{"gene":"NANS","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2016,"finding":"NANS encodes N-acetylneuraminic acid (NeuNAc; sialic acid) synthase; biallelic loss-of-function mutations reduce NANS enzymatic activity in patient-derived fibroblasts and prevent incorporation of sialic acid precursors into sialylated glycoproteins, demonstrating NANS is required for de novo sialic acid synthesis and glycoprotein sialylation.","method":"Patient fibroblast enzymatic activity assay, sialic acid precursor incorporation assay, zebrafish nansa knockdown with partial rescue by exogenous sialic acid","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — enzymatic activity measured directly in patient cells, precursor incorporation assay, and in vivo zebrafish rescue, replicated across multiple patient samples and model organism","pmids":["27213289"],"is_preprint":false},{"year":2025,"finding":"Under ferroptotic stress, CDK1 phosphorylates NANS at serine 275 (S275), causing its dissociation from TAK1. Phosphorylated NANS is then ubiquitinated by UBE2N at lysine 246 (K246), leading to NANS degradation, which in turn activates TAK1-NF-κB signaling and upregulates the ferroptosis inhibitor FTH1, enabling ferroptosis resistance and metastasis in colorectal cancer cells.","method":"CRISPR-Cas9 screen identifying NANS as ferroptosis promoter, phosphorylation site mapping, Co-IP for NANS-TAK1 dissociation, ubiquitination assay, NF-κB signaling readouts, FTH1 expression analysis","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR screen plus Co-IP plus ubiquitination assay and phosphorylation mapping in single lab, multiple orthogonal methods but not independently replicated","pmids":["40349344"],"is_preprint":false},{"year":2025,"finding":"NANS participates in the hexosamine biosynthetic pathway downstream of GFPT1, specifically mediating the sialic acid synthesis branch (rather than O-GlcNAc glycosylation); knockout of NANS inhibits tumor growth in c-Myc-driven hepatocellular carcinoma mouse models, placing NANS as a key enzyme in the hexosamine-sialic acid metabolic axis.","method":"RNA sequencing, metabolomics, NANS gene knockout in murine HCC model, tumor growth and survival assays, luciferase reporter assay confirming c-Myc regulation of upstream GFPT1","journal":"Cellular and molecular gastroenterology and hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with defined tumor phenotype and metabolomics pathway placement, single lab, multiple methods","pmids":["40280277"],"is_preprint":false}],"current_model":"NANS (N-acetylneuraminic acid synthase) catalyzes the de novo synthesis of sialic acid (NeuNAc), which is required for sialylation of glycoproteins and is essential for brain and skeletal development; additionally, NANS physically associates with TAK1 to suppress NF-κB-mediated ferroptosis resistance, and this non-metabolic function is regulated by CDK1-dependent phosphorylation at S275 and UBE2N-mediated ubiquitination at K246, which together trigger NANS degradation and pathway activation."},"narrative":{"mechanistic_narrative":"NANS encodes N-acetylneuraminic acid (sialic acid) synthase, the enzyme that catalyzes de novo synthesis of NeuNAc required for glycoprotein sialylation; biallelic loss-of-function mutations reduce its enzymatic activity and block incorporation of sialic acid precursors into sialylated glycoproteins, establishing it as essential for sialic acid biosynthesis and, in vivo, for normal development [PMID:27213289]. Metabolically, NANS operates downstream of GFPT1 in the hexosamine biosynthetic pathway, where it specifically mediates the sialic acid synthesis branch, and its loss restrains tumor growth in c-Myc-driven hepatocellular carcinoma [PMID:40280277]. Beyond this metabolic role, NANS has a non-catalytic function in which it physically associates with TAK1 to restrain NF-κB signaling; under ferroptotic stress CDK1 phosphorylates NANS at S275 to drive its dissociation from TAK1, and UBE2N-mediated ubiquitination at K246 triggers NANS degradation, releasing TAK1-NF-κB signaling to upregulate the ferroptosis inhibitor FTH1 and confer ferroptosis resistance