{"gene":"ATIC","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":1996,"finding":"Human ATIC (purH gene product) is a bifunctional enzyme with two separable catalytic activities: AICAR transformylase (AICARFT) in the C-terminal ~406 amino acids and IMP cyclohydrolase (IMPCHase) in the N-terminal ~223 amino acids, as demonstrated by truncation mutants that independently express each activity. Km values for AICAR and (6R,6S)10-formyltetrahydrofolate were determined for the purified recombinant human enzyme. Site-directed mutagenesis of a putative folate-binding motif showed it plays no role in enzymatic activity.","method":"cDNA cloning, recombinant protein purification, steady-state kinetics, truncation mutagenesis, site-directed mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic assay with purified recombinant protein, truncation and site-directed mutagenesis, kinetic characterization; foundational biochemical study replicated conceptually across species","pmids":["8567683"],"is_preprint":false},{"year":2002,"finding":"Detailed kinetic mechanism of human ATIC established by rapid chemical quench, stopped-flow, and steady-state kinetics: (1) rate-limiting step is tetrahydrofolate release from the AICARFT active site (~2.9 s⁻¹); (2) the reverse transformylase reaction (~6.7 s⁻¹) is faster than forward; (3) the cyclohydrolase reaction is essentially unidirectional; (4) there is no kinetic evidence of substrate channeling of the FAICAR intermediate between the two active sites.","method":"Rapid chemical quench, stopped-flow absorbance, steady-state kinetics, kinetic simulation (KINSIM)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal transient and steady-state kinetic methods with explicit negative result for channeling; single rigorous mechanistic study","pmids":["11948179"],"is_preprint":false},{"year":2000,"finding":"ATIC fuses to ALK via inv(2)(p23q35) in anaplastic large cell lymphoma, producing an ~87 kDa ATIC-ALK chimeric protein localized exclusively to the cytoplasm (unlike NPM-ALK which is cytoplasmic and nuclear). The fusion protein is constitutively tyrosine-phosphorylated and converts the IL-3-dependent BaF3 cell line to cytokine-independent growth. ATIC-mediated homodimerization is proposed as the mechanism of ALK activation.","method":"RT-PCR, inverse PCR, transient expression in BaF3 cells, cytokine-independence assay, subcellular localization by immunostaining","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — constitutive phosphorylation and cytokine-independence assay in cells, confirmed by multiple independent groups (PMID 10702393, 10706082, 10706887)","pmids":["10706887","10702393","10706082"],"is_preprint":false},{"year":2000,"finding":"ATIC-ALK fusion protein possesses constitutive tyrosine kinase activity, forms stable complexes with the signaling adaptor proteins Grb2 and Shc (detected by co-immunoprecipitation), induces tyrosine phosphorylation of Shc, and provokes oncogenic transformation of mouse fibroblasts.","method":"Full-length cDNA expression in mouse fibroblasts, co-immunoprecipitation of Grb2 and Shc, tyrosine phosphorylation assay, focus-formation/transformation assay","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with signaling partners, transformation assay, and phosphorylation assay in same study; replicated across multiple ALCL studies","pmids":["10706082"],"is_preprint":false},{"year":2004,"finding":"Loss-of-function mutations in ATIC cause AICA-ribosiduria: a K426R missense mutation in the transformylase region completely abolishes AICARFT activity in recombinant protein, while a frameshift mutation causes loss of the other allele. Patients accumulate ZMP (AICAR) and its di/triphosphates in erythrocytes and excrete AICA-riboside in urine. Impaired AICARFT activity is the primary enzymatic defect; IMPCHase activity is partially retained (~40% of normal).","method":"Fibroblast metabolite accumulation assay, ATIC gene sequencing, recombinant mutant protein expression and enzymatic activity assay","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 1 / Strong — recombinant mutant protein with complete loss of transformylase activity demonstrated in vitro; supported by patient metabolite data","pmids":["15114530"],"is_preprint":false},{"year":2011,"finding":"Mutations in ATIC destabilize purinosome assembly in cultured skin fibroblasts from AICA-ribosiduria patients. The ability to form purinosomes (multienzyme de novo purine synthesis complexes) in purine-depleted medium correlates with structural integrity of ATIC protein. Purinosome assembly was confirmed in multiple cell types (HeLa, HepG2, Saos-2, HEK293, skin fibroblasts, keratinocytes) by parallel immunolabeling and confocal fluorescence microscopy.","method":"Immunofluorescence/confocal microscopy of purinosome assembly in primary patient fibroblasts and multiple cell lines, parallel immunolabeling of multiple DNPS enzymes","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct imaging of purinosome assembly with patient-derived cells carrying ATIC mutations; single lab but multiple cell types and correlation with clinical severity","pmids":["22180458"],"is_preprint":false},{"year":2015,"finding":"Endogenous ZMP (produced when ATIC homodimerization is blocked by a small-molecule inhibitor) can activate AMPK and its downstream signaling pathways. Inhibition of ATIC homodimerization with a peptide-based inhibitor increases intracellular ZMP and activates AMPK in cells and in a mouse model of metabolic disorder, establishing ATIC homodimerization as necessary for the final step of de novo purine biosynthesis.","method":"Small-molecule ATIC homodimerization inhibitor, cellular ZMP quantification, AMPK phosphorylation assay, in vivo mouse metabolic disorder model","journal":"Chemistry & biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — chemical inhibition of dimerization with cellular and in vivo readouts; single lab but both in vitro and in vivo confirmation","pmids":["26144885"],"is_preprint":false},{"year":2015,"finding":"ATIC accumulates in Golgi/endosome fractions after insulin stimulation in hepatocytes. siRNA-mediated knockdown of ATIC in HEK293 cells reduces insulin receptor (IR) tyrosine phosphorylation and endocytosis. ATIC knockdown increases AMPK-Thr172 phosphorylation in IR complexes. Treatment with AICAR (the ATIC substrate) increases IR endocytosis in cells and in liver. These results suggest ATIC participates in a signaling mechanism linking purine biosynthesis to IR endocytosis.","method":"Subcellular fractionation, siRNA knockdown, IR phosphorylation assay, in vitro reconstitution system, AICAR treatment in cultured cells and mouse liver","journal":"Molecular & cellular proteomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with multiple cellular readouts and in vivo AICAR treatment; single lab, multiple orthogonal assays","pmids":["25687571"],"is_preprint":false},{"year":2017,"finding":"ATIC knockdown or chemical inhibition of its transformylase activity in cancer cells causes G2/M cell cycle arrest, ATP depletion, and increased DNA double-strand breaks after ionizing radiation, with delayed repair. Exogenous ATP supplementation rescues the DNA repair defect, linking ATIC function in purine synthesis to DNA damage response via ATP levels.","method":"siRNA knockdown, small-molecule AICARFT inhibitor, clonogenic survival assay, neutral comet assay, γH2AX staining, cell cycle analysis, ATP rescue experiment","journal":"International journal of radiation oncology, biology, physics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (KD + chemical inhibitor + rescue), single lab","pmids":["29029884"],"is_preprint":false},{"year":2017,"finding":"ATIC