{"gene":"AGMAT","run_date":"2026-06-09T22:02:42","timeline":{"discoveries":[{"year":2022,"finding":"Human AGMAT (annotated as agmatinase) was shown biochemically to hydrolyze linear guanidino acids (taurocyamine, guanidinobutyrate, guanidinopropionate, guanidinoacetate) but was virtually inactive with agmatine as substrate. A negatively charged group at the end opposing the guanidine moiety was essential for catalysis. Two naturally occurring variants differ in substrate preferences. The authors propose renaming AGMAT as guanidino acid hydrolase (GDAH). Additionally, AGMAT substrates taurocyamine, guanidinobutyrate, and guanidinopropionate were shown to be produced by human glycine amidinotransferase (GATM), placing AGMAT downstream of GATM in guanidino acid metabolism.","method":"In vitro biochemical assays, structural modelling, direct substrate profiling, mutagenesis/variant analysis","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro enzymatic assay with substrate panel, structural modelling with functional validation, variant analysis; single lab but multiple orthogonal methods","pmids":["36543883"],"is_preprint":false},{"year":2025,"finding":"In torpid bats, AGMAT co-localizes with carbamoyl-phosphate synthase 1 (CPS1) in liver, as demonstrated by proteomic analysis, confocal microscopy, and fluorescence resonance energy transfer (FRET), indicating a physical association (indirect interaction) between AGMAT and CPS1. This interaction was conserved across two phylogenetically distant bat species (Myotis ricketti and Rhinolophus ferrumequinum), suggesting AGMAT participates in coordinated nitrogen metabolism with the urea cycle during torpor.","method":"Proteomics, confocal co-localization microscopy, FRET","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-localization plus FRET in two species, but preprint and FRET indicates indirect rather than direct interaction; no reconstitution in vitro","pmids":["bio_10.1101_2025.09.26.678923"],"is_preprint":true},{"year":2014,"finding":"In vivo morpholino antisense knockdown of AGMAT (combined with ODC1 knockdown) in ovine conceptuses demonstrated that the ADC/AGMAT pathway (arginine → agmatine → putrescine) functions as a rescue/alternative polyamine biosynthesis route when the classical ODC1 pathway is compromised, supporting conceptus survival and development.","method":"In vivo morpholino antisense oligonucleotide knockdown, polyamine quantification, mRNA/protein analysis in ovine conceptuses","journal":"Biology of reproduction","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo loss-of-function with defined biochemical and developmental phenotype, replicated across multiple studies in the same system","pmids":["24648395"],"is_preprint":false},{"year":2017,"finding":"In vivo knockdown of AGMAT translation (combined with ODC1 knockdown) in ovine conceptuses resulted in 78% morphologically abnormal and non-elongated conceptuses and reduced pregnancy rate (22%), establishing that AGMAT is required for adequate polyamine synthesis and conceptus development during peri-implantation pregnancy. Compensation occurred through upregulation of ADC, SLC22A1, SLC22A2, and SLC22A3 mRNAs.","method":"In vivo morpholino antisense oligonucleotide knockdown, polyamine quantification, mRNA expression analysis, pregnancy outcome assessment","journal":"Amino acids","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo loss-of-function with defined biochemical and developmental phenotype, consistent with and extending prior work (PMID:24648395)","pmids":["29196820"],"is_preprint":false},{"year":2019,"finding":"AGMAT overexpression in lung adenocarcinoma cells promotes tumorigenesis by upregulating iNOS expression, thereby increasing nitric oxide (NO) release. Elevated NO activates MAPK and PI3K/Akt-dependent c-Myc activity, upregulating cyclin D1 and driving cell proliferation. This pathway was validated in vitro and in xenograft models using NO scavenger (Carboxy-PTIO), iNOS inhibitor (SMT), and confirmed by functional assays.","method":"Gain/loss-of-function cell assays, NO detection (DAF-FMDA probe, nitrite assay), pharmacological inhibitors, xenograft tumor model, western blot","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional and biochemical methods in vitro and in vivo, single lab","pmids":["31699997"],"is_preprint":false},{"year":2022,"finding":"AGMAT overexpression in pancreatic adenocarcinoma cells activates the TGFβ/Smad signaling pathway and enhances epithelial-mesenchymal transition (EMT), promoting cell proliferation and metastasis, as shown by gain- and loss-of-function experiments with western blot pathway analysis.","method":"Gain/loss-of-function experiments, CCK-8 assay, colony formation, migration/invasion assays, western blot for TGFβ/Smad pathway components","journal":"Experimental and therapeutic medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays with defined pathway readout, single lab","pmids":["35837051"],"is_preprint":false},{"year":2023,"finding":"The