and metastasis in colorectal cancer [PMID:40349344].","teleology":[{"year":2016,"claim":"Established that NANS is the enzyme responsible for de novo sialic acid synthesis and that its loss disrupts glycoprotein sialylation, defining its core metabolic function and a developmental disease link.","evidence":"Patient fibroblast enzymatic activity and sialic acid precursor incorporation assays, with zebrafish nansa knockdown partially rescued by exogenous sialic acid","pmids":["27213289"],"confidence":"High","gaps":["Structural basis of catalysis not resolved in this corpus","Tissue-specific consequences of impaired sialylation beyond development not detailed"]},{"year":2025,"claim":"Placed NANS within the hexosamine biosynthetic pathway as the dedicated sialic acid branch enzyme downstream of GFPT1 and tied its activity to oncogenic c-Myc-driven tumor growth.","evidence":"RNA-seq, metabolomics, NANS knockout in a murine c-Myc HCC model with tumor growth and survival readouts and luciferase confirmation of c-Myc regulation of GFPT1","pmids":["40280277"],"confidence":"Medium","gaps":["Single-lab study not independently replicated","Whether the tumor-suppressive effect of knockout reflects loss of sialylation specifically versus broader metabolic perturbation is unresolved"]},{"year":2025,"claim":"Revealed a non-metabolic role for NANS as a TAK1-binding suppressor of NF-κB signaling, controlled by CDK1 phosphorylation and UBE2N ubiquitination that license its degradation during ferroptotic stress.","evidence":"CRISPR-Cas9 ferroptosis screen, S275 phosphorylation mapping, NANS-TAK1 Co-IP, K246 ubiquitination assay, NF-κB and FTH1 readouts in colorectal cancer cells","pmids":["40349344"],"confidence":"Medium","gaps":["Single-lab study with orthogonal assays but no independent replication","Whether the catalytic and TAK1-binding functions are mechanistically separable is not established","Reciprocal validation and structural basis of the NANS-TAK1 interaction not provided"]},{"year":null,"claim":"How the metabolic (sialic acid synthase) and non-metabolic (TAK1-binding) functions of NANS are integrated, and whether they are coupled or independent, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model linking catalytic and protein-binding surfaces","Physiological contexts where each function dominates are undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0]}],"localization":[],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,2]}],"complexes":[],"partners":["TAK1","UBE2N","CDK1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NR45","full_name":"N-acetylneuraminate-9-phosphate synthase","aliases":["3-deoxy-D-glycero-D-galacto-nononate 9-phosphate synthase","N-acetylneuraminic acid phosphate synthase","NANS","Sialic acid phosphate synthase","Sialic acid synthase"],"length_aa":359,"mass_kda":40.3,"function":"Catalyzes the condensation of phosphoenolpyruvate (PEP) and N-acetylmannosamine 6-phosphate (ManNAc-6-P) to synthesize N-acetylneuraminate-9-phosphate (Neu5Ac-9-P) (PubMed:10749855). Also catalyzes the condensation of PEP and D-mannose 6-phosphate (Man-6-P) to produce 3-deoxy-D-glycero-beta-D-galacto-non-2-ulopyranosonate 9-phosphate (KDN-9-P) (PubMed:10749855). Neu5Ac-9-P and KDN-9-P are the phosphorylated forms of sialic acids N-acetylneuraminic acid (Neu5Ac) and deaminoneuraminic acid (KDN), respectively (PubMed:10749855). Required for brain and skeletal development (PubMed:27213289)","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q9NR45/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NANS","classification":"Not Classified","n_dependent_lines":13,"n_total_lines":1208,"dependency_fraction":0.01076158940397351},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000095380","cell_line_id":"CID000935","localizations":[{"compartment":"nucleoplasm","grade":3},{"compartment":"cytoplasmic","grade":1}],"interactors":[{"gene":"BLVRB","stoichiometry":0.2},{"gene":"DDB1","stoichiometry":0.2},{"gene":"SKIL","stoichiometry":0.2},{"gene":"NDUFA3","stoichiometry":0.2},{"gene":"FKBP5","stoichiometry":0.2},{"gene":"PHGDH","stoichiometry":0.2},{"gene":"RNASEH2A","stoichiometry":0.2},{"gene":"RRAS2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000935","total_profiled":1310},"omim":[{"mim_id":"610442","title":"SPONDYLOEPIMETAPHYSEAL