{"gene":"AKR1A1","run_date":"2026-06-09T22:02:43","timeline":{"discoveries":[{"year":2001,"finding":"AKR1A1 (aldehyde reductase) oxidizes PAH trans-dihydrodiol proximate carcinogens to reactive o-quinones using NADP+. The enzyme displays rigid regioselectivity (preferentially oxidizing non-K-region trans-dihydrodiols) and stereoselectively oxidizes the metabolically relevant (-)-benzo[a]pyrene-7(R),8(R)-dihydrodiol with higher V(max)/K(m) than any other human AKR tested. The o-quinone product was trapped and characterized as a thioether conjugate by LC/MS.","method":"Recombinant enzyme purified from E. coli, in vitro kinetic assays, circular dichroism, LC/MS product characterization","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified recombinant enzyme, kinetic characterization across multiple substrates, product identity confirmed by LC/MS, replicated in companion paper (PMID:11306097)","pmids":["11535067","11306097"],"is_preprint":false},{"year":2019,"finding":"AKR1A1 is a primary NADPH-dependent S-nitroso-glutathione (GSNO) reductase in mammalian tissues in addition to its known SNO-CoA reductase activity. De novo purification of NADPH-coupled GSNOR activity from tissues identified AKR1A1. Deletion of AKR1A1 from murine tissues dramatically lowered NADPH-dependent GSNOR activity. Mutagenesis identified Arg-312 as a key residue mediating specific interaction with GSNO, while substitution of the SNO-CoA-binding residue Lys-127 minimally affected GSNO-reducing activity, indicating distinct binding modes for the two substrates. GSNOR-deficient mice had increased AKR1A1 activity, revealing cross-talk among denitrosylases.","method":"De novo biochemical purification from tissue, kinetic analysis, AKR1A1 knockout mice, site-directed mutagenesis, molecular modeling","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — de novo purification identifying the enzyme, KO mouse validation, mutagenesis of specific residues, multiple orthogonal methods in one study","pmids":["31649033"],"is_preprint":false},{"year":2017,"finding":"AKR1A1 catalyzes the conversion of D-glucuronate to L-gulonate in the ascorbic acid synthesis pathway in vivo. Knockout of Akr1a1 in mice results in insufficient serum ascorbic acid, abnormal bone development, and osteoporosis that is rescued by ascorbic acid supplementation, establishing AKR1A1 as essential for this biosynthetic step.","method":"Akr1a1 knockout mouse (genomic deletion), serum metabolite measurement, micro-CT bone analysis, ascorbic acid rescue experiment","journal":"Oncotarget","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with defined phenotypic readout, substrate-product pathway established by rescue experiment","pmids":["28060768"],"is_preprint":false},{"year":2011,"finding":"AKR1A1 knockdown in human 1321N1 astrocytoma cells reduced succinic semialdehyde (SSA) reductase activity at high SSA concentrations (1 mM) but not at low concentrations (10 µM), and did not significantly affect intracellular or extracellular GHB levels, indicating that AKR1A1 does not play a major role in GHB biosynthesis in this cell line. Alternative enzymes such as AKR7A2 likely play a more significant role.","method":"siRNA knockdown, qRT-PCR, Western blot, enzymatic activity assay, GC/MS measurement of GHB","journal":"Chemico-biological interactions","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with quantified enzymatic activity and metabolite measurement, single lab, this is a negative finding for GHB biosynthesis","pmids":["21276435"],"is_preprint":false},{"year":2014,"finding":"AKR1A1 catalyzes NADP-dependent oxidation of GHB (gamma-hydroxybutyrate) to succinic semialdehyde at high concentrations in hepatoma HepG2 cells. siRNA knockdown of AKR1A1 caused 82% decrease in NADP-dependent GHB-dehydrogenase activity at 10 mM GHB and a two-fold increase in intracellular GHB levels. AKR1A1 is not involved in endogenous GHB production (SSA reductase activity unaffected).","method":"siRNA knockdown in HepG2 cells, qRT-PCR, Western blot, enzymatic activity assay, GC/MS measurement of GHB","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with enzymatic and metabolite readouts, multiple orthogonal methods, single lab","pmids":["25256836"],"is_preprint":false},{"year":2021,"finding":"A silent variant c.753G>A (rs745484618, p.Arg251Arg) in AKR1A1 associated with schizophrenia induces exon 8 skipping via a minigene assay, causing a frameshift and protein truncation. Recombinant truncated AKR1A1 protein completely loses enzymatic activity, and individuals carrying this variant show lower AKR activity and reduced AKR1A1 mRNA expression, leading to accumulation of glucuronate.","method":"Minigene splicing assay, recombinant protein expression and enzymatic activity assay, qRT-PCR in patient blood","journal":"Frontiers in genetics","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro splicing assay plus recombinant enzyme activity, but single lab and limited sample size for clinical correlation","pmids":["34938315"],"is_preprint":false},{"year":2013,"finding":"AKR1A1 knockdown in 1321N1 astrocytoma cells increased sensitivity to H2O2 and 4-hydroxynonenal (4-HNE)-induced cytotoxicity and elevated intracellular ROS levels, indicating AKR1A1 contributes to cellular resistance to oxidative stress and metabolism of the toxic aldehyde 4-HNE.","method":"siRNA knockdown, Western blot, qRT-PCR, MTT cell viability assay, DCFH-DA ROS measurement","journal":"Xi bao yu fen zi mian yi xue za zhi","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single siRNA approach, phenotypic readout without direct enzymatic confirmation of 4-HNE metabolism","pmids":["23643085"],"is_preprint":false},{"year":2007,"finding":"Site-specifically immobilized AKR1A1 (via intein-mediated thioester formation and biotin ligation to streptavidin templates) retains activity comparable to solution-phase enzyme and is 60–300-fold more active than randomly immobilized enzyme, demonstrating that active-site accessibility is critical for catalytic activity and that the C-terminus can be modified without abolishing function.","method":"Expressed protein ligation, biotin-streptavidin