \"Mechanism linking enzyme loss to hemolysis not resolved\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"A nonsense Arg107Stop allele producing a truncated inactive protein confirmed the genotype-phenotype link and extended it to psychomotor impairment.\",\n      \"evidence\": \"cDNA sequencing and erythrocyte AK activity assay in patients\",\n      \"pmids\": [\"10233365\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single family\", \"Basis of neurological involvement not established\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Determining AK1's quantitative role in cardiac energetics, a knockout showing near-total loss of AK phosphotransfer with collapse of ATP buffering and adenosine signaling under hypoxia established AK1 as essential for myocardial energetic homeostasis under stress.\",\n      \"evidence\": \"[18O] phosphoryl analysis, 31P NMR, and mass spectrometry in AK1 knockout mouse hearts\",\n      \"pmids\": [\"11006295\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Compensating pathways not yet quantified\", \"Does not address membrane-bound isoform\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Resolving how hearts survive AK1 loss, ischemia-reperfusion studies showed compensatory creatine kinase, glycolytic, and AK-isoform flux restores postischemic recovery despite acute contractile vulnerability.\",\n      \"evidence\": \"31P NMR, 18O labeling, and metabolite assays in AK1 knockout hearts under ischemia-reperfusion\",\n      \"pmids\": [\"12124227\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity and regulation of upregulated AK isoforms not detailed\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Testing AK1's contribution to muscle ATPase fueling, double knockout with M-CK demonstrated that AK1 phosphotransfer supports phosphoryl delivery to the actomyosin ATPase and total ATP turnover under load.\",\n      \"evidence\": \"18O labeling, in vitro actomyosin complex assay, and metabolite measurements in M-CK/AK1 double-knockout skeletal muscle\",\n      \"pmids\": [\"12730234\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of AK1 alone versus M-CK not separated\", \"Mechanism of phosphoryl channeling to ATPase not structurally defined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Characterizing the gene's two products, alternative promoter/polyadenylation usage was shown to yield cytosolic AK1 and membrane-bound AK1beta, the latter activating KATP channels, linking AK1 phosphotransfer to membrane excitability.\",\n      \"evidence\": \"Northern analysis, transfection localization, in vitro phosphorylation, and patch-clamp of recombinant KATP channels\",\n      \"pmids\": [\"14977170\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous tissue distribution of AK1beta not mapped\", \"Direct channel interaction versus local nucleotide effect not distinguished\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Directly measuring the metabolic cost of AK1 loss in muscle revealed large free ADP accumulation during fatiguing contractions, yet fatigue profiles were unchanged, indicating redundancy in energetic buffering.\",\n      \"evidence\": \"31P NMR of in situ contracting gastrocnemius in AK1 knockout mice\",\n      \"pmids\": [\"15689408\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Compensating buffering systems not identified in this assay\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Connecting AK1 to vascular function, knockout studies showed AK1 deletion uncouples contractility from coronary flow and that AK1beta-facilitated adenosine production, restorable pharmacologically, drives post-ischemic coronary reflow.\",\n      \"evidence\": \"18O-assisted 31P NMR, coronary flow measurement, and adenosine rescue in AK1 knockout hearts\",\n      \"pmids\": [\"17704060\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Step linking AK1beta to adenosine-producing enzymes not defined\", \"AK1beta-specific genetic ablation not performed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identifying a context-specific binding partner, ODF4 was shown to co-IP with AK1 and be required for AK1 retention in sperm flagella, linking AK1 localization to flagellar morphology and male fertility.\",\n      \"evidence\": \"Reciprocal Co-IP, Odf4 knockout/rescue mouse model, immunolocalization, and fertility assays\",\n      \"pmids\": [\"36804949\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Whether ODF4 binds AK1 directly versus within a complex not resolved\", \"Functional role of flagellar AK1 not directly tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defining pharmacological modulation, dinucleoside polyphosphates including Ap5A were shown to potently inhibit human AK1 in vitro, providing chemical tools and structural binding models.\",\n      \"evidence\": \"In vitro enzymatic inhibition with purified hAK1, molecular docking, and QSAR analysis\",\n      \"pmids\": [\"38744169\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No mutagenesis validation of docked binding mode\", \"Cellular efficacy not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How AK1beta is physically coupled to KATP channels and adenosine-generating enzymes at the sarcolemma, and whether the cytosolic and membrane isoforms have separable in vivo roles, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No isoform-specific knockout reported\", \"No structure of AK1beta-channel assembly\", \"Direct adenosine-generation enzyme partner not identified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 3, 7, 8, 11]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3, 9]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-397014\", \"supporting_discovery_ids\": [2, 4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ODF4\", \"AK2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}