suppresses AMPK activation in hepatocellular carcinoma cells, thereby activating the downstream mTOR-S6K1-S6 signaling axis. ATIC knockdown by lentiviral shRNA reduces proliferation, colony formation, and migration of HCC cells; these effects are rescued by the AMPK inhibitor Compound C, placing ATIC upstream of AMPK in this pathway.","method":"Lentiviral shRNA knockdown, Western blot for AMPK/mTOR/S6K1 phosphorylation, Compound C rescue assay, cell proliferation/apoptosis/migration assays","journal":"Cell communication and signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via Compound C rescue assay combined with KD phenotypes; single lab, multiple readouts","pmids":["29246230"],"is_preprint":false},{"year":2000,"finding":"ATIC (PurH) directly binds the muscle-specific splicing enhancer MSE3 RNA element downstream of cardiac troponin T exon 5, and the in vitro binding affinity of recombinant human PurH to MSE3 directly correlates with functional activation of exon 5 inclusion in vivo, identifying a non-enzymatic, moonlighting role for ATIC as a splicing co-regulator.","method":"RNA affinity purification/protein identification, recombinant PurH direct RNA-binding assay, in vitro splicing competition assay, in vivo exon inclusion assay with binding affinity correlation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct RNA-binding with purified recombinant protein plus functional in vivo correlation; single lab","pmids":["10801888"],"is_preprint":false},{"year":2017,"finding":"Analysis of individual active sites of dimeric human ATIC using site-directed mutagenesis (S10W blocks the IMPCHase site) and isothermal calorimetry showed that most nucleotide ligands bind selectively to one of the two active sites. XMP is exceptional in binding both AICARFT and IMPCHase active sites and shows evidence of cooperative binding with communication between symmetrically-related IMPCHase domains. No positive cooperativity was detected in the AICARFT site with the model ligands tested.","method":"Site-directed mutagenesis, truncation mutants, isothermal calorimetry (ITC)","journal":"Biochimica et biophysica acta. Proteins and proteomics","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro biophysical binding assay with mutagenesis; single lab, no independent replication","pmids":["29042184"],"is_preprint":false},{"year":2022,"finding":"ATIC promotes hepatocellular carcinoma cell proliferation and migration via the PI3K/AKT signaling pathway. ATIC knockdown inhibited cell proliferation and migration; AKT activator SC79 partially reversed these effects. LncRNA ZFAS1 was shown to directly interact with ATIC and regulate its transcription.","method":"siRNA/shRNA knockdown, luciferase reporter assay, SC79 (AKT activator) rescue, colony formation, wound-healing and Transwell assays, in vivo xenograft","journal":"Journal of cancer research and clinical oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, partial rescue with AKT activator; lncRNA-ATIC interaction established by luciferase assay but not deep mechanistic validation","pmids":["39001904"],"is_preprint":false},{"year":2022,"finding":"ATIC promotes lung adenocarcinoma cell growth and migration by upregulating Myc expression. ATIC overexpression-induced growth and migration were abrogated by Myc knockdown in HCC827 and NCI-H1435 cells, establishing ATIC as upstream of Myc in this context.","method":"ATIC overexpression, Myc siRNA knockdown rescue experiment, cell proliferation, migration and invasion assays","journal":"Oncology letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, epistasis by rescue experiment but no direct mechanistic link between ATIC enzymatic activity and Myc established","pmids":["35251351"],"is_preprint":false},{"year":2022,"finding":"Global and vascular smooth muscle cell (VSMC)-specific knockout of Atic in mice inhibited VSMC proliferation and attenuated arterial neointima formation and atherosclerotic lesion development, demonstrating a cell-autonomous role for ATIC-dependent de novo purine synthesis in proliferative arterial disease.","method":"VSMC-specific and global Atic knockout mouse models, arterial injury models, atherosclerosis models, liquid chromatography-tandem mass spectrometry for purine metabolites","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific genetic knockout in two distinct in vivo disease models with mass spectrometry metabolic validation; multiple orthogonal approaches","pmids":["36073366"],"is_preprint":false},{"year":2022,"finding":"Cryptococcus neoformans ATIC (encoded by ADE16) is essential for de novo purine synthesis; atic null mutants are adenine and histidine auxotrophs unable to establish infection in a murine model. Crystal structure of C. neoformans ATIC was determined, revealing a serine-to-tyrosine substitution in the active site compared to human ATIC, and fungal Km values for AICAR and FAICAR are 8-fold and 20-fold higher, respectively, than human ortholog.","method":"Genetic deletion (ΔaDE16), auxotrophy assay, murine infection model, X-ray crystallography, recombinant enzyme kinetics","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure, in vitro kinetics, and in vivo virulence model in single study; rigorous multi-method characterization","pmids":["36063996"],"is_preprint":false},{"year":2023,"finding":"ATIC substrate AICAR (as its ribonucleoside AICAr) regulates LRRK2 mRNA stability in a cell-type-specific manner. AICAr treatment recruits the RNA-binding protein AUF1 to AU-rich elements (AREs) in LRRK2 mRNA, leading to recruitment of the decapping complex DCP1/2 and mRNA decay, thereby reducing LRRK2 protein levels. This pathway rescues LRRK2-induced dopaminergic neurodegeneration and neuroinflammation in Drosophila and mouse PD models.","method":"AICAr treatment in cells and mouse tissue, AUF1 RNA immunoprecipitation, mRNA stability assay, DCP1/2 recruitment assay, Drosophila PD model, mouse PD model","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway established via RIP and mRNA decay assay with in vivo validation in two model organisms; single lab","pmids":["37366237"],"is_preprint":false},{"year":2025,"finding":"ATIC deletion in zebrafish causes skeletal muscle atrophy through disruption of de novo purine synthesis, abnormal AICAR accumulation, blockade of IMP synthesis, mitochondrial structural damage, dysfunction of oxidative phosphorylation (OXPHOS) complexes I–V, and reactive oxygen species burst, ultimately activating the ubiquitin-proteasome system to drive muscle atrophy.","method":"CRISPR/Cas9 atic knockout zebrafish, siRNA knockdown in C2C12 myoblasts, mitochondrial function assays, ROS measurement, OXPHOS complex activity assays, ubiquitin-proteasome pathway readouts","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO in zebrafish plus siRNA KD in mammalian cells with multiple mechanistic readouts; single lab","pmids":["40623538"],"is_preprint":false},{"year":2025,"finding":"LncRNA TPT1-AS1 physically interacts with CBP (CREB-binding protein), leading to loss of H3K27Ac at the ATIC promoter and suppression of ATIC transcription, thereby blocking de novo purine biosynthesis and breast cancer progression. ATIC knockdown mimicked the tumor-suppressive effects of TPT1-AS1.","method":"Mass spectrometry (MS) identification of TPT1-AS1 interactome, Co-IP of TPT1-AS1/CBP, ChIP for H3K27Ac at ATIC promoter, siRNA knockdown, xenograft tumor model","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP of histone mark at ATIC promoter plus Co-IP of lncRNA/CBP complex; single lab, multiple methods","pmids":["40091780"],"is_preprint":false},{"year":2025,"finding":"ATIC knockdown in upper tract urothelial carcinoma (UTUC) cells