immobilization, kinetic parameter measurement","journal":"Chembiochem","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with kinetic characterization, single lab, directly probes functional consequences of orientation","pmids":["17508367"],"is_preprint":false},{"year":1999,"finding":"The human AKR1A1 gene spans approximately 16 kb, contains eight exons encoding the entire coding region, and is localized to chromosome 1p33→p32.","method":"Genomic DNA isolation, sequencing, fluorescence in situ hybridization (FISH)","journal":"Cytogenetics and cell genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct FISH localization and genomic characterization, single lab but standard methods","pmids":["10393438"],"is_preprint":false},{"year":2026,"finding":"In classically activated macrophages, AKR1A1 induction requires both NO• and LPS/IFNγ stimulation. The SNO-CoA reductase activity of AKR1A1 mitigates NO•-driven inhibition of pyruvate dehydrogenase complex (PDC) by limiting inhibitory S-nitrosylation of the lipoyl cofactor of PDC. Knockout of Akr1a1 in macrophages causes accelerated TCA cycle remodeling, dysregulated immunoregulatory metabolite levels, and altered cytokine production, establishing AKR1A1 as a negative regulator of NO•-mediated metabolic remodeling during immune response.","method":"Multi-omic proteomics and transcriptomics, Akr1a1 knockout macrophages, metabolite measurements, functional cytokine assays","journal":"Redox biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined metabolic and functional phenotypes, multi-omic approach, mechanistic link to PDC inhibition via lipoyl cofactor SNO, reported in both preprint and peer-reviewed journal","pmids":["42048774","41509239"],"is_preprint":false},{"year":2025,"finding":"Mice lacking SCoR2/AKR1A1 exhibit robust protection in a myocardial infarction model. AKR1A1 (SCoR2) regulates ketolytic energy availability, antioxidant levels, and polyol homeostasis via S-nitrosylation of key metabolic effectors. Deletion coordinately reprograms multiple metabolic pathways—ketone body utilization, glycolysis, pentose phosphate shunt, and polyol metabolism—to limit infarct size.","method":"Akr1a1 knockout mice, myocardial infarction model, metabolomics, S-nitrosylation proteomics","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with defined phenotypic readouts and metabolic pathway mapping, preprint not yet peer-reviewed, single lab","pmids":["bio_10.1101_2025.03.12.642752"],"is_preprint":true},{"year":2025,"finding":"RORα transcriptionally regulates AKR1A1 indirectly: RORα deletion upregulates β-catenin, which stabilizes the transcription factor E47, increasing AKR1A1 transcriptional activity in gastric cancer cells. Elevated AKR1A1 expression in this context drives glycolytic reprogramming and lipid synthesis, promoting proliferation and chemoresistance.","method":"Co-immunoprecipitation, ChIP, luciferase reporter assay, immunofluorescence colocalization, gain/loss-of-function experiments, Seahorse assay","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, ChIP, luciferase) in single lab identifying E47 as AKR1A1 transcription factor downstream of RORα/β-catenin axis","pmids":["40096932"],"is_preprint":false},{"year":2025,"finding":"AKR1A1 expression is elevated and undergoes lactylation (lysine lactylation) in RAW264.7 macrophages treated with lactate and osteoporotic serum. Co-immunoprecipitation validated AKR1A1 lactylation in this context. AKR1A1 participates in the SPP1-CD44 intercellular signaling pathway based on CellChat analysis, mediating communication between monocytes and macrophages.","method":"Western blot, qPCR, co-immunoprecipitation (Co-IP), CellChat intercellular communication analysis, single-cell RNA-seq analysis","journal":"Frontiers in immunology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, Co-IP for lactylation is suggestive but pathway placement via CellChat is computational, limited direct mechanistic validation","pmids":["41246341"],"is_preprint":false}],"current_model":"AKR1A1 (aldehyde reductase / SNO-CoA Reductase 2, SCoR2) is an NADPH-dependent oxidoreductase with multiple established enzymatic functions: it oxidizes PAH trans-dihydrodiol carcinogens to reactive o-quinones with high regioselectivity and stereoselectivity; catalyzes the conversion of D-glucuronate to L-gulonate in the ascorbic acid biosynthesis pathway; reduces both S-nitroso-CoA (SNO-CoA) and S-nitroso-glutathione (GSNO) using distinct substrate-binding residues (Lys-127 for SNO-CoA, Arg-312 for GSNO), making it a multi-LMW-SNO denitrosylase controlling protein S-nitrosylation; and in activated macrophages, its SNO-CoA reductase activity limits inhibitory S-nitrosylation of the pyruvate dehydrogenase complex lipoyl cofactor, forming a negative regulatory loop on NO•-driven metabolic remodeling. In the heart, AKR1A1/SCoR2 loss coordinately reprograms ketone body utilization, glycolysis, pentose phosphate, and polyol pathways via S-nitrosylation of metabolic effectors, conferring cardioprotection."},"narrative":{"mechanistic_narrative":"AKR1A1 is an NADPH-dependent aldo-keto reductase that operates at the intersection of detoxification metabolism, ascorbate biosynthesis, and nitric oxide–based redox signaling [PMID:31649033, PMID:28060768]. As a classical oxidoreductase it oxidizes polycyclic aromatic hydrocarbon trans-dihydrodiols to reactive o-quinones with strict regio- and stereoselectivity [PMID:11535067, PMID:11306097] and catalyzes the conversion of D-glucuronate to L-gulonate, an essential step in ascorbic acid synthesis; its genetic ablation in mice causes ascorbate insufficiency, abnormal bone development, and osteoporosis that is reversed by ascorbate supplementation [PMID:28060768]. Beyond these reductase roles, AKR1A1 functions as a low-molecular-weight S-nitroso denitrosylase (SCoR2), reducing both S-nitroso-CoA and S-nitroso-glutathione through distinct substrate-binding residues—Lys-127 for SNO-CoA and Arg-312 for GSNO—thereby controlling cellular protein S-nitrosylation [PMID:31649033]. In classically activated macrophages, induction of AKR1A1 requires both NO• and LPS/IFNγ, and its SNO-CoA reductase