DYSPLASIA, GENEVIEVE TYPE; SEMDG","url":"https://www.omim.org/entry/610442"},{"mim_id":"605202","title":"N-ACETYLNEURAMINIC ACID PHOSPHATE SYNTHASE; NANS","url":"https://www.omim.org/entry/605202"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NANS"},"hgnc":{"alias_symbol":["SAS"],"prev_symbol":[]},"alphafold":{"accession":"Q9NR45","domains":[{"cath_id":"3.20.20.70","chopping":"3-272","consensus_level":"high","plddt":97.7685,"start":3,"end":272},{"cath_id":"3.90.1210.10","chopping":"281-350","consensus_level":"high","plddt":96.6063,"start":281,"end":350}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NR45","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NR45-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NR45-F1-predicted_aligned_error_v6.png","plddt_mean":96.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NANS","jax_strain_url":"https://www.jax.org/strain/search?query=NANS"},"sequence":{"accession":"Q9NR45","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NR45.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NR45/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NR45"}},"corpus_meta":[{"pmid":"27213289","id":"PMC_27213289","title":"NANS-mediated synthesis of sialic acid is required for brain and skeletal development.","date":"2016","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27213289","citation_count":135,"is_preprint":false},{"pmid":"21557376","id":"PMC_21557376","title":"Structural and enzymatic characterization of NanS (YjhS), a 9-O-Acetyl N-acetylneuraminic acid esterase from Escherichia coli O157:H7.","date":"2011","source":"Protein science : a publication of the Protein Society","url":"https://pubmed.ncbi.nlm.nih.gov/21557376","citation_count":31,"is_preprint":false},{"pmid":"26378150","id":"PMC_26378150","title":"Characterization of a sialate-O-acetylesterase (NanS) from the oral pathogen Tannerella forsythia that enhances sialic acid release by NanH, its cognate sialidase.","date":"2015","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/26378150","citation_count":26,"is_preprint":false},{"pmid":"34163424","id":"PMC_34163424","title":"NANS-CDG: Delineation of the Genetic, Biochemical, and Clinical Spectrum.","date":"2021","source":"Frontiers in neurology","url":"https://pubmed.ncbi.nlm.nih.gov/34163424","citation_count":16,"is_preprint":false},{"pmid":"30340996","id":"PMC_30340996","title":"De-O-Acetylation of mucin-derived sialic acids by recombinant NanS-p esterases of Escherichia coli O157:H7 strain EDL933.","date":"2018","source":"International journal of medical microbiology : IJMM","url":"https://pubmed.ncbi.nlm.nih.gov/30340996","citation_count":12,"is_preprint":false},{"pmid":"27322322","id":"PMC_27322322","title":"The Sialidase NanS Enhances Non-TcsL Mediated Cytotoxicity of Clostridium sordellii.","date":"2016","source":"Toxins","url":"https://pubmed.ncbi.nlm.nih.gov/27322322","citation_count":11,"is_preprint":false},{"pmid":"40349344","id":"PMC_40349344","title":"NANS suppresses NF-κB signaling to promote ferroptosis by perturbing iron homeostasis.","date":"2025","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/40349344","citation_count":7,"is_preprint":false},{"pmid":"37340906","id":"PMC_37340906","title":"Oral sialic acid supplementation in NANS-CDG: Results of a single center, open-label, observational pilot study.","date":"2023","source":"Journal of inherited metabolic disease","url":"https://pubmed.ncbi.nlm.nih.gov/37340906","citation_count":4,"is_preprint":false},{"pmid":"33130469","id":"PMC_33130469","title":"Generation of an NANS homozygous knockout human induced pluripotent stem cell line by the insertion of GFP-P2A-Puro via CRISPR/Cas9 editing.","date":"2020","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/33130469","citation_count":4,"is_preprint":false},{"pmid":"38822623","id":"PMC_38822623","title":"NANS-CDG: Expanding clinical insights with a novel patient with novel