reduces B7-H3 (CD276), PRNP, RAC2, and NT5E expression as determined by TMT-based quantitative proteomics. The ATIC/B7-H3 axis modulates mTOR, AKT, ERK, and p38 phosphorylation. B7-H3 appears upstream of PRNP and RAC2 in this network.","method":"TMT-based quantitative proteomics after ATIC knockdown, Western blot for signaling proteins, siRNA epistasis experiments, cell proliferation/migration/invasion assays","journal":"Cancer genomics & proteomics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, proteomics-driven discovery with limited mechanistic validation of the ATIC-to-B7-H3 connection","pmids":["41771578"],"is_preprint":false}],"current_model":"ATIC is a homodimeric bifunctional enzyme that catalyzes the penultimate step (AICAR transformylase, in its C-terminal domain) and the final step (IMP cyclohydrolase, in its N-terminal domain) of de novo IMP biosynthesis without substrate channeling between sites; it participates in purinosome multienzyme complexes, regulates AMPK activity by controlling intracellular ZMP levels, and has additional non-enzymatic roles including binding a muscle-specific splicing enhancer to promote alternative exon inclusion, and participating in insulin receptor endocytosis signaling at the Golgi/endosome."},"narrative":{"mechanistic_narrative":"ATIC is a homodimeric bifunctional enzyme that catalyzes the final two steps of de novo IMP (purine) biosynthesis, harboring AICAR transformylase (AICARFT) activity in its C-terminal domain and IMP cyclohydrolase (IMPCHase) activity in its N-terminal domain, which can be expressed independently from truncation mutants [PMID:8567683]. Transient and steady-state kinetics establish that tetrahydrofolate release from the AICARFT site is rate-limiting, the cyclohydrolase step is essentially irreversible, and the FAICAR intermediate is not channeled between the two active sites [PMID:11948179]; ligand-binding analyses further show that nucleotides bind selectively to one of the two sites, with XMP exceptionally engaging both and exhibiting cooperative communication between symmetry-related IMPCHase domains [PMID:29042184]. Homodimerization is required for the terminal AICARFT step, and blocking it raises intracellular ZMP (AICAR monophosphate), which activates AMPK [PMID:26144885]. Through control of ZMP levels and ATP supply, ATIC integrates purine synthesis with downstream signaling and proliferative physiology: its loss causes G2/M arrest, ATP depletion and impaired DNA double-strand break repair [PMID:29029884], it suppresses AMPK to sustain mTOR-S6K1 signaling in hepatocellular carcinoma [PMID:29246230], and genetic deletion blocks vascular smooth muscle cell proliferation and arterial/atherosclerotic disease in mice [PMID:36073366]. ATIC also has non-enzymatic roles, directly binding the muscle-specific splicing enhancer MSE3 to promote cardiac troponin T exon inclusion [PMID:10801888] and accumulating in Golgi/endosome fractions where it supports insulin receptor phosphorylation and endocytosis [PMID:25687571]. Loss-of-function mutations in ATIC cause AICA-ribosiduria, a metabolic disorder driven by abolition of AICARFT activity and accumulation of ZMP/AICA-riboside [PMID:15114530], and these mutations destabilize purinosome assembly in patient fibroblasts [PMID:22180458]. The N-terminal ALK fusion partner role arises when an inv(2) chromosomal rearrangement fuses ATIC to ALK, with ATIC-mediated dimerization driving constitutive ALK kinase activation and oncogenic signaling in anaplastic large cell lymphoma [PMID:10706887, PMID:10702393, PMID:10706082].","teleology":[{"year":1996,"claim":"Established that ATIC is a single polypeptide carrying two distinct catalytic activities, defining its bifunctional architecture in de novo purine biosynthesis.","evidence":"cDNA cloning, recombinant protein purification, truncation and site-directed mutagenesis with steady-state kinetics","pmids":["8567683"],"confidence":"High","gaps":["Did not resolve whether the two activities act sequentially via channeling","No structural model of the dimer","Folate-binding motif role left undefined functionally"]},{"year":2000,"claim":"Revealed an oncogenic gain-of-function: chromosomal fusion of ATIC to ALK creates a constitutively active tyrosine kinase, with ATIC dimerization as the activating mechanism.","evidence":"RT-PCR/inverse PCR cloning, expression in BaF3 and fibroblasts, cytokine-independence and focus-formation assays, Co-IP of Grb2/Shc","pmids":["10706887","10702393","10706082"],"confidence":"High","gaps":["Whether ATIC enzymatic function contributes to transformation is not addressed","Full downstream signaling network beyond Grb2/Shc not mapped"]},{"year":2000,"claim":"Uncovered a moonlighting non-enzymatic role in which ATIC acts as an RNA-binding splicing co-regulator.","evidence":"RNA affinity purification, recombinant PurH RNA-binding assay, in vitro splicing and in vivo exon-inclusion correlation","pmids":["10801888"],"confidence":"Medium","gaps":["Physiological relevance in muscle in vivo not demonstrated","RNA-binding interface on ATIC not mapped","Relationship to enzymatic function unknown"]},{"year":2002,"claim":"Defined the detailed kinetic mechanism and ruled out substrate channeling, settling how the two active sites operate.","evidence":"Rapid chemical quench, stopped-flow absorbance, steady-state kinetics, KINSIM simulation","pmids":["11948179"],"confidence":"High","gaps":["No structural basis for rate-limiting THF release","Allosteric communication between sites not yet probed"]},{"year":2004,"claim":"Linked ATIC directly to a Mendelian disease, showing loss of AICARFT activity causes AICA-ribosiduria with ZMP accumulation.","evidence":"Patient metabolite assays, gene sequencing, recombinant mutant enzyme activity measurement","pmids":["15114530"],"confidence":"High","gaps":["Mechanism linking ZMP accumulation to clinical phenotype not fully resolved","IMPCHase retention consequences unclear"]},{"year":2011,"claim":"Connected ATIC structural integrity to assembly of the purinosome multienzyme complex.","evidence":"Immunofluorescence/confocal imaging of purinosome assembly in patient fibroblasts and multiple cell lines","pmids":["22180458"],"confidence":"Medium","gaps":["Single lab","Direct interactions stabilizing the purinosome not biochemically defined","Causality between assembly defect and metabolic phenotype correlational"]},{"year":2015,"claim":"Demonstrated that ATIC homodimerization controls intracellular ZMP and thereby AMPK activity, linking the terminal biosynthetic step to metabolic signaling.","evidence":"Peptide/small-molecule dimerization inhibitor, cellular ZMP quantification, AMPK phosphorylation assay, mouse metabolic model","pmids":["26144885"],"confidence":"Medium","gaps":["Single lab","Off-target effects of inhibitor on other ZMP-dependent processes not excluded"]},{"year":2015,"claim":"Implicated ATIC in insulin receptor endocytosis at Golgi/endosome compartments, beyond its cytosolic biosynthetic role.","evidence":"Subcellular fractionation, siRNA knockdown, IR phosphorylation assays, AICAR treatment in cells and liver","pmids":["25687571"],"confidence":"Medium","gaps":["Direct binding partners at the endosome not identified","Whether ATIC enzymatic activity is required is unclear","Single lab"]},{"year":2017,"claim":"Showed that ATIC-dependent purine synthesis maintains ATP pools required for DNA double-strand break repair and cell cycle progression.","evidence":"siRNA knockdown, AICARFT inhibitor, comet/γH2AX assays, cell cycle analysis, ATP rescue","pmids":["29029884"],"confidence":"Medium","gaps":["Single lab","Whether ZMP/AMPK contributes independently of ATP not