activity limits inhibitory S-nitrosylation of the pyruvate dehydrogenase complex lipoyl cofactor, forming a negative regulatory loop that restrains NO•-driven TCA cycle remodeling and shapes immunometabolite and cytokine output [PMID:42048774, PMID:41509239]. Loss-of-function variants link AKR1A1 to human disease: a silent c.753G>A variant induces exon 8 skipping, abolishing enzymatic activity and causing glucuronate accumulation, in an association with schizophrenia [PMID:34938315]. AKR1A1 additionally contributes to cellular handling of reactive aldehydes and oxidative stress [PMID:23643085] and is transcriptionally driven by an E47/β-catenin axis downstream of RORα in gastric cancer, where it promotes glycolytic and lipogenic reprogramming [PMID:40096932].","teleology":[{"year":1999,"claim":"Establishing the genomic architecture of human AKR1A1 provided the foundation for interpreting later coding and splicing variants.","evidence":"Genomic sequencing and FISH localization to chromosome 1p33→p32","pmids":["10393438"],"confidence":"Medium","gaps":["No functional or enzymatic characterization","Does not address tissue expression or regulation"]},{"year":2001,"claim":"Defining AKR1A1 as an oxidative metabolizer of PAH trans-dihydrodiols answered whether the enzyme contributes to carcinogen activation and showed it does so with marked selectivity.","evidence":"In vitro kinetics with purified recombinant enzyme, CD, and LC/MS product trapping","pmids":["11535067","11306097"],"confidence":"High","gaps":["In vivo relevance to carcinogenesis not tested","Cellular regulation of this activity unknown"]},{"year":2007,"claim":"Site-specific immobilization studies established that active-site accessibility, not the C-terminus, governs catalytic competence.","evidence":"Expressed protein ligation and biotin-streptavidin immobilization with kinetic comparison","pmids":["17508367"],"confidence":"Medium","gaps":["Technical/biophysical focus rather than physiological","No structural model of the active site provided"]},{"year":2011,"claim":"Testing AKR1A1's role in GHB metabolism in astrocytoma resolved that it is not a major contributor to endogenous GHB biosynthesis, narrowing its physiological substrate scope.","evidence":"siRNA knockdown with enzymatic activity assays and GC/MS GHB measurement in 1321N1 cells","pmids":["21276435"],"confidence":"Medium","gaps":["Negative finding in a single cell line","Did not identify the dominant SSA reductase"]},{"year":2013,"claim":"Knockdown phenotypes implicated AKR1A1 in resistance to oxidative and aldehyde stress, extending its role to cytoprotection.","evidence":"siRNA knockdown with viability and ROS assays in 1321N1 astrocytoma cells","pmids":["23643085"],"confidence":"Low","gaps":["Single siRNA approach without enzymatic confirmation of 4-HNE turnover","No rescue experiment","Single cell line"]},{"year":2014,"claim":"HepG2 knockdown clarified that AKR1A1 oxidizes GHB to succinic semialdehyde only at high concentrations, defining a catabolic but not biosynthetic role.","evidence":"siRNA knockdown with NADP-dependent activity assays and GC/MS GHB quantitation in HepG2 cells","pmids":["25256836"],"confidence":"Medium","gaps":["Physiological GHB concentrations may not engage this activity","Single cell line"]},{"year":2017,"claim":"Knockout mice established AKR1A1 as the in vivo D-glucuronate-to-L-gulonate enzyme essential for ascorbate synthesis, linking enzyme loss to skeletal pathology.","evidence":"Akr1a1 knockout mice, serum metabolite measurement, micro-CT, and ascorbate rescue","pmids":["28060768"],"confidence":"High","gaps":["Human ascorbate dependence differs from mouse","Other AKRs may compensate in some tissues"]},{"year":2019,"claim":"De novo purification and KO validation identified AKR1A1 as a primary GSNO reductase with substrate-binding residues distinct from those for SNO-CoA, establishing it as a multi-LMW-SNO denitrosylase with cross-talk to GSNOR.","evidence":"Tissue purification of NADPH-coupled GSNOR activity, AKR1A1 KO mice, and Arg-312/Lys-127 mutagenesis with modeling","pmids":["31649033"],"confidence":"High","gaps":["Downstream S-nitrosylated protein targets not enumerated here","Physiological consequences of denitrosylase activity not yet mapped"]},{"year":2021,"claim":"A schizophrenia-associated silent variant was shown to cause exon 8 skipping and complete loss of enzyme activity, providing a mechanistic genotype-to-function link and a disease association.","evidence":"Minigene splicing assay, recombinant truncated protein activity, and patient blood mRNA/AKR activity","pmids":["34938315"],"confidence":"Medium","gaps":["Small clinical sample for the schizophrenia association","Causal mechanism connecting glucuronate accumulation to phenotype unestablished"]},{"year":2025,"claim":"Cancer and macrophage studies connected AKR1A1 expression to metabolic reprogramming, placing it under an E47/β-catenin/RORα transcriptional axis and within lactylation-modulated signaling.","evidence":"Co-IP, ChIP, luciferase, Seahorse in gastric cancer cells; Co-IP lactylation and CellChat analysis in RAW264.7 macrophages","pmids":["40096932","41246341"],"confidence":"Medium","gaps":["Lactylation pathway placement is largely computational (CellChat)","Whether reprogramming requires enzymatic vs. expression-level changes is unresolved"]},{"year":2025,"claim":"Cardiac SCoR2/AKR1A1 deletion was shown to coordinately reprogram ketone, glycolytic, pentose phosphate, and polyol metabolism via S-nitrosylation, conferring myocardial-infarction protection.","evidence":"Akr1a1 KO mice in a myocardial infarction model with metabolomics and S-nitrosylation proteomics (preprint)","pmids":["bio_10.1101_2025.03.12.642752"],"confidence":"Medium","gaps":["Preprint, not peer-reviewed","Specific S-nitrosylated effectors driving cardioprotection not pinpointed"]},{"year":2026,"claim":"Macrophage studies defined AKR1A1 as a negative regulator of NO•-driven metabolic remodeling by limiting inhibitory S-nitrosylation of the PDC lipoyl cofactor.","evidence":"Multi-omics, Akr1a1 KO macrophages, metabolite and cytokine assays","pmids":["42048774","41509239"],"confidence":"High","gaps":["Direct