oncogenic transcription factor c-Myc binds to the AGMAT promoter and transcriptionally upregulates AGMAT expression in colorectal cancer cells, as demonstrated by promoter-binding assays. AGMAT knockdown via AAV9-shRNA in a colitis-associated CRC mouse model reduced tumor number and size, decreased PCNA expression, and inhibited AKT and ERK phosphorylation, placing AGMAT upstream of PI3K/AKT and ERK signaling in CRC progression.","method":"Promoter-binding assay (c-Myc binding to AGMAT promoter), AAV9-shRNA knockdown in AOM/DSS mouse model, western blot for AKT/ERK phosphorylation, in vitro proliferation/apoptosis assays","journal":"Human gene therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo knockdown with defined pathway readout plus c-Myc promoter-binding evidence, single lab","pmids":["36680755"],"is_preprint":false},{"year":2023,"finding":"AGMAT was validated as a direct target of miR-151a-5p in colorectal carcinoma by dual luciferase reporter assay, establishing that miR-151a-5p suppresses AGMAT to promote CRC cell proliferation, migration, invasion, and epithelial-mesenchymal transition.","method":"Dual luciferase reporter assay, gain/loss-of-function cell assays for proliferation, migration, invasion","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional validation of miRNA-target interaction by luciferase assay with cellular phenotypic readout, single lab","pmids":["36704851"],"is_preprint":false},{"year":2023,"finding":"AGMAT overexpression in the ventral hippocampus of rats elicited depressive- and anxiety-like behaviors, whereas AGMAT knockdown in the same region had antidepressant and anxiolytic effects in chronic restraint stress animals. Electrophysiological recordings revealed that AGMAT blockade increased Schaffer collateral-CA1 excitatory synaptic transmission both pre- and post-synaptically, likely through inhibition of AGMAT-expressing local interneurons.","method":"Stereotaxic viral vector overexpression/knockdown in rat ventral hippocampus, behavioral testing, field and whole-cell electrophysiological recordings","journal":"Neuropharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo gain/loss-of-function with electrophysiological and behavioral readouts, single lab","pmids":["36849038"],"is_preprint":false},{"year":2016,"finding":"Agmatinase (Agmat) is upregulated in the prefrontal cortex and hippocampus of CRTC1 knockout mice, and this upregulation is localized to parvalbumin- and somatostatin-positive interneurons, as confirmed by confocal immunofluorescence microscopy and qPCR/western blot. Acute agmatine treatment rescued the depressive-like behavior of Crtc1−/− mice, consistent with agmatine deficit due to elevated AGMAT-mediated degradation. Agmatine also decreased eEF2 phosphorylation in the PFC, suggesting NMDA receptor antagonist-like mechanism.","method":"Microarray gene expression profiling, qPCR, western blot, confocal immunofluorescence microscopy, behavioral testing (forced swim test), pharmacological agmatine/ketamine treatment","journal":"Translational psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (transcriptomic, protein, cell-type localization, behavioral rescue), single lab","pmids":["27404284"],"is_preprint":false},{"year":2025,"finding":"Exosomal miR-33a secreted by cancer cells targets AGMAT in cancer-associated fibroblasts (CAFs), suppressing putrescine biosynthesis. Reduced putrescine in CAFs inhibits KDM5C demethylase expression, altering H3K4me3 levels at the TIA1 locus and reducing stress granule (SG) formation in stromal CAFs, thereby supporting cancer cell survival under glucose starvation.","method":"Extracellular vesicle isolation, miR-33a overexpression/targeting of AGMAT in CAFs, KDM5C and H3K4me3 chromatin analysis, stress granule formation assays, ACO1 RNA-binding protein interaction studies","journal":"Journal of extracellular vesicles","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional pathway from miR-33a to AGMAT to putrescine to KDM5C/H3K4me3/TIA1 established with multiple methods, single lab","pmids":["40903826"],"is_preprint":false}],"current_model":"AGMAT encodes an enzyme whose canonical activity in humans is hydrolysis of linear guanidino acids (not agmatine, as previously assumed), placing it in guanidino acid catabolism downstream of GATM; in developmental contexts (especially mammalian conceptus trophectoderm) it functions as part of the alternative ADC/AGMAT pathway converting arginine via agmatine to putrescine for polyamine synthesis; in the brain, AGMAT degrades agmatine in specific interneuron populations and its dysregulation modulates hippocampal excitatory synaptic transmission and mood-related behaviors; in cancer, AGMAT expression is transcriptionally driven by c-Myc and promotes tumor cell proliferation via NO/MAPK/PI3K-AKT signaling (lung) and TGFβ/Smad/EMT pathways (pancreas/colorectum), and is also targeted by miR-151a-5p; in the tumor microenvironment, exosomal miR-33a suppresses AGMAT in CAFs to reduce putrescine and remodel stromal stress granule formation; additionally, AGMAT physically associates with CPS1 in bat liver during torpor, suggesting integration into urea cycle nitrogen metabolism."