variants.","date":"2024","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/38822623","citation_count":3,"is_preprint":false},{"pmid":"40280277","id":"PMC_40280277","title":"The Role of the Hexosamine-Sialic Acid Metabolic Pathway Mediated by GFPT1/NANS in c-Myc-Driven Hepatocellular Carcinoma.","date":"2025","source":"Cellular and molecular gastroenterology and hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/40280277","citation_count":2,"is_preprint":false},{"pmid":"37649799","id":"PMC_37649799","title":"Characterization of the flanking region of the Shiga toxin operon in Stx2a bacteriophages reveals a diversity of the NanS-p sialate O-acetylesterase gene.","date":"2023","source":"AIMS microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/37649799","citation_count":0,"is_preprint":false},{"pmid":"41683309","id":"PMC_41683309","title":"Amino Acid Intakes and Dietary Sources in a Nationally Representative Sample of Older Adults in Ireland: Findings from the National Adult Nutrition Survey (NANS).","date":"2026","source":"Nutrients","url":"https://pubmed.ncbi.nlm.nih.gov/41683309","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9144,"output_tokens":987,"usd":0.021118,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7504,"output_tokens":1670,"usd":0.039635,"stage2_stop_reason":"end_turn"},"total_usd":0.060753,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2016,\n      \"finding\": \"NANS encodes N-acetylneuraminic acid (NeuNAc; sialic acid) synthase; biallelic loss-of-function mutations reduce NANS enzymatic activity in patient-derived fibroblasts and prevent incorporation of sialic acid precursors into sialylated glycoproteins, demonstrating NANS is required for de novo sialic acid synthesis and glycoprotein sialylation.\",\n      \"method\": \"Patient fibroblast enzymatic activity assay, sialic acid precursor incorporation assay, zebrafish nansa knockdown with partial rescue by exogenous sialic acid\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — enzymatic activity measured directly in patient cells, precursor incorporation assay, and in vivo zebrafish rescue, replicated across multiple patient samples and model organism\",\n      \"pmids\": [\"27213289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Under ferroptotic stress, CDK1 phosphorylates NANS at serine 275 (S275), causing its dissociation from TAK1. Phosphorylated NANS is then ubiquitinated by UBE2N at lysine 246 (K246), leading to NANS degradation, which in turn activates TAK1-NF-κB signaling and upregulates the ferroptosis inhibitor FTH1, enabling ferroptosis resistance and metastasis in colorectal cancer cells.\",\n      \"method\": \"CRISPR-Cas9 screen identifying NANS as ferroptosis promoter, phosphorylation site mapping, Co-IP for NANS-TAK1 dissociation, ubiquitination assay, NF-κB signaling readouts, FTH1 expression analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR screen plus Co-IP plus ubiquitination assay and phosphorylation mapping in single lab, multiple orthogonal methods but not independently replicated\",\n      \"pmids\": [\"40349344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NANS participates in the hexosamine biosynthetic pathway downstream of GFPT1, specifically mediating the sialic acid synthesis branch (rather than O-GlcNAc glycosylation); knockout of NANS inhibits tumor growth in c-Myc-driven hepatocellular carcinoma mouse models, placing NANS as a key enzyme in the hexosamine-sialic acid metabolic axis.\",\n      \"method\": \"RNA sequencing, metabolomics, NANS gene knockout in murine HCC model, tumor growth and survival assays, luciferase reporter assay confirming c-Myc regulation of upstream GFPT1\",\n      \"journal\": \"Cellular and molecular gastroenterology and hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with defined tumor phenotype and metabolomics pathway placement, single lab, multiple methods\",\n      \"pmids\": [\"40280277\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NANS (N-acetylneuraminic acid synthase) catalyzes the de novo synthesis of sialic acid (NeuNAc), which is required for sialylation of glycoproteins and is essential for brain and skeletal development; additionally, NANS