demonstration that PDC lipoyl SNO is the proximate AKR1A1 substrate in cells is inferential","Generalization beyond classically activated macrophages untested"]},{"year":null,"claim":"How AKR1A1's distinct activities—carcinogen oxidation, ascorbate synthesis, and SNO denitrosylation—are coordinately regulated and prioritized across tissues remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural basis distinguishing reductase vs. denitrosylase substrate selection in vivo","The full set of S-nitrosylated protein targets controlled by AKR1A1 is uncatalogued","Tissue-specific determinants of which activity dominates are unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[0,1,2,4]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[1,9]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[9]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[2,9,10]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[9]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P14550","full_name":"Aldo-keto reductase family 1 member A1","aliases":["Alcohol dehydrogenase [NADP(+)]","Aldehyde reductase","Glucuronate reductase","Glucuronolactone reductase","S-nitroso-CoA reductase","ScorR"],"length_aa":325,"mass_kda":36.6,"function":"Catalyzes the NADPH-dependent reduction of a wide variety of carbonyl-containing compounds to their corresponding alcohols (PubMed:10510318, PubMed:30538128). Displays enzymatic activity towards endogenous metabolites such as aromatic and aliphatic aldehydes, ketones, monosaccharides and bile acids, with a preference for negatively charged substrates, such as glucuronate and succinic semialdehyde (PubMed:10510318, PubMed:30538128). Functions as a detoxifiying enzyme by reducing a range of toxic aldehydes (By similarity). Reduces methylglyoxal and 3-deoxyglucosone, which are present at elevated levels under hyperglycemic conditions and are cytotoxic (By similarity). Involved also in the detoxification of lipid-derived aldehydes like acrolein (By similarity). Plays a role in the activation of procarcinogens, such as polycyclic aromatic hydrocarbon trans-dihydrodiols, and in the metabolism of various xenobiotics and drugs, including the anthracyclines doxorubicin (DOX) and daunorubicin (DAUN) (PubMed:11306097, PubMed:18276838). Also acts as an inhibitor of protein S-nitrosylation by mediating degradation of S-nitroso-coenzyme A (S-nitroso-CoA), a cofactor required to S-nitrosylate proteins (PubMed:30538128). S-nitroso-CoA reductase activity is involved in reprogramming intermediary metabolism in renal proximal tubules, notably by inhibiting protein S-nitrosylation of isoform 2 of PKM (PKM2) (By similarity). Also acts as a S-nitroso-glutathione reductase by catalyzing the NADPH-dependent reduction of S-nitrosoglutathione (PubMed:31649033). Displays no reductase activity towards retinoids (By similarity)","subcellular_location":"Cytoplasm, cytosol; Apical cell membrane","url":"https://www.uniprot.org/uniprotkb/P14550/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/AKR1A1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000117448","cell_line_id":"CID001900","localizations":[{"compartment":"big_aggregates","grade":3},{"compartment":"cytoplasmic","grade":3}],"interactors":[{"gene":"PRKAA1","stoichiometry":0.2},{"gene":"SAR1B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001900","total_profiled":1310},"omim":[{"mim_id":"179050","title":"PYRUVATE KINASE, MUSCLE; PKM","url":"https://www.omim.org/entry/179050"},{"mim_id":"103830","title":"ALDO-KETO REDUCTASE FAMILY 1, MEMBER A1; AKR1A1","url":"https://www.omim.org/entry/103830"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/AKR1A1"},"hgnc":{"alias_symbol":["ALR","DD3"],"prev_symbol":[]},"alphafold":{"accession":"P14550","domains":[{"cath_id":"3.20.20.100","chopping":"4-310","consensus_level":"high","plddt":96.9679,"start":4,"end":310}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P14550","model_url":"https://alphafold.ebi.ac.uk/files/AF-P14550-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P14550-F1-predicted_aligned_error_v6.png","plddt_mean":96.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=AKR1A1","jax_strain_url":"https://www.jax.org/strain/search?query=AKR1A1"},"sequence":{"accession":"P14550","fasta_url":"https://rest.uniprot.org/uniprotkb/P14550.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P14550/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P14550"}},"corpus_meta":[{"pmid":"11535067","id":"PMC_11535067","title":"The ubiquitous aldehyde reductase (AKR1A1) oxidizes proximate carcinogen trans-dihydrodiols to o-quinones: potential role in polycyclic aromatic hydrocarbon activation.","date":"2001","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11535067","citation_count":101,"is_preprint":false},{"pmid":"31649033","id":"PMC_31649033","title":"AKR1A1 is a novel mammalian S-nitroso-glutathione reductase.","date":"2019","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31649033","citation_count":40,"is_preprint":false},{"pmid":"11306097","id":"PMC_11306097","title":"Metabolic activation of polycyclic aromatic hydrocarbon trans-dihydrodiols by ubiquitously expressed aldehyde reductase (AKR1A1).","date":"2001","source":"Chemico-biological interactions","url":"https://pubmed.ncbi.nlm.nih.gov/11306097","citation_count":28,"is_preprint":false},{"pmid":"17508367","id":"PMC_17508367","title":"Specifically immobilised aldo/keto reductase AKR1A1 shows a dramatic increase in activity relative to the randomly immobilised enzyme.","date":"2007","source":"Chembiochem : a European journal of chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/17508367","citation_count":26,"is_preprint":false},{"pmid":"28060768","id":"PMC_28060768","title":"A novel osteoporosis model with ascorbic acid deficiency in Akr1A1 gene knockout mice.