},"narrative":{"mechanistic_narrative":"AGMAT is a metabolic hydrolase that in humans acts on linear guanidino acids rather than agmatine, hydrolyzing taurocyamine, guanidinobutyrate, guanidinopropionate, and guanidinoacetate while remaining virtually inactive toward agmatine, and operates downstream of the amidinotransferase GATM in guanidino acid catabolism [PMID:36543883]. In a parallel developmental context, AGMAT functions in the alternative ADC/AGMAT polyamine-biosynthesis route that converts arginine via agmatine to putrescine; in vivo knockdown in ovine conceptuses impairs polyamine synthesis and produces non-elongated, morphologically abnormal conceptuses with reduced pregnancy rates, establishing its requirement during peri-implantation development [PMID:24648395, PMID:29196820]. In the brain, AGMAT is expressed in parvalbumin- and somatostatin-positive hippocampal and cortical interneurons where it degrades agmatine, and its overexpression or loss bidirectionally modulates Schaffer collateral-CA1 excitatory transmission and mood-related behaviors [PMID:36849038, PMID:27404284]. In cancer, AGMAT is a c-Myc-driven, miR-151a-5p-targeted oncogenic effector that promotes proliferation and metastasis through iNOS/NO-dependent MAPK and PI3K/AKT signaling and through TGFβ/Smad-driven EMT [PMID:31699997, PMID:35837051, PMID:36680755, PMID:36704851]; within the tumor microenvironment, exosomal miR-33a suppresses AGMAT in cancer-associated fibroblasts to lower putrescine and remodel stromal stress-granule biology [PMID:40903826]. AGMAT also physically associates with the urea-cycle enzyme CPS1 in torpid bat liver, linking it to coordinated nitrogen metabolism [PMID:bio_10.1101_2025.09.26.678923].","teleology":[{"year":2014,"claim":"Whether the ADC/AGMAT route can substitute for the classical ODC1 polyamine pathway was unresolved; combined knockdown showed AGMAT provides a rescue route for putrescine synthesis supporting conceptus survival.","evidence":"In vivo morpholino knockdown of AGMAT and ODC1 with polyamine quantification in ovine conceptuses","pmids":["24648395"],"confidence":"High","gaps":["Did not isolate AGMAT contribution independent of ODC1","Enzymatic activity on agmatine in this system not directly measured"]},{"year":2016,"claim":"It was unclear how agmatine signaling is regulated in mood circuits; AGMAT upregulation in PV/SST interneurons of CRTC1-null mice linked elevated AGMAT-mediated agmatine degradation to depressive-like behavior reversible by agmatine.","evidence":"Transcriptomics, qPCR/western blot, confocal immunofluorescence cell-type localization, and pharmacological rescue in Crtc1−/− mice","pmids":["27404284"],"confidence":"Medium","gaps":["Causal role of AGMAT itself not tested by direct AGMAT manipulation","Mechanism linking eEF2 dephosphorylation to AGMAT activity not established"]},{"year":2017,"claim":"The developmental requirement for AGMAT was quantified; its knockdown caused abnormal, non-elongated conceptuses and reduced pregnancy, with compensatory upregulation of ADC and SLC22 transporters.","evidence":"In vivo morpholino knockdown with developmental phenotyping and mRNA expression analysis in ovine conceptuses","pmids":["29196820"],"confidence":"High","gaps":["Compensatory transporter upregulation not mechanistically dissected","Combined ODC1 knockdown confounds AGMAT-specific attribution"]},{"year":2019,"claim":"How AGMAT promotes tumor growth was unknown; in lung adenocarcinoma it was shown to drive iNOS/NO-dependent MAPK and PI3K/Akt c-Myc activity and cyclin D1 induction.","evidence":"Gain/loss-of-function assays, NO detection, pharmacological inhibitors, and xenograft models","pmids":["31699997"],"confidence":"Medium","gaps":["Link between AGMAT enzymatic activity and iNOS induction not defined","Single tumor lineage and single lab"]},{"year":2022,"claim":"The substrate identity of human AGMAT was redefined: it hydrolyzes linear guanidino acids rather than agmatine and lies downstream of GATM, prompting the proposed name guanidino acid hydrolase.","evidence":"In vitro enzymatic substrate profiling, structural modeling, and variant/mutagenesis analysis","pmids":["36543883"],"confidence":"High","gaps":["In vivo relevance of guanidino acid hydrolysis versus polyamine-pathway roles not reconciled","Physiological tissue context of each variant not established"]},{"year":2022,"claim":"A second oncogenic mechanism was established in pancreatic cancer, where AGMAT activates TGFβ/Smad signaling and EMT to promote proliferation and metastasis.","evidence":"Gain/loss-of-function with proliferation, migration/invasion assays and TGFβ/Smad western blots","pmids":["35837051"],"confidence":"Medium","gaps":["No mechanistic link between AGMAT metabolic output and TGFβ activation","Single