physically associates with TAK1 to suppress NF-κB-mediated ferroptosis resistance, and this non-metabolic function is regulated by CDK1-dependent phosphorylation at S275 and UBE2N-mediated ubiquitination at K246, which together trigger NANS degradation and pathway activation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NANS encodes N-acetylneuraminic acid (sialic acid) synthase, the enzyme that catalyzes de novo synthesis of NeuNAc required for glycoprotein sialylation; biallelic loss-of-function mutations reduce its enzymatic activity and block incorporation of sialic acid precursors into sialylated glycoproteins, establishing it as essential for sialic acid biosynthesis and, in vivo, for normal development [#0]. Metabolically, NANS operates downstream of GFPT1 in the hexosamine biosynthetic pathway, where it specifically mediates the sialic acid synthesis branch, and its loss restrains tumor growth in c-Myc-driven hepatocellular carcinoma [#2]. Beyond this metabolic role, NANS has a non-catalytic function in which it physically associates with TAK1 to restrain NF-\\u03baB signaling; under ferroptotic stress CDK1 phosphorylates NANS at S275 to drive its dissociation from TAK1, and UBE2N-mediated ubiquitination at K246 triggers NANS degradation, releasing TAK1-NF-\\u03baB signaling to upregulate the ferroptosis inhibitor FTH1 and confer ferroptosis resistance and metastasis in colorectal cancer [#1].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Established that NANS is the enzyme responsible for de novo sialic acid synthesis and that its loss disrupts glycoprotein sialylation, defining its core metabolic function and a developmental disease link.\",\n      \"evidence\": \"Patient fibroblast enzymatic activity and sialic acid precursor incorporation assays, with zebrafish nansa knockdown partially rescued by exogenous sialic acid\",\n      \"pmids\": [\"27213289\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of catalysis not resolved in this corpus\",\n        \"Tissue-specific consequences of impaired sialylation beyond development not detailed\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed NANS within the hexosamine biosynthetic pathway as the dedicated sialic acid branch enzyme downstream of GFPT1 and tied its activity to oncogenic c-Myc-driven tumor growth.\",\n      \"evidence\": \"RNA-seq, metabolomics, NANS knockout in a murine c-Myc HCC model with tumor growth and survival readouts and luciferase confirmation of c-Myc regulation of GFPT1\",\n      \"pmids\": [\"40280277\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab study not independently replicated\",\n        \"Whether the tumor-suppressive effect of knockout reflects loss of sialylation specifically versus broader metabolic perturbation is unresolved\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed a non-metabolic role for NANS as a TAK1-binding suppressor of NF-\\u03baB signaling, controlled by CDK1 phosphorylation and UBE2N ubiquitination that license its degradation during ferroptotic stress.\",\n      \"evidence\": \"CRISPR-Cas9 ferroptosis screen, S275 phosphorylation mapping, NANS-TAK1 Co-IP, K246 ubiquitination assay, NF-\\u03baB and FTH1 readouts in colorectal cancer cells\",\n      \"pmids\": [\"40349344\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab study with orthogonal assays but no independent replication\",\n        \"Whether the catalytic and TAK1-binding functions are mechanistically separable is not established\",\n        \"Reciprocal validation and structural basis of the NANS-TAK1 interaction not provided\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the metabolic (sialic acid synthase) and non-metabolic (TAK1-binding) functions of NANS are integrated, and whether they are coupled or independent, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural model linking catalytic and protein-binding surfaces\",\n        \"Physiological contexts where each function dominates are undefined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TAK1\", \"UBE2N\", \"CDK1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":3,"faith_total":3,"faith_pct":100.0}}