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/28060768","citation_count":20,"is_preprint":false},{"pmid":"38394643","id":"PMC_38394643","title":"Multiomics Analyses Identify AKR1A1 as a Biomarker for Diabetic Kidney Disease.","date":"2024","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/38394643","citation_count":16,"is_preprint":false},{"pmid":"36252352","id":"PMC_36252352","title":"Kefir peptides ameliorate osteoporosis in AKR1A1 knockout mice with vitamin C deficiency by promoting osteoblastogenesis and inhibiting osteoclastogenesis.","date":"2022","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/36252352","citation_count":13,"is_preprint":false},{"pmid":"27087367","id":"PMC_27087367","title":"Sexually Dimorphic Expression of eGFP Transgene in the Akr1A1 Locus of Mouse Liver Regulated by Sex Hormone-Related Epigenetic Remodeling.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27087367","citation_count":10,"is_preprint":false},{"pmid":"21276435","id":"PMC_21276435","title":"The role of aldehyde reductase AKR1A1 in the metabolism of γ-hydroxybutyrate in 1321N1 human astrocytoma cells.","date":"2011","source":"Chemico-biological interactions","url":"https://pubmed.ncbi.nlm.nih.gov/21276435","citation_count":10,"is_preprint":false},{"pmid":"25256836","id":"PMC_25256836","title":"Metabolism of gamma hydroxybutyrate in human hepatoma HepG2 cells by the aldo-keto reductase AKR1A1.","date":"2014","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/25256836","citation_count":8,"is_preprint":false},{"pmid":"34938315","id":"PMC_34938315","title":"AKR1A1 Variant Associated With Schizophrenia Causes Exon Skipping, Leading to Loss of Enzymatic Activity.","date":"2021","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34938315","citation_count":7,"is_preprint":false},{"pmid":"22394341","id":"PMC_22394341","title":"Benzo(a)pyrene induces hepatic AKR1A1 mRNA expression in tilapia fish (Oreochromis niloticus).","date":"2012","source":"Toxicology mechanisms and methods","url":"https://pubmed.ncbi.nlm.nih.gov/22394341","citation_count":5,"is_preprint":false},{"pmid":"10393438","id":"PMC_10393438","title":"The structural organization of the human aldehyde reductase gene, AKR1A1, and mapping to chromosome 1p33-->p32.","date":"1999","source":"Cytogenetics and cell 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fish.","date":"2016","source":"Toxicology mechanisms and methods","url":"https://pubmed.ncbi.nlm.nih.gov/27800707","citation_count":3,"is_preprint":false},{"pmid":"40096932","id":"PMC_40096932","title":"RORα inhibits proliferation and chemoresistance through AKR1A1-induced glucose and lipid reprogramming in gastric cancer.","date":"2025","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/40096932","citation_count":2,"is_preprint":false},{"pmid":"23643085","id":"PMC_23643085","title":"[Effect of AKR1A1 knock-down on H2;O2; and 4-hydroxynonenal-induced cytotoxicity in human 1321N1 astrocytoma cells].","date":"2013","source":"Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/23643085","citation_count":1,"is_preprint":false},{"pmid":"41051883","id":"PMC_41051883","title":"Serum AKR1A1 Levels Predict eGFR Decline Rate in Black Americans with Type 2 Diabetes.","date":"2025","source":"Kidney360","url":"https://pubmed.ncbi.nlm.nih.gov/41051883","citation_count":1,"is_preprint":false},{"pmid":"41509239","id":"PMC_41509239","title":"Multi-omic analysis reveals nitric oxide dependent remodeling in classically activated macrophages and identifies negative regulation mediated by AKR1A1.","date":"2026","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41509239","citation_count":1,"is_preprint":false},{"pmid":"42048774","id":"PMC_42048774","title":"Multi-omic analysis reveals nitric oxide dependent remodeling in classically activated macrophages and identifies negative regulation mediated by AKR1A1.","date":"2026","source":"Redox biology","url":"https://pubmed.ncbi.nlm.nih.gov/42048774","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.03.12.642752","title":"The denitrosylase SCoR2 controls cardioprotective metabolic reprogramming","date":"2025-03-14","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.12.642752","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14716,"output_tokens":3841,"usd":0.050882,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11587,"output_tokens":3826,"usd":0.076792,"stage2_stop_reason":"end_turn"},"total_usd":0.127674,"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\": 2001,\n      \"finding\": \"AKR1A1 (aldehyde reductase) oxidizes PAH trans-dihydrodiol proximate carcinogens to reactive o-quinones using NADP+. The enzyme displays rigid regioselectivity (preferentially oxidizing non-K-region trans-dihydrodiols) and stereoselectively oxidizes the metabolically relevant (-)-benzo[a]pyrene-7(R),8(R)-dihydrodiol with higher V(max)/K(m) than any other human AKR tested. The o-quinone product was trapped and characterized as a thioether conjugate by LC/MS.\",\n      \"method\": \"Recombinant enzyme purified from E. coli, in vitro kinetic assays, circular dichroism, LC/MS product characterization\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified recombinant enzyme, kinetic characterization across multiple substrates, product identity confirmed by LC/MS, replicated in companion paper (PMID:11306097)\",\n      \"pmids\": [\"11535067\", \"11306097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"AKR1A1 is a primary NADPH-dependent S-nitroso-glutathione (GSNO) reductase in mammalian tissues in addition to its known SNO-CoA reductase activity. De novo purification of NADPH-coupled GSNOR activity from tissues identified AKR1A1. Deletion of AKR1A1 from murine tissues dramatically lowered NADPH-dependent GSNOR activity. Mutagenesis identified Arg-312 as a key residue mediating specific interaction with GSNO, while substitution of the SNO-CoA-binding residue Lys-127 minimally affected GSNO-reducing activity, indicating distinct binding modes for the two substrates. GSNOR-deficient mice had increased AKR1A1 activity, revealing cross-talk among denitrosylases.\",\n      \"method\": \"De novo biochemical purification from tissue, kinetic analysis, AKR1A1 knockout mice, site-directed mutagenesis, molecular modeling\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — de novo purification identifying the enzyme, KO mouse validation, mutagenesis of specific residues, multiple orthogonal methods in one study\",\n      \"pmids\": [\"31649033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"AKR1A1 catalyzes the conversion of D-glucuronate to L-gulonate in the ascorbic acid synthesis pathway in vivo. Knockout of Akr1a1 in mice results in insufficient serum ascorbic acid, abnormal bone development, and osteoporosis that is rescued by ascorbic acid supplementation, establishing AKR1A1 as essential for this biosynthetic step.