lab, in vitro emphasis"]},{"year":2023,"claim":"Upstream regulation and downstream signaling of AGMAT in colorectal cancer were defined: c-Myc transcriptionally activates AGMAT, miR-151a-5p directly represses it, and AGMAT drives AKT/ERK signaling and tumor growth in vivo.","evidence":"Promoter-binding assays, dual luciferase reporter, AAV9-shRNA knockdown in AOM/DSS mouse model, and pathway western blots","pmids":["36680755","36704851"],"confidence":"Medium","gaps":["Whether AGMAT acts via enzymatic product or non-enzymatic function in CRC unresolved","Direct biochemical demonstration of c-Myc occupancy in vivo limited"]},{"year":2025,"claim":"A stromal, non-cell-autonomous role emerged: tumor-derived exosomal miR-33a suppresses AGMAT in CAFs, lowering putrescine and remodeling KDM5C/H3K4me3/TIA1-dependent stress granule formation to aid cancer survival.","evidence":"Extracellular vesicle isolation, AGMAT targeting in CAFs, chromatin analysis, and stress granule assays","pmids":["40903826"],"confidence":"Medium","gaps":["Direct enzymatic dependence on AGMAT for putrescine in CAFs not isolated from other polyamine enzymes","Single lab"]},{"year":2025,"claim":"A potential integration with urea-cycle nitrogen metabolism was identified through conserved physical association of AGMAT with CPS1 in torpid bat liver.","evidence":"Proteomics, confocal co-localization, and FRET across two bat species (preprint)","pmids":["bio_10.1101_2025.09.26.678923"],"confidence":"Medium","gaps":["FRET indicates proximity not direct binding; no in vitro reconstitution","Functional consequence of the association not tested","Preprint, not peer-reviewed"]},{"year":null,"claim":"It remains unresolved how AGMAT's redefined guanidino acid hydrolase activity mechanistically connects to its polyamine-pathway, neuronal, and oncogenic roles, which are largely framed around agmatine/putrescine metabolism.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No study reconciles the in vitro substrate redefinition with in vivo agmatine-based models","Substrate flux measured in tumor, neuronal, and stromal contexts not directly determined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[2,3]}],"localization":[],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,2,3]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,6]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,5,6,7,10]}],"complexes":[],"partners":["CPS1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BSE5","full_name":"Guanidino acid hydrolase, mitochondrial","aliases":["Arginase, mitochondrial","Guanidinobutyrase, mitochondrial","Guanidinopropionase, mitochondrial"],"length_aa":352,"mass_kda":37.7,"function":"Hydrolyzes linear guanidino acids to form urea and the corresponding amines. Displays specificity for substrates having a negatively charged head group and short chains including taurocyamine, guanidino propanoic and butanoic acids. May protect cells by detoxifying potentially harmful amounts of guanidino acids. Metabolizes L-arginine with low efficiency","subcellular_location":"Mitochondrion","url":"https://www.uniprot.org/uniprotkb/Q9BSE5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/AGMAT","classification":"Not Classified","n_dependent_lines":12,"n_total_lines":1208,"dependency_fraction":0.009933774834437087},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/AGMAT","total_profiled":1310},"omim":[{"mim_id":"617887","title":"AGMATINASE; AGMAT","url":"https://www.omim.org/entry/617887"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"kidney","ntpm":125.0},{"tissue":"liver","ntpm":58.0},{"tissue":"skeletal muscle","ntpm":32.1}],"url":"https://www.proteinatlas.org/search/AGMAT"},"hgnc":{"alias_symbol":["FLJ23384"],"prev_symbol":[]},"alphafold":{"accession":"Q9BSE5","domains":[{"cath_id":"3.40.800.10","chopping":"71-344","consensus_level":"high","plddt":97.9688,"start":71,"end":344}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BSE5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BSE5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BSE5-F1-predicted_aligned_error_v6.png","plddt_mean":91.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=AGMAT","jax_strain_url":"https://www.jax.org/strain/search?query=AGMAT"},"sequence":{"accession":"Q9BSE5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BSE5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BSE5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BSE5"}},"corpus_meta":[{"pmid":"37804830","id":"PMC_37804830","title":"Arginine reprograms metabolism in liver cancer via RBM39.","date":"2023","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/37804830","citation_count":226,"is_preprint":false},{"pmid":"28587687","id":"PMC_28587687","title":"Physiological importance of polyamines.","date":"2017","source":"Zygote (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/28587687","citation_count":115,"is_preprint":false},{"pmid":"24648395","id":"PMC_24648395","title":"Arginine decarboxylase and