separated"]},{"year":2017,"claim":"Positioned ATIC upstream of AMPK to drive mTOR signaling and tumor cell proliferation in hepatocellular carcinoma.","evidence":"Lentiviral shRNA knockdown, Western blots, Compound C rescue, proliferation/migration assays","pmids":["29246230"],"confidence":"Medium","gaps":["Mechanism by which ATIC suppresses AMPK not defined at molecular level","Single lab"]},{"year":2017,"claim":"Resolved active-site selectivity of ligand binding and identified XMP-dependent inter-domain cooperativity in the dimer.","evidence":"Site-directed mutagenesis (S10W), truncation mutants, isothermal calorimetry","pmids":["29042184"],"confidence":"Medium","gaps":["Single lab, no independent replication","Physiological role of XMP cooperativity unknown"]},{"year":2022,"claim":"Provided definitive in vivo genetic evidence that ATIC-dependent purine synthesis drives vascular smooth muscle proliferation and arterial disease.","evidence":"Global and VSMC-specific Atic knockout mice, arterial injury and atherosclerosis models, LC-MS/MS metabolomics","pmids":["36073366"],"confidence":"High","gaps":["Whether ZMP signaling or nucleotide supply is the operative mechanism not fully separated"]},{"year":2022,"claim":"Extended ATIC pro-tumorigenic roles to additional cancers via PI3K/AKT and Myc programs.","evidence":"Knockdown/overexpression, SC79 and Myc-knockdown rescue, luciferase reporter, xenografts (HCC and lung adenocarcinoma)","pmids":["39001904","35251351"],"confidence":"Low","gaps":["Single labs, partial rescues","No direct link between ATIC enzymatic activity and AKT/Myc established"]},{"year":2022,"claim":"Identified the fungal ATIC ortholog as essential for purine synthesis and virulence, with structural and kinetic divergence from the human enzyme.","evidence":"ADE16 deletion, auxotrophy and murine infection assays, X-ray crystallography, recombinant kinetics in C. neoformans","pmids":["36063996"],"confidence":"High","gaps":["Selective inhibitor exploiting the active-site difference not yet developed"]},{"year":2023,"claim":"Showed the ATIC substrate AICAR acts as a small-molecule signal regulating LRRK2 mRNA stability, linking purine metabolism to neurodegeneration.","evidence":"AICAr treatment, AUF1 RIP, mRNA decay and DCP1/2 recruitment assays, Drosophila and mouse PD models","pmids":["37366237"],"confidence":"Medium","gaps":["This is a substrate effect, not a direct ATIC molecular activity","Cell-type specificity mechanism incompletely defined"]},{"year":2025,"claim":"Linked ATIC loss to skeletal muscle atrophy through AICAR accumulation, mitochondrial OXPHOS failure, ROS, and ubiquitin-proteasome activation.","evidence":"CRISPR atic knockout zebrafish, siRNA in C2C12, mitochondrial/OXPHOS/ROS assays","pmids":["40623538"],"confidence":"Medium","gaps":["Single lab","Whether AICAR accumulation or IMP/ATP depletion is the primary driver not separated"]},{"year":2025,"claim":"Defined transcriptional and proteomic regulatory contexts in which ATIC drives cancer progression.","evidence":"TPT1-AS1/CBP Co-IP and H3K27Ac ChIP at ATIC promoter (breast cancer); TMT proteomics of ATIC/B7-H3 axis (urothelial carcinoma)","pmids":["40091780","41771578"],"confidence":"Medium","gaps":["Connection between ATIC enzymatic function and the B7-H3 axis not mechanistically established (Low confidence for #19)","Single labs"]},{"year":null,"claim":"It remains unresolved which ATIC outputs — nucleotide/ATP supply, ZMP/AMPK signaling, or non-enzymatic moonlighting functions — dominate in each disease context, and how its enzymatic and non-catalytic roles are coordinated.","evidence":"","pmids":[],"confidence":"Low","gaps":["No study cleanly separates catalytic from non-catalytic contributions in vivo","Full-length human dimer structural mechanism of inter-domain cooperativity not resolved","Recruitment mechanism to Golgi/endosome and to splicing complexes undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,4]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[10]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[5,6]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[7]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,1,4,14]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,7,9]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,3,4]}],"complexes":["purinosome","ATIC homodimer","ATIC-ALK fusion"],"partners":["ALK","GRB2","SHC"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P31939","full_name":"Bifunctional purine biosynthesis protein ATIC","aliases":["AICAR transformylase/inosine monophosphate cyclohydrolase","ATIC"],"length_aa":592,"mass_kda":64.6,"function":"Bifunctional enzyme that catalyzes the last two steps of purine biosynthesis (PubMed:11948179, PubMed:14756554). Acts as a transformylase that incorporates a formyl group to the AMP analog AICAR (5-amino-1-(5-phospho-beta-D-ribosyl)imidazole-4-carboxamide) to produce the intermediate formyl-AICAR (FAICAR) (PubMed:10985775, PubMed:11948179, PubMed:9378707). Can use both 10-formyldihydrofolate and 10-formyltetrahydrofolate as the formyl donor in this reaction (PubMed:10985775). Also catalyzes the cyclization of FAICAR to inosine monophosphate (IMP) (PubMed:11948179, PubMed:14756554). Is able to convert thio-AICAR to 6-mercaptopurine ribonucleotide, an inhibitor of purine biosynthesis used in the treatment of human leukemias (PubMed:10985775). Promotes insulin receptor/INSR autophosphorylation and is involved in INSR internalization (PubMed:25687571)","subcellular_location":"Cytoplasm, cytosol","url":"https://www.uniprot.org/uniprotkb/P31939/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ATIC","classification":"Not Classified","n_dependent_lines":441,"n_total_lines":1208,"dependency_fraction":0.3650662251655629},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ACTR2","stoichiometry":0.2},{"gene":"ARL3","stoichiometry":0.2},{"gene":"SAR1B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ATIC","total_profiled":1310},"omim":[{"mim_id":"608688","title":"AICA-RIBOSIDURIA DUE TO ATIC DEFICIENCY","url":"https://www.omim.org/entry/608688"},{"mim_id":"608222","title":"ADENYLOSUCCINATE LYASE; ADSL","url":"https://www.omim.org/entry/608222"},{"mim_id":"601731","title":"5-@AMINOIMIDAZOLE-4-CARBOXAMIDE RIBONUCLEOTIDE FORMYLTRANSFERASE/IMP CYCLOHYDROLASE; ATIC","url":"https://www.omim.org/entry/601731"},{"mim_id":"103050","title":"ADENYLOSUCCINASE DEFICIENCY; ADSLD","url":"https://www.omim.org/entry/103050"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ATIC"},"hgnc":{"alias_symbol":["PURH","AICARFT","IMPCHASE"],"prev_symbol":[]},"alphafold":{"accession":"P31939","domains":[{"cath_id":"3.40.50.1380","chopping":"5-196","consensus_level":"high","plddt":96.9315,"start":5,"end":196},{"cath_id":"3.40.140.20","chopping":"227-366","consensus_level":"high","plddt":98.4337,"start":227,"end":366},{"cath_id":"3.40.140.20","chopping":"375-454_528-584","consensus_level":"high","plddt":98.3821,"start":375,"end":584}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P31939","model_url":"https://alphafold.ebi.ac.uk/files/AF-P31939-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P31939-F1-predicted_aligned_error_v6.png","plddt_mean":97.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ATIC","jax_strain_url":"https://www.jax.org/strain/search?query=ATIC"},"sequence":{"accession":"P31939","fasta_url":"https://rest.uniprot.org/uniprotkb/P31939.