\",\n      \"method\": \"Akr1a1 knockout mouse (genomic deletion), serum metabolite measurement, micro-CT bone analysis, ascorbic acid rescue experiment\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with defined phenotypic readout, substrate-product pathway established by rescue experiment\",\n      \"pmids\": [\"28060768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"AKR1A1 knockdown in human 1321N1 astrocytoma cells reduced succinic semialdehyde (SSA) reductase activity at high SSA concentrations (1 mM) but not at low concentrations (10 µM), and did not significantly affect intracellular or extracellular GHB levels, indicating that AKR1A1 does not play a major role in GHB biosynthesis in this cell line. Alternative enzymes such as AKR7A2 likely play a more significant role.\",\n      \"method\": \"siRNA knockdown, qRT-PCR, Western blot, enzymatic activity assay, GC/MS measurement of GHB\",\n      \"journal\": \"Chemico-biological interactions\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with quantified enzymatic activity and metabolite measurement, single lab, this is a negative finding for GHB biosynthesis\",\n      \"pmids\": [\"21276435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"AKR1A1 catalyzes NADP-dependent oxidation of GHB (gamma-hydroxybutyrate) to succinic semialdehyde at high concentrations in hepatoma HepG2 cells. siRNA knockdown of AKR1A1 caused 82% decrease in NADP-dependent GHB-dehydrogenase activity at 10 mM GHB and a two-fold increase in intracellular GHB levels. AKR1A1 is not involved in endogenous GHB production (SSA reductase activity unaffected).\",\n      \"method\": \"siRNA knockdown in HepG2 cells, qRT-PCR, Western blot, enzymatic activity assay, GC/MS measurement of GHB\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with enzymatic and metabolite readouts, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"25256836\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A silent variant c.753G>A (rs745484618, p.Arg251Arg) in AKR1A1 associated with schizophrenia induces exon 8 skipping via a minigene assay, causing a frameshift and protein truncation. Recombinant truncated AKR1A1 protein completely loses enzymatic activity, and individuals carrying this variant show lower AKR activity and reduced AKR1A1 mRNA expression, leading to accumulation of glucuronate.\",\n      \"method\": \"Minigene splicing assay, recombinant protein expression and enzymatic activity assay, qRT-PCR in patient blood\",\n      \"journal\": \"Frontiers in genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro splicing assay plus recombinant enzyme activity, but single lab and limited sample size for clinical correlation\",\n      \"pmids\": [\"34938315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"AKR1A1 knockdown in 1321N1 astrocytoma cells increased sensitivity to H2O2 and 4-hydroxynonenal (4-HNE)-induced cytotoxicity and elevated intracellular ROS levels, indicating AKR1A1 contributes to cellular resistance to oxidative stress and metabolism of the toxic aldehyde 4-HNE.\",\n      \"method\": \"siRNA knockdown, Western blot, qRT-PCR, MTT cell viability assay, DCFH-DA ROS measurement\",\n      \"journal\": \"Xi bao yu fen zi mian yi xue za zhi\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single siRNA approach, phenotypic readout without direct enzymatic confirmation of 4-HNE metabolism\",\n      \"pmids\": [\"23643085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Site-specifically immobilized AKR1A1 (via intein-mediated thioester formation and biotin ligation to streptavidin templates) retains activity comparable to solution-phase enzyme and is 60–300-fold more active than randomly immobilized enzyme, demonstrating that active-site accessibility is critical for catalytic activity and that the C-terminus can be modified without abolishing function.\",\n      \"method\": \"Expressed protein ligation, biotin-streptavidin immobilization, kinetic parameter measurement\",\n      \"journal\": \"Chembiochem\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with kinetic characterization, single lab, directly probes functional consequences of orientation\",\n      \"pmids\": [\"17508367\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The human AKR1A1 gene spans approximately 16 kb, contains eight exons encoding the entire coding region, and is localized to chromosome 1p33→p32.\",\n      \"method\": \"Genomic DNA isolation, sequencing, fluorescence in situ hybridization (FISH)\",\n      \"journal\": \"Cytogenetics and cell genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct FISH localization and genomic characterization, single lab but standard methods\",\n      \"pmids\": [\"10393438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In classically activated macrophages, AKR1A1 induction requires both NO• and LPS/IFNγ stimulation. The SNO-CoA reductase activity of AKR1A1 mitigates NO•-driven inhibition of pyruvate dehydrogenase complex (PDC) by limiting inhibitory S-nitrosylation of the lipoyl cofactor of PDC. Knockout of Akr1a1 in macrophages causes accelerated TCA cycle remodeling, dysregulated immunoregulatory metabolite levels, and altered cytokine production, establishing AKR1A1 as a negative regulator of NO•-mediated metabolic remodeling during immune response.\",\n      \"method\": \"Multi-omic proteomics and transcriptomics, Akr1a1 knockout macrophages, metabolite measurements, functional cytokine assays\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined metabolic and functional phenotypes, multi-omic approach, mechanistic link to PDC inhibition via lipoyl cofactor SNO, reported in both preprint and peer-reviewed journal\",\n      \"pmids\": [\"42048774\", \"41509239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Mice lacking SCoR2/AKR1A1 exhibit robust protection in a myocardial infarction model. AKR1A1 (SCoR2) regulates ketolytic energy availability, antioxidant levels, and polyol homeostasis via S-nitrosylation of key metabolic effectors. Deletion coordinately reprograms multiple metabolic pathways—ketone body utilization, glycolysis, pentose phosphate shunt, and polyol metabolism—to limit infarct size.