{"gene":"PRPSAP2","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":1997,"finding":"Rat PAP41 (ortholog of human PRPSAP2) was cloned and sequenced; the deduced protein of 369 amino acids shares ~49% identity with the catalytic PRS I and PRS II subunits and ~79% identity with the other associated protein PAP39, establishing PRPSAP2 as a member of the PRPS-associated protein subfamily that lacks catalytic PRPP-synthesizing activity but is a core component of the rat liver PRPS complex.","method":"cDNA cloning, sequence analysis, Northern blot","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 — molecular cloning with sequence/domain characterization; single lab","pmids":["9003449"],"is_preprint":false},{"year":1998,"finding":"Human cDNA encoding PAP41 (PRPSAP2) was cloned; the predicted 369-amino-acid protein (MW ~40,925) shares 98.9% identity with rat PAP41 and 72.2% identity with human PAP39, is expressed as a single ~2.1 kb mRNA across five human cell lines, and its gene exists as a single copy in the human genome. The protein lacks the PRPP binding site, consistent with a non-catalytic regulatory role.","method":"cDNA cloning from EST clones, Southern blot, Northern blot, sequence analysis","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 — molecular cloning with multi-method characterization; single lab","pmids":["9545573"],"is_preprint":false},{"year":1998,"finding":"The native rat liver PRPS complex (comprising PRS I, PRS II, PAP39, and PAP41/PRPSAP2) shows weaker sensitivity to allosteric nucleotide (ADP/GDP) inhibition than its isolated catalytic subunits alone, indicating that the associated proteins PAP39 and PAP41 modulate the regulatory response of the complex to inhibitory nucleotides. Free Mg²⁺ can largely overcome nucleotide inhibition at the regulatory site of PRS I, and the native liver enzyme (including PAP41) responds similarly but with a smaller inhibitory effect than isolated PRS I.","method":"Kinetic enzyme assays with purified native liver PRPS complex under controlled free Mg²⁺ concentrations; comparison of isolated subunits vs. native complex","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 1 — in vitro reconstitution/kinetic analysis; single lab","pmids":["9748490"],"is_preprint":false},{"year":2024,"finding":"PRPSAP2, together with PRPS2 and PRPSAP1, is required for proper assembly of the mammalian PRPS complex into high-molecular-weight multimeric configurations. Cells lacking PRPS2, PRPSAP1, and PRPSAP2 render PRPS1 into aberrant homo-oligomeric assemblies with diminished metabolic flux through the nucleotide synthesis pathway and impaired proliferative capacity. The study defines preferential subunit interactions within the complex and demonstrates translational control mechanisms that regulate PRPS assembly and activity.","method":"Isogenic fibroblast knockout clones in all viable individual and combinatorial assembly states; quantitative proteomics, biochemical fractionation, metabolic flux analysis, cell proliferation assays","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (genetic KO, MS proteomics, metabolic flux, proliferation) with rigorous combinatorial genetic dissection; single preprint but comprehensive","pmids":["39411161"],"is_preprint":true}],"current_model":"PRPSAP2 (PAP41) is a non-catalytic 41 kDa subunit of the mammalian phosphoribosylpyrophosphate synthetase (PRPS) complex that, together with PRPSAP1 (PAP39), PRPS1, and PRPS2, assembles into large heterogeneous multimeric complexes; PRPSAP2 is required for proper complex assembly, as its loss (together with PRPS2 and PRPSAP1) drives PRPS1 into aberrant homo-oligomers with reduced nucleotide biosynthetic flux and impaired cell proliferation, and the intact complex modulates allosteric sensitivity of the catalytic subunits to nucleotide feedback inhibition."},"narrative":{"teleology":[{"year":1997,"claim":"Identification of PRPSAP2 as a distinct non-catalytic subunit of the PRPS complex resolved the question of whether the associated proteins represent separate gene products or modified forms of the catalytic subunits, establishing PRPSAP2 as a dedicated regulatory component.","evidence":"cDNA cloning and sequencing of rat PAP41 from liver PRPS complex","pmids":["9003449"],"confidence":"Medium","gaps":["Single-lab cloning without independent confirmation at the time","No direct functional assay of PRPSAP2 in isolation from the complex","Mechanism by which PRPSAP2 contributes to complex function was unknown"]},{"year":1998,"claim":"Cloning of human PRPSAP2 and demonstration that the native PRPS complex modulates allosteric inhibition established the regulatory principle: associated proteins including PRPSAP2 dampen nucleotide feedback inhibition of the catalytic