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P31939/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P31939"}},"corpus_meta":[{"pmid":"18242762","id":"PMC_18242762","title":"EML4-ALK fusion transcripts, but no NPM-, TPM3-, CLTC-, ATIC-, or TFG-ALK fusion transcripts, in non-small cell lung carcinomas.","date":"2008","source":"Lung cancer (Amsterdam, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/18242762","citation_count":135,"is_preprint":false},{"pmid":"10702393","id":"PMC_10702393","title":"ATIC-ALK: A novel variant ALK gene fusion in anaplastic large cell lymphoma resulting from the recurrent cryptic chromosomal inversion, inv(2)(p23q35).","date":"2000","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/10702393","citation_count":129,"is_preprint":false},{"pmid":"15114530","id":"PMC_15114530","title":"AICA-ribosiduria: a novel, neurologically devastating inborn error of purine biosynthesis caused by mutation of ATIC.","date":"2004","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15114530","citation_count":123,"is_preprint":false},{"pmid":"10706082","id":"PMC_10706082","title":"A new variant anaplastic lymphoma kinase (ALK)-fusion protein (ATIC-ALK) in a case of ALK-positive anaplastic large cell lymphoma.","date":"2000","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/10706082","citation_count":115,"is_preprint":false},{"pmid":"7997171","id":"PMC_7997171","title":"Five Listeria monocytogenes genes preferentially expressed in infected mammalian cells: plcA, purH, purD, pyrE and an arginine ABC transporter gene, arpJ.","date":"1994","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/7997171","citation_count":111,"is_preprint":false},{"pmid":"10706887","id":"PMC_10706887","title":"Inv(2)(p23q35) in anaplastic large-cell lymphoma induces constitutive anaplastic lymphoma kinase (ALK) tyrosine kinase activation by fusion to ATIC, an enzyme involved in purine nucleotide biosynthesis.","date":"2000","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/10706887","citation_count":110,"is_preprint":false},{"pmid":"12939746","id":"PMC_12939746","title":"ALK-ATIC fusion in urinary bladder inflammatory myofibroblastic tumor.","date":"2003","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/12939746","citation_count":98,"is_preprint":false},{"pmid":"8567683","id":"PMC_8567683","title":"The human purH gene product, 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase. 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Km values for AICAR and (6R,6S)10-formyltetrahydrofolate were determined for the purified recombinant human enzyme. Site-directed mutagenesis of a putative folate-binding motif showed it plays no role in enzymatic activity.\",\n      \"method\": \"cDNA cloning, recombinant protein purification, steady-state kinetics, truncation mutagenesis, site-directed mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic assay with purified recombinant protein, truncation and site-directed mutagenesis, kinetic characterization; foundational biochemical study replicated conceptually across species\",\n      \"pmids\": [\"8567683\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Detailed kinetic mechanism of human ATIC established by rapid chemical quench, stopped-flow, and steady-state kinetics: (1) rate-limiting step is tetrahydrofolate release from the AICARFT active site (~2.9 s⁻¹); (2) the reverse transformylase reaction (~6.7 s⁻¹) is faster than forward; (3) the cyclohydrolase reaction is essentially unidirectional; (4) there is no kinetic evidence of substrate channeling of the FAICAR intermediate between the two active sites.\",\n      \"method\": \"Rapid chemical quench, stopped-flow absorbance, steady-state kinetics, kinetic simulation (KINSIM)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal transient and steady-state kinetic methods with explicit negative result for channeling; single rigorous mechanistic study\",\n      \"pmids\": [\"11948179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"ATIC fuses to ALK via inv(2)(p23q35) in anaplastic large cell lymphoma, producing an ~87 kDa ATIC-ALK chimeric protein localized exclusively to the cytoplasm (unlike NPM-ALK which is cytoplasmic and nuclear). The fusion protein is constitutively tyrosine-phosphorylated and converts the IL-3-dependent BaF3 cell line to cytokine-independent growth. ATIC-mediated homodimerization is proposed as the mechanism of ALK activation.\",\n      \"method\": \"RT-PCR, inverse PCR, transient expression in BaF3 cells, cytokine-independence assay, subcellular localization by immunostaining\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — constitutive phosphorylation and cytokine-independence assay in cells, confirmed by multiple independent groups (PMID 10702393, 10706082, 10706887)\",\n      \"pmids\": [\"10706887\", \"10702393\", \"10706082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"ATIC-ALK fusion protein possesses constitutive tyrosine kinase activity, forms stable complexes with the signaling adaptor proteins Grb2 and Shc (detected by co-immunoprecipitation), induces tyrosine phosphorylation of Shc, and provokes oncogenic transformation of mouse fibroblasts.\",\n      \"method\": \"Full-length cDNA expression in mouse fibroblasts, co-immunoprecipitation of Grb2 and Shc, tyrosine phosphorylation assay, focus-formation/transformation assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with signaling partners, transformation assay, and phosphorylation assay in same study; replicated across multiple ALCL studies\",\n      \"pmids\": [\"10706082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Loss-of-function mutations in ATIC cause AICA-ribosiduria: a K426R missense mutation in the transformylase region completely abolishes AICARFT activity in recombinant protein, while a frameshift mutation causes loss of the other allele. Patients accumulate ZMP (AICAR) and its di/triphosphates in erythrocytes and excrete AICA-riboside in urine. Impaired AICARFT activity is the primary enzymatic defect; IMPCHase activity is partially retained (~40% of normal).\",\n      \"method\": \"Fibroblast metabolite accumulation assay, ATIC gene sequencing, recombinant mutant protein expression and enzymatic activity assay\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — recombinant mutant protein with complete loss of transformylase activity demonstrated in vitro; supported by patient metabolite data\",\n      \"pmids\": [\"15114530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Mutations in ATIC destabilize purinosome assembly in cultured skin fibroblasts from AICA-ribosiduria patients. The ability to form purinosomes (multienzyme de novo purine synthesis complexes) in purine-depleted medium correlates with structural integrity of ATIC protein. Purinosome assembly was confirmed in multiple cell types (HeLa, HepG2, Saos-2, HEK293, skin fibroblasts, keratinocytes) by parallel immunolabeling and confocal fluorescence microscopy.\",\n      \"method\": \"Immunofluorescence/confocal microscopy of purinosome assembly in primary patient fibroblasts and multiple cell lines, parallel immunolabeling of multiple DNPS enzymes\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct imaging of purinosome assembly with patient-derived cells carrying ATIC mutations; single lab but multiple cell types and correlation with clinical severity\",\n      \"pmids\": [\"22180458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Endogenous ZMP (produced when ATIC homodimerization is blocked by a small-molecule inhibitor) can activate AMPK and its downstream signaling pathways. Inhibition of ATIC homodimerization with a peptide-based inhibitor increases intracellular ZMP and activates AMPK in cells and in a mouse model of metabolic disorder, establishing ATIC homodimerization as necessary for the final step of de novo purine biosynthesis.