agmatinase: an alternative pathway for de novo biosynthesis of polyamines for development of mammalian conceptuses.","date":"2014","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/24648395","citation_count":101,"is_preprint":false},{"pmid":"27433286","id":"PMC_27433286","title":"The Dysregulation of Polyamine Metabolism in Colorectal Cancer Is Associated with Overexpression of c-Myc and C/EBPβ rather than Enterotoxigenic Bacteroides fragilis Infection.","date":"2016","source":"Oxidative medicine and cellular longevity","url":"https://pubmed.ncbi.nlm.nih.gov/27433286","citation_count":75,"is_preprint":false},{"pmid":"27404284","id":"PMC_27404284","title":"Involvement of the agmatinergic system in the depressive-like phenotype of the Crtc1 knockout mouse model of depression.","date":"2016","source":"Translational psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/27404284","citation_count":50,"is_preprint":false},{"pmid":"31699997","id":"PMC_31699997","title":"Agmatinase promotes the lung adenocarcinoma tumorigenesis by activating the NO-MAPKs-PI3K/Akt pathway.","date":"2019","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/31699997","citation_count":31,"is_preprint":false},{"pmid":"33827696","id":"PMC_33827696","title":"Pre-implantation exogenous progesterone and pregnancy in sheep. 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Bats","date":"2025-09-29","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.26.678923","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":20405,"output_tokens":3254,"usd":0.055012,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10848,"output_tokens":3302,"usd":0.068395,"stage2_stop_reason":"end_turn"},"total_usd":0.123407,"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\": 2022,\n      \"finding\": \"Human AGMAT (annotated as agmatinase) was shown biochemically to hydrolyze linear guanidino acids (taurocyamine, guanidinobutyrate, guanidinopropionate, guanidinoacetate) but was virtually inactive with agmatine as substrate. A negatively charged group at the end opposing the guanidine moiety was essential for catalysis. Two naturally occurring variants differ in substrate preferences. The authors propose renaming AGMAT as guanidino acid hydrolase (GDAH). Additionally, AGMAT substrates taurocyamine, guanidinobutyrate, and guanidinopropionate were shown to be produced by human glycine amidinotransferase (GATM), placing AGMAT downstream of GATM in guanidino acid metabolism.\",\n      \"method\": \"In vitro biochemical assays, structural modelling, direct substrate profiling, mutagenesis/variant analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro enzymatic assay with substrate panel, structural modelling with functional validation, variant analysis; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"36543883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In torpid bats, AGMAT co-localizes with carbamoyl-phosphate synthase 1 (CPS1) in liver, as demonstrated by proteomic analysis, confocal microscopy, and fluorescence resonance energy transfer (FRET), indicating a physical association (indirect interaction) between AGMAT and CPS1. This interaction was conserved across two phylogenetically distant bat species (Myotis ricketti and Rhinolophus ferrumequinum), suggesting AGMAT participates in coordinated nitrogen metabolism with the urea cycle during torpor.\",\n      \"method\": \"Proteomics, confocal co-localization microscopy, FRET\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-localization plus FRET in two species, but preprint and FRET indicates indirect rather than direct interaction; no reconstitution in vitro\",\n      \"pmids\": [\"bio_10.1101_2025.09.26.678923\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In vivo morpholino antisense knockdown of AGMAT (combined with ODC1 knockdown) in ovine conceptuses demonstrated that the ADC/AGMAT pathway (arginine → agmatine → putrescine) functions as a rescue/alternative polyamine biosynthesis route when the classical ODC1 pathway is compromised, supporting conceptus survival and development.\",\n      \"method\": \"In vivo morpholino antisense oligonucleotide knockdown, polyamine quantification, mRNA/protein analysis in ovine conceptuses\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo loss-of-function with defined biochemical and developmental phenotype, replicated across multiple studies in the same system\",\n      \"pmids\": [\"24648395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In vivo knockdown of AGMAT translation (combined with ODC1 knockdown) in ovine conceptuses resulted in 78% morphologically abnormal and non-elongated conceptuses and reduced pregnancy rate (22%), establishing that AGMAT is required for adequate polyamine synthesis and conceptus development during peri-implantation pregnancy. Compensation occurred through upregulation of ADC, SLC22A1, SLC22A2, and SLC22A3 mRNAs.