\",\n      \"method\": \"Akr1a1 knockout mice, myocardial infarction model, metabolomics, S-nitrosylation proteomics\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with defined phenotypic readouts and metabolic pathway mapping, preprint not yet peer-reviewed, single lab\",\n      \"pmids\": [\"bio_10.1101_2025.03.12.642752\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RORα transcriptionally regulates AKR1A1 indirectly: RORα deletion upregulates β-catenin, which stabilizes the transcription factor E47, increasing AKR1A1 transcriptional activity in gastric cancer cells. Elevated AKR1A1 expression in this context drives glycolytic reprogramming and lipid synthesis, promoting proliferation and chemoresistance.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, luciferase reporter assay, immunofluorescence colocalization, gain/loss-of-function experiments, Seahorse assay\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, ChIP, luciferase) in single lab identifying E47 as AKR1A1 transcription factor downstream of RORα/β-catenin axis\",\n      \"pmids\": [\"40096932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AKR1A1 expression is elevated and undergoes lactylation (lysine lactylation) in RAW264.7 macrophages treated with lactate and osteoporotic serum. Co-immunoprecipitation validated AKR1A1 lactylation in this context. AKR1A1 participates in the SPP1-CD44 intercellular signaling pathway based on CellChat analysis, mediating communication between monocytes and macrophages.\",\n      \"method\": \"Western blot, qPCR, co-immunoprecipitation (Co-IP), CellChat intercellular communication analysis, single-cell RNA-seq analysis\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, Co-IP for lactylation is suggestive but pathway placement via CellChat is computational, limited direct mechanistic validation\",\n      \"pmids\": [\"41246341\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"AKR1A1 (aldehyde reductase / SNO-CoA Reductase 2, SCoR2) is an NADPH-dependent oxidoreductase with multiple established enzymatic functions: it oxidizes PAH trans-dihydrodiol carcinogens to reactive o-quinones with high regioselectivity and stereoselectivity; catalyzes the conversion of D-glucuronate to L-gulonate in the ascorbic acid biosynthesis pathway; reduces both S-nitroso-CoA (SNO-CoA) and S-nitroso-glutathione (GSNO) using distinct substrate-binding residues (Lys-127 for SNO-CoA, Arg-312 for GSNO), making it a multi-LMW-SNO denitrosylase controlling protein S-nitrosylation; and in activated macrophages, its SNO-CoA reductase activity limits inhibitory S-nitrosylation of the pyruvate dehydrogenase complex lipoyl cofactor, forming a negative regulatory loop on NO•-driven metabolic remodeling. In the heart, AKR1A1/SCoR2 loss coordinately reprograms ketone body utilization, glycolysis, pentose phosphate, and polyol pathways via S-nitrosylation of metabolic effectors, conferring cardioprotection.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"AKR1A1 is an NADPH-dependent aldo-keto reductase that operates at the intersection of detoxification metabolism, ascorbate biosynthesis, and nitric oxide–based redox signaling [#1, #2]. As a classical oxidoreductase it oxidizes polycyclic aromatic hydrocarbon trans-dihydrodiols to reactive o-quinones with strict regio- and stereoselectivity [#0] and catalyzes the conversion of D-glucuronate to L-gulonate, an essential step in ascorbic acid synthesis; its genetic ablation in mice causes ascorbate insufficiency, abnormal bone development, and osteoporosis that is reversed by ascorbate supplementation [#2]. Beyond these reductase roles, AKR1A1 functions as a low-molecular-weight S-nitroso denitrosylase (SCoR2), reducing both S-nitroso-CoA and S-nitroso-glutathione through distinct substrate-binding residues—Lys-127 for SNO-CoA and Arg-312 for GSNO—thereby controlling cellular protein S-nitrosylation [#1]. In classically activated macrophages, induction of AKR1A1 requires both NO\\u2022 and LPS/IFN\\u03b3, and its SNO-CoA reductase activity limits inhibitory S-nitrosylation of the pyruvate dehydrogenase complex lipoyl cofactor, forming a negative regulatory loop that restrains NO\\u2022-driven TCA cycle remodeling and shapes immunometabolite and cytokine output [#9]. Loss-of-function variants link AKR1A1 to human disease: a silent c.753G>A variant induces exon 8 skipping, abolishing enzymatic activity and causing glucuronate accumulation, in an association with schizophrenia [#5]. AKR1A1 additionally contributes to cellular handling of reactive aldehydes and oxidative stress [#6] and is transcriptionally driven by an E47/\\u03b2-catenin axis downstream of ROR\\u03b1 in gastric cancer, where it promotes glycolytic and lipogenic reprogramming [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Establishing the genomic architecture of human AKR1A1 provided the foundation for interpreting later coding and splicing variants.\",\n      \"evidence\": \"Genomic sequencing and FISH localization to chromosome 1p33\\u2192p32\",\n      \"pmids\": [\"10393438\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional or enzymatic characterization\", \"Does not address tissue expression or regulation\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defining AKR1A1 as an oxidative metabolizer of PAH trans-dihydrodiols answered whether the enzyme contributes to carcinogen activation and showed it does so with marked selectivity.\",\n      \"evidence\": \"In vitro kinetics with purified recombinant enzyme, CD, and LC/MS product trapping\",\n      \"pmids\": [\"11535067\", \"11306097\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance to carcinogenesis not tested\", \"Cellular regulation of this activity unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Site-specific immobilization studies established that active-site accessibility, not the C-terminus, governs catalytic competence.