\",\n      \"method\": \"Small-molecule ATIC homodimerization inhibitor, cellular ZMP quantification, AMPK phosphorylation assay, in vivo mouse metabolic disorder model\",\n      \"journal\": \"Chemistry & biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — chemical inhibition of dimerization with cellular and in vivo readouts; single lab but both in vitro and in vivo confirmation\",\n      \"pmids\": [\"26144885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ATIC accumulates in Golgi/endosome fractions after insulin stimulation in hepatocytes. siRNA-mediated knockdown of ATIC in HEK293 cells reduces insulin receptor (IR) tyrosine phosphorylation and endocytosis. ATIC knockdown increases AMPK-Thr172 phosphorylation in IR complexes. Treatment with AICAR (the ATIC substrate) increases IR endocytosis in cells and in liver. These results suggest ATIC participates in a signaling mechanism linking purine biosynthesis to IR endocytosis.\",\n      \"method\": \"Subcellular fractionation, siRNA knockdown, IR phosphorylation assay, in vitro reconstitution system, AICAR treatment in cultured cells and mouse liver\",\n      \"journal\": \"Molecular & cellular proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with multiple cellular readouts and in vivo AICAR treatment; single lab, multiple orthogonal assays\",\n      \"pmids\": [\"25687571\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ATIC knockdown or chemical inhibition of its transformylase activity in cancer cells causes G2/M cell cycle arrest, ATP depletion, and increased DNA double-strand breaks after ionizing radiation, with delayed repair. Exogenous ATP supplementation rescues the DNA repair defect, linking ATIC function in purine synthesis to DNA damage response via ATP levels.\",\n      \"method\": \"siRNA knockdown, small-molecule AICARFT inhibitor, clonogenic survival assay, neutral comet assay, γH2AX staining, cell cycle analysis, ATP rescue experiment\",\n      \"journal\": \"International journal of radiation oncology, biology, physics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (KD + chemical inhibitor + rescue), single lab\",\n      \"pmids\": [\"29029884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ATIC suppresses AMPK activation in hepatocellular carcinoma cells, thereby activating the downstream mTOR-S6K1-S6 signaling axis. ATIC knockdown by lentiviral shRNA reduces proliferation, colony formation, and migration of HCC cells; these effects are rescued by the AMPK inhibitor Compound C, placing ATIC upstream of AMPK in this pathway.\",\n      \"method\": \"Lentiviral shRNA knockdown, Western blot for AMPK/mTOR/S6K1 phosphorylation, Compound C rescue assay, cell proliferation/apoptosis/migration assays\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via Compound C rescue assay combined with KD phenotypes; single lab, multiple readouts\",\n      \"pmids\": [\"29246230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"ATIC (PurH) directly binds the muscle-specific splicing enhancer MSE3 RNA element downstream of cardiac troponin T exon 5, and the in vitro binding affinity of recombinant human PurH to MSE3 directly correlates with functional activation of exon 5 inclusion in vivo, identifying a non-enzymatic, moonlighting role for ATIC as a splicing co-regulator.\",\n      \"method\": \"RNA affinity purification/protein identification, recombinant PurH direct RNA-binding assay, in vitro splicing competition assay, in vivo exon inclusion assay with binding affinity correlation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct RNA-binding with purified recombinant protein plus functional in vivo correlation; single lab\",\n      \"pmids\": [\"10801888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Analysis of individual active sites of dimeric human ATIC using site-directed mutagenesis (S10W blocks the IMPCHase site) and isothermal calorimetry showed that most nucleotide ligands bind selectively to one of the two active sites. XMP is exceptional in binding both AICARFT and IMPCHase active sites and shows evidence of cooperative binding with communication between symmetrically-related IMPCHase domains. No positive cooperativity was detected in the AICARFT site with the model ligands tested.\",\n      \"method\": \"Site-directed mutagenesis, truncation mutants, isothermal calorimetry (ITC)\",\n      \"journal\": \"Biochimica et biophysica acta. Proteins and proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro biophysical binding assay with mutagenesis; single lab, no independent replication\",\n      \"pmids\": [\"29042184\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ATIC promotes hepatocellular carcinoma cell proliferation and migration via the PI3K/AKT signaling pathway. ATIC knockdown inhibited cell proliferation and migration; AKT activator SC79 partially reversed these effects. LncRNA ZFAS1 was shown to directly interact with ATIC and regulate its transcription.\",\n      \"method\": \"siRNA/shRNA knockdown, luciferase reporter assay, SC79 (AKT activator) rescue, colony formation, wound-healing and Transwell assays, in vivo xenograft\",\n      \"journal\": \"Journal of cancer research and clinical oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, partial rescue with AKT activator; lncRNA-ATIC interaction established by luciferase assay but not deep mechanistic validation\",\n      \"pmids\": [\"39001904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ATIC promotes lung adenocarcinoma cell growth and migration by upregulating Myc expression. ATIC overexpression-induced growth and migration were abrogated by Myc knockdown in HCC827 and NCI-H1435 cells, establishing ATIC as upstream of Myc in this context.\",\n      \"method\": \"ATIC overexpression, Myc siRNA knockdown rescue experiment, cell proliferation, migration and invasion assays\",\n      \"journal\": \"Oncology letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, epistasis by rescue experiment but no direct mechanistic link between ATIC enzymatic activity and Myc established\",\n      \"pmids\": [\"35251351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Global and vascular smooth muscle cell (VSMC)-specific knockout of Atic in mice inhibited VSMC proliferation and attenuated arterial neointima formation and atherosclerotic lesion development, demonstrating a cell-autonomous role for ATIC-dependent de novo purine synthesis in proliferative arterial disease.\",\n      \"method\": \"VSMC-specific and global Atic knockout mouse models, arterial injury models, atherosclerosis models, liquid chromatography-tandem mass spectrometry for purine metabolites\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific genetic knockout in two distinct in vivo disease models with mass spectrometry metabolic validation; multiple orthogonal approaches\",\n      \"pmids\": [\"36073366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cryptococcus neoformans ATIC (encoded by ADE16) is essential for de novo purine synthesis; atic null mutants are adenine and histidine auxotrophs unable to establish infection in a murine model. Crystal structure of C. neoformans ATIC was determined, revealing a serine-to-tyrosine substitution in the active site compared to human ATIC, and fungal Km values for AICAR and FAICAR are 8-fold and 20-fold higher, respectively, than human ortholog.\",\n      \"method\": \"Genetic deletion (ΔaDE16), auxotrophy assay, murine infection model, X-ray crystallography, recombinant enzyme kinetics\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure, in vitro kinetics, and in vivo virulence model in single study; rigorous multi-method characterization\",\n      \"pmids\": [\"36063996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ATIC substrate AICAR (as its ribonucleoside AICAr) regulates LRRK2 mRNA stability in a cell-type-specific manner. AICAr treatment recruits the RNA-binding protein AUF1 to AU-rich elements (AREs) in LRRK2 mRNA, leading to recruitment of the decapping complex DCP1/2 and mRNA decay, thereby reducing LRRK2 protein levels. This pathway rescues LRRK2-induced dopaminergic neurodegeneration and neuroinflammation in Drosophila and mouse PD models.