\",\n      \"method\": \"In vivo morpholino antisense oligonucleotide knockdown, polyamine quantification, mRNA expression analysis, pregnancy outcome assessment\",\n      \"journal\": \"Amino acids\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo loss-of-function with defined biochemical and developmental phenotype, consistent with and extending prior work (PMID:24648395)\",\n      \"pmids\": [\"29196820\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"AGMAT overexpression in lung adenocarcinoma cells promotes tumorigenesis by upregulating iNOS expression, thereby increasing nitric oxide (NO) release. Elevated NO activates MAPK and PI3K/Akt-dependent c-Myc activity, upregulating cyclin D1 and driving cell proliferation. This pathway was validated in vitro and in xenograft models using NO scavenger (Carboxy-PTIO), iNOS inhibitor (SMT), and confirmed by functional assays.\",\n      \"method\": \"Gain/loss-of-function cell assays, NO detection (DAF-FMDA probe, nitrite assay), pharmacological inhibitors, xenograft tumor model, western blot\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional and biochemical methods in vitro and in vivo, single lab\",\n      \"pmids\": [\"31699997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"AGMAT overexpression in pancreatic adenocarcinoma cells activates the TGFβ/Smad signaling pathway and enhances epithelial-mesenchymal transition (EMT), promoting cell proliferation and metastasis, as shown by gain- and loss-of-function experiments with western blot pathway analysis.\",\n      \"method\": \"Gain/loss-of-function experiments, CCK-8 assay, colony formation, migration/invasion assays, western blot for TGFβ/Smad pathway components\",\n      \"journal\": \"Experimental and therapeutic medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays with defined pathway readout, single lab\",\n      \"pmids\": [\"35837051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The oncogenic transcription factor c-Myc binds to the AGMAT promoter and transcriptionally upregulates AGMAT expression in colorectal cancer cells, as demonstrated by promoter-binding assays. AGMAT knockdown via AAV9-shRNA in a colitis-associated CRC mouse model reduced tumor number and size, decreased PCNA expression, and inhibited AKT and ERK phosphorylation, placing AGMAT upstream of PI3K/AKT and ERK signaling in CRC progression.\",\n      \"method\": \"Promoter-binding assay (c-Myc binding to AGMAT promoter), AAV9-shRNA knockdown in AOM/DSS mouse model, western blot for AKT/ERK phosphorylation, in vitro proliferation/apoptosis assays\",\n      \"journal\": \"Human gene therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knockdown with defined pathway readout plus c-Myc promoter-binding evidence, single lab\",\n      \"pmids\": [\"36680755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"AGMAT was validated as a direct target of miR-151a-5p in colorectal carcinoma by dual luciferase reporter assay, establishing that miR-151a-5p suppresses AGMAT to promote CRC cell proliferation, migration, invasion, and epithelial-mesenchymal transition.\",\n      \"method\": \"Dual luciferase reporter assay, gain/loss-of-function cell assays for proliferation, migration, invasion\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional validation of miRNA-target interaction by luciferase assay with cellular phenotypic readout, single lab\",\n      \"pmids\": [\"36704851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"AGMAT overexpression in the ventral hippocampus of rats elicited depressive- and anxiety-like behaviors, whereas AGMAT knockdown in the same region had antidepressant and anxiolytic effects in chronic restraint stress animals. Electrophysiological recordings revealed that AGMAT blockade increased Schaffer collateral-CA1 excitatory synaptic transmission both pre- and post-synaptically, likely through inhibition of AGMAT-expressing local interneurons.\",\n      \"method\": \"Stereotaxic viral vector overexpression/knockdown in rat ventral hippocampus, behavioral testing, field and whole-cell electrophysiological recordings\",\n      \"journal\": \"Neuropharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo gain/loss-of-function with electrophysiological and behavioral readouts, single lab\",\n      \"pmids\": [\"36849038\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Agmatinase (Agmat) is upregulated in the prefrontal cortex and hippocampus of CRTC1 knockout mice, and this upregulation is localized to parvalbumin- and somatostatin-positive interneurons, as confirmed by confocal immunofluorescence microscopy and qPCR/western blot. Acute agmatine treatment rescued the depressive-like behavior of Crtc1−/− mice, consistent with agmatine deficit due to elevated AGMAT-mediated degradation. Agmatine also decreased eEF2 phosphorylation in the PFC, suggesting NMDA receptor antagonist-like mechanism.