\",\n      \"evidence\": \"Expressed protein ligation and biotin-streptavidin immobilization with kinetic comparison\",\n      \"pmids\": [\"17508367\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Technical/biophysical focus rather than physiological\", \"No structural model of the active site provided\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Testing AKR1A1's role in GHB metabolism in astrocytoma resolved that it is not a major contributor to endogenous GHB biosynthesis, narrowing its physiological substrate scope.\",\n      \"evidence\": \"siRNA knockdown with enzymatic activity assays and GC/MS GHB measurement in 1321N1 cells\",\n      \"pmids\": [\"21276435\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Negative finding in a single cell line\", \"Did not identify the dominant SSA reductase\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Knockdown phenotypes implicated AKR1A1 in resistance to oxidative and aldehyde stress, extending its role to cytoprotection.\",\n      \"evidence\": \"siRNA knockdown with viability and ROS assays in 1321N1 astrocytoma cells\",\n      \"pmids\": [\"23643085\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single siRNA approach without enzymatic confirmation of 4-HNE turnover\", \"No rescue experiment\", \"Single cell line\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"HepG2 knockdown clarified that AKR1A1 oxidizes GHB to succinic semialdehyde only at high concentrations, defining a catabolic but not biosynthetic role.\",\n      \"evidence\": \"siRNA knockdown with NADP-dependent activity assays and GC/MS GHB quantitation in HepG2 cells\",\n      \"pmids\": [\"25256836\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological GHB concentrations may not engage this activity\", \"Single cell line\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Knockout mice established AKR1A1 as the in vivo D-glucuronate-to-L-gulonate enzyme essential for ascorbate synthesis, linking enzyme loss to skeletal pathology.\",\n      \"evidence\": \"Akr1a1 knockout mice, serum metabolite measurement, micro-CT, and ascorbate rescue\",\n      \"pmids\": [\"28060768\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Human ascorbate dependence differs from mouse\", \"Other AKRs may compensate in some tissues\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"De novo purification and KO validation identified AKR1A1 as a primary GSNO reductase with substrate-binding residues distinct from those for SNO-CoA, establishing it as a multi-LMW-SNO denitrosylase with cross-talk to GSNOR.\",\n      \"evidence\": \"Tissue purification of NADPH-coupled GSNOR activity, AKR1A1 KO mice, and Arg-312/Lys-127 mutagenesis with modeling\",\n      \"pmids\": [\"31649033\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream S-nitrosylated protein targets not enumerated here\", \"Physiological consequences of denitrosylase activity not yet mapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"A schizophrenia-associated silent variant was shown to cause exon 8 skipping and complete loss of enzyme activity, providing a mechanistic genotype-to-function link and a disease association.\",\n      \"evidence\": \"Minigene splicing assay, recombinant truncated protein activity, and patient blood mRNA/AKR activity\",\n      \"pmids\": [\"34938315\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Small clinical sample for the schizophrenia association\", \"Causal mechanism connecting glucuronate accumulation to phenotype unestablished\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Cancer and macrophage studies connected AKR1A1 expression to metabolic reprogramming, placing it under an E47/\\u03b2-catenin/ROR\\u03b1 transcriptional axis and within lactylation-modulated signaling.\",\n      \"evidence\": \"Co-IP, ChIP, luciferase, Seahorse in gastric cancer cells; Co-IP lactylation and CellChat analysis in RAW264.7 macrophages\",\n      \"pmids\": [\"40096932\", \"41246341\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Lactylation pathway placement is largely computational (CellChat)\", \"Whether reprogramming requires enzymatic vs. expression-level changes is unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Cardiac SCoR2/AKR1A1 deletion was shown to coordinately reprogram ketone, glycolytic, pentose phosphate, and polyol metabolism via S-nitrosylation, conferring myocardial-infarction protection.\",\n      \"evidence\": \"Akr1a1 KO mice in a myocardial infarction model with metabolomics and S-nitrosylation proteomics (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.03.12.642752\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"Specific S-nitrosylated effectors driving cardioprotection not pinpointed\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Macrophage studies defined AKR1A1 as a negative regulator of NO\\u2022-driven metabolic remodeling by limiting inhibitory S-nitrosylation of the PDC lipoyl cofactor.\",\n      \"evidence\": \"Multi-omics, Akr1a1 KO macrophages, metabolite and cytokine assays\",\n      \"pmids\": [\"42048774\", \"41509239\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct demonstration that PDC lipoyl SNO is the proximate AKR1A1 substrate in cells is inferential\", \"Generalization beyond classically activated macrophages untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How AKR1A1's distinct activities—carcinogen oxidation, ascorbate synthesis, and SNO denitrosylation—are coordinately regulated and prioritized across tissues remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural basis distinguishing reductase vs. denitrosylase substrate selection in vivo\", \"The full set of S-nitrosylated protein targets controlled by AKR1A1 is uncatalogued\", \"Tissue-specific determinants of which activity dominates are unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 1, 2, 4]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [1, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [2, 9, 10]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}