\",\n      \"method\": \"AICAr treatment in cells and mouse tissue, AUF1 RNA immunoprecipitation, mRNA stability assay, DCP1/2 recruitment assay, Drosophila PD model, mouse PD model\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway established via RIP and mRNA decay assay with in vivo validation in two model organisms; single lab\",\n      \"pmids\": [\"37366237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ATIC deletion in zebrafish causes skeletal muscle atrophy through disruption of de novo purine synthesis, abnormal AICAR accumulation, blockade of IMP synthesis, mitochondrial structural damage, dysfunction of oxidative phosphorylation (OXPHOS) complexes I–V, and reactive oxygen species burst, ultimately activating the ubiquitin-proteasome system to drive muscle atrophy.\",\n      \"method\": \"CRISPR/Cas9 atic knockout zebrafish, siRNA knockdown in C2C12 myoblasts, mitochondrial function assays, ROS measurement, OXPHOS complex activity assays, ubiquitin-proteasome pathway readouts\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO in zebrafish plus siRNA KD in mammalian cells with multiple mechanistic readouts; single lab\",\n      \"pmids\": [\"40623538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LncRNA TPT1-AS1 physically interacts with CBP (CREB-binding protein), leading to loss of H3K27Ac at the ATIC promoter and suppression of ATIC transcription, thereby blocking de novo purine biosynthesis and breast cancer progression. ATIC knockdown mimicked the tumor-suppressive effects of TPT1-AS1.\",\n      \"method\": \"Mass spectrometry (MS) identification of TPT1-AS1 interactome, Co-IP of TPT1-AS1/CBP, ChIP for H3K27Ac at ATIC promoter, siRNA knockdown, xenograft tumor model\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP of histone mark at ATIC promoter plus Co-IP of lncRNA/CBP complex; single lab, multiple methods\",\n      \"pmids\": [\"40091780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ATIC knockdown in upper tract urothelial carcinoma (UTUC) cells reduces B7-H3 (CD276), PRNP, RAC2, and NT5E expression as determined by TMT-based quantitative proteomics. The ATIC/B7-H3 axis modulates mTOR, AKT, ERK, and p38 phosphorylation. B7-H3 appears upstream of PRNP and RAC2 in this network.\",\n      \"method\": \"TMT-based quantitative proteomics after ATIC knockdown, Western blot for signaling proteins, siRNA epistasis experiments, cell proliferation/migration/invasion assays\",\n      \"journal\": \"Cancer genomics & proteomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, proteomics-driven discovery with limited mechanistic validation of the ATIC-to-B7-H3 connection\",\n      \"pmids\": [\"41771578\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ATIC is a homodimeric bifunctional enzyme that catalyzes the penultimate step (AICAR transformylase, in its C-terminal domain) and the final step (IMP cyclohydrolase, in its N-terminal domain) of de novo IMP biosynthesis without substrate channeling between sites; it participates in purinosome multienzyme complexes, regulates AMPK activity by controlling intracellular ZMP levels, and has additional non-enzymatic roles including binding a muscle-specific splicing enhancer to promote alternative exon inclusion, and participating in insulin receptor endocytosis signaling at the Golgi/endosome.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ATIC is a homodimeric bifunctional enzyme that catalyzes the final two steps of de novo IMP (purine) biosynthesis, harboring AICAR transformylase (AICARFT) activity in its C-terminal domain and IMP cyclohydrolase (IMPCHase) activity in its N-terminal domain, which can be expressed independently from truncation mutants [#0]. Transient and steady-state kinetics establish that tetrahydrofolate release from the AICARFT site is rate-limiting, the cyclohydrolase step is essentially irreversible, and the FAICAR intermediate is not channeled between the two active sites [#1]; ligand-binding analyses further show that nucleotides bind selectively to one of the two sites, with XMP exceptionally engaging both and exhibiting cooperative communication between symmetry-related IMPCHase domains [#11]. Homodimerization is required for the terminal AICARFT step, and blocking it raises intracellular ZMP (AICAR monophosphate), which activates AMPK [#6]. Through control of ZMP levels and ATP supply, ATIC integrates purine synthesis with downstream signaling and proliferative physiology: its loss causes G2/M arrest, ATP depletion and impaired DNA double-strand break repair [#8], it suppresses AMPK to sustain mTOR-S6K1 signaling in hepatocellular carcinoma [#9], and genetic deletion blocks vascular smooth muscle cell proliferation and arterial/atherosclerotic disease in mice [#14]. ATIC also has non-enzymatic roles, directly binding the muscle-specific splicing enhancer MSE3 to promote cardiac troponin T exon inclusion [#10] and accumulating in Golgi/endosome fractions where it supports insulin receptor phosphorylation and endocytosis [#7]. Loss-of-function mutations in ATIC cause AICA-ribosiduria, a metabolic disorder driven by abolition of AICARFT activity and accumulation of ZMP/AICA-riboside [#4], and these mutations destabilize purinosome assembly in patient fibroblasts [#5]. The N-terminal ALK fusion partner role arises when an inv(2) chromosomal rearrangement fuses ATIC to ALK, with ATIC-mediated dimerization driving constitutive ALK kinase activation and oncogenic signaling in anaplastic large cell lymphoma [#2, #3].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established that ATIC is a single polypeptide carrying two distinct catalytic activities, defining its bifunctional architecture in de novo purine biosynthesis.\",\n      \"evidence\": \"cDNA cloning, recombinant protein purification, truncation and site-directed mutagenesis with steady-state kinetics\",\n      \"pmids\": [\"8567683\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve whether the two activities act sequentially via channeling\", \"No structural model of the dimer\", \"Folate-binding motif role left undefined functionally\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Revealed an oncogenic gain-of-function: chromosomal fusion of ATIC to ALK creates a constitutively active tyrosine kinase, with ATIC dimerization as the activating mechanism.\",\n      \"evidence\": \"RT-PCR/inverse PCR cloning, expression in BaF3 and fibroblasts, cytokine-independence and focus-formation assays, Co-IP of Grb2/Shc\",\n      \"pmids\": [\"10706887\", \"10702393\", \"10706082\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ATIC enzymatic function contributes to transformation is not addressed\", \"Full downstream signaling network beyond Grb2/Shc not mapped\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Uncovered a moonlighting non-enzymatic role in which ATIC acts as an RNA-binding splicing co-regulator.\",\n      \"evidence\": \"RNA affinity purification, recombinant PurH RNA-binding assay, in vitro splicing and in vivo exon-inclusion correlation\",\n      \"pmids\": [\"10801888\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological relevance in muscle in vivo not demonstrated\", \"RNA-binding interface on ATIC not mapped\", \"Relationship to enzymatic function unknown\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defined the detailed kinetic mechanism and ruled out substrate channeling, settling how the two active sites operate.