\",\n      \"method\": \"Microarray gene expression profiling, qPCR, western blot, confocal immunofluorescence microscopy, behavioral testing (forced swim test), pharmacological agmatine/ketamine treatment\",\n      \"journal\": \"Translational psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (transcriptomic, protein, cell-type localization, behavioral rescue), single lab\",\n      \"pmids\": [\"27404284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Exosomal miR-33a secreted by cancer cells targets AGMAT in cancer-associated fibroblasts (CAFs), suppressing putrescine biosynthesis. Reduced putrescine in CAFs inhibits KDM5C demethylase expression, altering H3K4me3 levels at the TIA1 locus and reducing stress granule (SG) formation in stromal CAFs, thereby supporting cancer cell survival under glucose starvation.\",\n      \"method\": \"Extracellular vesicle isolation, miR-33a overexpression/targeting of AGMAT in CAFs, KDM5C and H3K4me3 chromatin analysis, stress granule formation assays, ACO1 RNA-binding protein interaction studies\",\n      \"journal\": \"Journal of extracellular vesicles\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional pathway from miR-33a to AGMAT to putrescine to KDM5C/H3K4me3/TIA1 established with multiple methods, single lab\",\n      \"pmids\": [\"40903826\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"AGMAT encodes an enzyme whose canonical activity in humans is hydrolysis of linear guanidino acids (not agmatine, as previously assumed), placing it in guanidino acid catabolism downstream of GATM; in developmental contexts (especially mammalian conceptus trophectoderm) it functions as part of the alternative ADC/AGMAT pathway converting arginine via agmatine to putrescine for polyamine synthesis; in the brain, AGMAT degrades agmatine in specific interneuron populations and its dysregulation modulates hippocampal excitatory synaptic transmission and mood-related behaviors; in cancer, AGMAT expression is transcriptionally driven by c-Myc and promotes tumor cell proliferation via NO/MAPK/PI3K-AKT signaling (lung) and TGFβ/Smad/EMT pathways (pancreas/colorectum), and is also targeted by miR-151a-5p; in the tumor microenvironment, exosomal miR-33a suppresses AGMAT in CAFs to reduce putrescine and remodel stromal stress granule formation; additionally, AGMAT physically associates with CPS1 in bat liver during torpor, suggesting integration into urea cycle nitrogen metabolism.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"AGMAT is a metabolic hydrolase that in humans acts on linear guanidino acids rather than agmatine, hydrolyzing taurocyamine, guanidinobutyrate, guanidinopropionate, and guanidinoacetate while remaining virtually inactive toward agmatine, and operates downstream of the amidinotransferase GATM in guanidino acid catabolism [#0]. In a parallel developmental context, AGMAT functions in the alternative ADC/AGMAT polyamine-biosynthesis route that converts arginine via agmatine to putrescine; in vivo knockdown in ovine conceptuses impairs polyamine synthesis and produces non-elongated, morphologically abnormal conceptuses with reduced pregnancy rates, establishing its requirement during peri-implantation development [#2, #3]. In the brain, AGMAT is expressed in parvalbumin- and somatostatin-positive hippocampal and cortical interneurons where it degrades agmatine, and its overexpression or loss bidirectionally modulates Schaffer collateral-CA1 excitatory transmission and mood-related behaviors [#8, #9]. In cancer, AGMAT is a c-Myc-driven, miR-151a-5p-targeted oncogenic effector that promotes proliferation and metastasis through iNOS/NO-dependent MAPK and PI3K/AKT signaling and through TGF\\u03b2/Smad-driven EMT [#4, #5, #6, #7]; within the tumor microenvironment, exosomal miR-33a suppresses AGMAT in cancer-associated fibroblasts to lower putrescine and remodel stromal stress-granule biology [#10]. AGMAT also physically associates with the urea-cycle enzyme CPS1 in torpid bat liver, linking it to coordinated nitrogen metabolism [#1].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Whether the ADC/AGMAT route can substitute for the classical ODC1 polyamine pathway was unresolved; combined knockdown showed AGMAT provides a rescue route for putrescine synthesis supporting conceptus survival.\",\n      \"evidence\": \"In vivo morpholino knockdown of AGMAT and ODC1 with polyamine quantification in ovine conceptuses\",\n      \"pmids\": [\"24648395\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not isolate AGMAT contribution independent of ODC1\", \"Enzymatic activity on agmatine in this system not directly measured\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"It was unclear how agmatine signaling is regulated in mood circuits; AGMAT upregulation in PV/SST interneurons of CRTC1-null mice linked elevated AGMAT-mediated agmatine degradation to depressive-like behavior reversible by agmatine.