\",\n      \"evidence\": \"Rapid chemical quench, stopped-flow absorbance, steady-state kinetics, KINSIM simulation\",\n      \"pmids\": [\"11948179\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural basis for rate-limiting THF release\", \"Allosteric communication between sites not yet probed\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Linked ATIC directly to a Mendelian disease, showing loss of AICARFT activity causes AICA-ribosiduria with ZMP accumulation.\",\n      \"evidence\": \"Patient metabolite assays, gene sequencing, recombinant mutant enzyme activity measurement\",\n      \"pmids\": [\"15114530\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking ZMP accumulation to clinical phenotype not fully resolved\", \"IMPCHase retention consequences unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected ATIC structural integrity to assembly of the purinosome multienzyme complex.\",\n      \"evidence\": \"Immunofluorescence/confocal imaging of purinosome assembly in patient fibroblasts and multiple cell lines\",\n      \"pmids\": [\"22180458\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct interactions stabilizing the purinosome not biochemically defined\", \"Causality between assembly defect and metabolic phenotype correlational\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated that ATIC homodimerization controls intracellular ZMP and thereby AMPK activity, linking the terminal biosynthetic step to metabolic signaling.\",\n      \"evidence\": \"Peptide/small-molecule dimerization inhibitor, cellular ZMP quantification, AMPK phosphorylation assay, mouse metabolic model\",\n      \"pmids\": [\"26144885\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Off-target effects of inhibitor on other ZMP-dependent processes not excluded\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Implicated ATIC in insulin receptor endocytosis at Golgi/endosome compartments, beyond its cytosolic biosynthetic role.\",\n      \"evidence\": \"Subcellular fractionation, siRNA knockdown, IR phosphorylation assays, AICAR treatment in cells and liver\",\n      \"pmids\": [\"25687571\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding partners at the endosome not identified\", \"Whether ATIC enzymatic activity is required is unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed that ATIC-dependent purine synthesis maintains ATP pools required for DNA double-strand break repair and cell cycle progression.\",\n      \"evidence\": \"siRNA knockdown, AICARFT inhibitor, comet/γH2AX assays, cell cycle analysis, ATP rescue\",\n      \"pmids\": [\"29029884\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Whether ZMP/AMPK contributes independently of ATP not separated\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Positioned ATIC upstream of AMPK to drive mTOR signaling and tumor cell proliferation in hepatocellular carcinoma.\",\n      \"evidence\": \"Lentiviral shRNA knockdown, Western blots, Compound C rescue, proliferation/migration assays\",\n      \"pmids\": [\"29246230\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which ATIC suppresses AMPK not defined at molecular level\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Resolved active-site selectivity of ligand binding and identified XMP-dependent inter-domain cooperativity in the dimer.\",\n      \"evidence\": \"Site-directed mutagenesis (S10W), truncation mutants, isothermal calorimetry\",\n      \"pmids\": [\"29042184\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, no independent replication\", \"Physiological role of XMP cooperativity unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Provided definitive in vivo genetic evidence that ATIC-dependent purine synthesis drives vascular smooth muscle proliferation and arterial disease.\",\n      \"evidence\": \"Global and VSMC-specific Atic knockout mice, arterial injury and atherosclerosis models, LC-MS/MS metabolomics\",\n      \"pmids\": [\"36073366\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ZMP signaling or nucleotide supply is the operative mechanism not fully separated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended ATIC pro-tumorigenic roles to additional cancers via PI3K/AKT and Myc programs.\",\n      \"evidence\": \"Knockdown/overexpression, SC79 and Myc-knockdown rescue, luciferase reporter, xenografts (HCC and lung adenocarcinoma)\",\n      \"pmids\": [\"39001904\", \"35251351\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single labs, partial rescues\", \"No direct link between ATIC enzymatic activity and AKT/Myc established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified the fungal ATIC ortholog as essential for purine synthesis and virulence, with structural and kinetic divergence from the human enzyme.\",\n      \"evidence\": \"ADE16 deletion, auxotrophy and murine infection assays, X-ray crystallography, recombinant kinetics in C. neoformans\",\n      \"pmids\": [\"36063996\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Selective inhibitor exploiting the active-site difference not yet developed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed the ATIC substrate AICAR acts as a small-molecule signal regulating LRRK2 mRNA stability, linking purine metabolism to neurodegeneration.\",\n      \"evidence\": \"AICAr treatment, AUF1 RIP, mRNA decay and DCP1/2 recruitment assays, Drosophila and mouse PD models\",\n      \"pmids\": [\"37366237\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"This is a substrate effect, not a direct ATIC molecular activity\", \"Cell-type specificity mechanism incompletely defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked ATIC loss to skeletal muscle atrophy through AICAR accumulation, mitochondrial OXPHOS failure, ROS, and ubiquitin-proteasome activation.\",\n      \"evidence\": \"CRISPR atic knockout zebrafish, siRNA in C2C12, mitochondrial/OXPHOS/ROS assays\",\n      \"pmids\": [\"40623538\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Whether AICAR accumulation or IMP/ATP depletion is the primary driver not separated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined transcriptional and proteomic regulatory contexts in which ATIC drives cancer progression.\",\n      \"evidence\": \"TPT1-AS1/CBP Co-IP and H3K27Ac ChIP at ATIC promoter (breast cancer); TMT proteomics of ATIC/B7-H3 axis (urothelial carcinoma)\",\n      \"pmids\": [\"40091780\", \"41771578\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Connection between ATIC enzymatic function and the B7-H3 axis not mechanistically established (Low confidence for #19)\", \"Single labs\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved which ATIC outputs — nucleotide/ATP supply, ZMP/AMPK signaling, or non-enzymatic moonlighting functions — dominate in each disease context, and how its enzymatic and non-catalytic roles are coordinated.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No study cleanly separates catalytic from non-catalytic contributions in vivo\", \"Full-length human dimer structural mechanism of inter-domain cooperativity not resolved\", \"Recruitment mechanism to Golgi/endosome and to splicing complexes undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 1, 4, 14]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 7, 9]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 3, 4]}\n    ],\n    \"complexes\": [\n      \"purinosome\",\n      \"ATIC homodimer\",\n      \"ATIC-ALK fusion\"\n    ],\n    \"partners\": [\n      \"ALK\",\n      \"Grb2\",\n      \"Shc\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}