\",\n      \"evidence\": \"Transcriptomics, qPCR/western blot, confocal immunofluorescence cell-type localization, and pharmacological rescue in Crtc1\\u2212/\\u2212 mice\",\n      \"pmids\": [\"27404284\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal role of AGMAT itself not tested by direct AGMAT manipulation\", \"Mechanism linking eEF2 dephosphorylation to AGMAT activity not established\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"The developmental requirement for AGMAT was quantified; its knockdown caused abnormal, non-elongated conceptuses and reduced pregnancy, with compensatory upregulation of ADC and SLC22 transporters.\",\n      \"evidence\": \"In vivo morpholino knockdown with developmental phenotyping and mRNA expression analysis in ovine conceptuses\",\n      \"pmids\": [\"29196820\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Compensatory transporter upregulation not mechanistically dissected\", \"Combined ODC1 knockdown confounds AGMAT-specific attribution\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"How AGMAT promotes tumor growth was unknown; in lung adenocarcinoma it was shown to drive iNOS/NO-dependent MAPK and PI3K/Akt c-Myc activity and cyclin D1 induction.\",\n      \"evidence\": \"Gain/loss-of-function assays, NO detection, pharmacological inhibitors, and xenograft models\",\n      \"pmids\": [\"31699997\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Link between AGMAT enzymatic activity and iNOS induction not defined\", \"Single tumor lineage and single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The substrate identity of human AGMAT was redefined: it hydrolyzes linear guanidino acids rather than agmatine and lies downstream of GATM, prompting the proposed name guanidino acid hydrolase.\",\n      \"evidence\": \"In vitro enzymatic substrate profiling, structural modeling, and variant/mutagenesis analysis\",\n      \"pmids\": [\"36543883\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of guanidino acid hydrolysis versus polyamine-pathway roles not reconciled\", \"Physiological tissue context of each variant not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"A second oncogenic mechanism was established in pancreatic cancer, where AGMAT activates TGF\\u03b2/Smad signaling and EMT to promote proliferation and metastasis.\",\n      \"evidence\": \"Gain/loss-of-function with proliferation, migration/invasion assays and TGF\\u03b2/Smad western blots\",\n      \"pmids\": [\"35837051\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No mechanistic link between AGMAT metabolic output and TGF\\u03b2 activation\", \"Single lab, in vitro emphasis\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Upstream regulation and downstream signaling of AGMAT in colorectal cancer were defined: c-Myc transcriptionally activates AGMAT, miR-151a-5p directly represses it, and AGMAT drives AKT/ERK signaling and tumor growth in vivo.\",\n      \"evidence\": \"Promoter-binding assays, dual luciferase reporter, AAV9-shRNA knockdown in AOM/DSS mouse model, and pathway western blots\",\n      \"pmids\": [\"36680755\", \"36704851\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether AGMAT acts via enzymatic product or non-enzymatic function in CRC unresolved\", \"Direct biochemical demonstration of c-Myc occupancy in vivo limited\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A stromal, non-cell-autonomous role emerged: tumor-derived exosomal miR-33a suppresses AGMAT in CAFs, lowering putrescine and remodeling KDM5C/H3K4me3/TIA1-dependent stress granule formation to aid cancer survival.\",\n      \"evidence\": \"Extracellular vesicle isolation, AGMAT targeting in CAFs, chromatin analysis, and stress granule assays\",\n      \"pmids\": [\"40903826\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct enzymatic dependence on AGMAT for putrescine in CAFs not isolated from other polyamine enzymes\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A potential integration with urea-cycle nitrogen metabolism was identified through conserved physical association of AGMAT with CPS1 in torpid bat liver.\",\n      \"evidence\": \"Proteomics, confocal co-localization, and FRET across two bat species (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.09.26.678923\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"FRET indicates proximity not direct binding; no in vitro reconstitution\", \"Functional consequence of the association not tested\", \"Preprint, not peer-reviewed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how AGMAT's redefined guanidino acid hydrolase activity mechanistically connects to its polyamine-pathway, neuronal, and oncogenic roles, which are largely framed around agmatine/putrescine metabolism.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No study reconciles the in vitro substrate redefinition with in vivo agmatine-based models\", \"Substrate flux measured in tumor, neuronal, and stromal contexts not directly determined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 6]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 5, 6, 7, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CPS1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":4,"faith_total":4,"faith_pct":100.0}}