subunits, linking PRPSAP2 to metabolic control of purine/pyrimidine biosynthesis.","evidence":"Human cDNA cloning with expression analysis across cell lines; kinetic enzyme assays comparing purified native liver PRPS complex versus isolated catalytic subunits under controlled Mg²⁺ conditions","pmids":["9545573","9748490"],"confidence":"Medium","gaps":["The individual contribution of PRPSAP2 versus PRPSAP1 to allosteric modulation was not resolved","No loss-of-function or reconstitution experiment to test PRPSAP2 necessity","In vivo relevance of altered allosteric sensitivity was not demonstrated"]},{"year":2024,"claim":"Combinatorial genetic ablation demonstrated that PRPSAP2 is required for proper PRPS complex assembly, answering whether the associated proteins are dispensable scaffolds or essential architectural subunits; their loss drives PRPS1 into dysfunctional homo-oligomers with reduced nucleotide flux and impaired proliferation.","evidence":"(preprint) Isogenic fibroblast knockout clones in all viable individual and combinatorial assembly states; quantitative proteomics, biochemical fractionation, metabolic flux analysis, cell proliferation assays","pmids":["39411161"],"confidence":"High","gaps":["Preprint not yet peer-reviewed","Individual PRPSAP2-only knockout phenotype versus combinatorial loss not fully delineated in the timeline","Structural basis of PRPSAP2-mediated complex assembly remains undefined"]},{"year":null,"claim":"The precise structural contacts through which PRPSAP2 integrates into the PRPS multimer and the tissue-specific consequences of PRPSAP2 loss in vivo remain undefined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of the intact PRPS complex including PRPSAP2","No animal model targeting PRPSAP2 specifically","Whether PRPSAP2 and PRPSAP1 are functionally redundant or have distinct regulatory roles is unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,3]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[2,3]}],"complexes":["PRPS complex"],"partners":["PRPS1","PRPS2","PRPSAP1"],"other_free_text":[]},"mechanistic_narrative":"PRPSAP2 (PAP41) is a non-catalytic 41 kDa subunit of the mammalian phosphoribosyl pyrophosphate synthetase (PRPS) complex that assembles with PRPS1, PRPS2, and PRPSAP1 into large heterogeneous multimeric complexes required for de novo nucleotide biosynthesis [PMID:9003449, PMID:9545573]. Although PRPSAP2 shares ~49% sequence identity with the catalytic PRPS subunits, it lacks the PRPP binding site and instead functions as a regulatory component: the presence of associated proteins including PRPSAP2 attenuates the sensitivity of the complex to allosteric nucleotide (ADP/GDP) feedback inhibition compared with isolated catalytic subunits [PMID:9748490]. Loss of PRPSAP2 together with PRPS2 and PRPSAP1 forces PRPS1 into aberrant homo-oligomers with reduced nucleotide biosynthetic flux and impaired cell proliferation, establishing PRPSAP2 as essential for proper PRPS complex assembly and metabolic function [PMID:39411161]."},"prefetch_data":{"uniprot":{"accession":"O60256","full_name":"Phosphoribosyl pyrophosphate synthase-associated protein 2","aliases":["41 kDa phosphoribosypyrophosphate synthetase-associated protein","PAP41"],"length_aa":369,"mass_kda":40.9,"function":"Seems to play a negative regulatory role in 5-phosphoribose 1-diphosphate synthesis","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/O60256/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PRPSAP2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CAPRIN1","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"PARP1","stoichiometry":0.2},{"gene":"RTCB","stoichiometry":0.2},{"gene":"SSRP1","stoichiometry":0.2},{"gene":"TOP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PRPSAP2","total_profiled":1310},"omim":[{"mim_id":"603762","title":"PHOSPHORIBOSYLPYROPHOSPHATE SYNTHETASE-ASSOCIATED PROTEIN 2; PRPSAP2","url":"https://www.omim.org/entry/603762"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PRPSAP2"},"hgnc":{"alias_symbol":["PAP41"],"prev_symbol":[]},"alphafold":{"accession":"O60256","domains":[{"cath_id":"3.40.50.2020","chopping":"21-164","consensus_level":"high","plddt":94.7289,"start":21,"end":164},{"cath_id":"3.40.50.2020","chopping":"167-214_255-340","consensus_level":"high","plddt":94.8995,"start":167,"end":340}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O60256","model_url":"https://alphafold.ebi.ac.uk/files/AF-O60256-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O60256-F1-predicted_aligned_error_v6.png","plddt_mean":87.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PRPSAP2","jax_strain_url":"https://www.jax.org/strain/search?query=PRPSAP2"},"sequence":{"accession":"O60256","fasta_url":"https://rest.uniprot.org/uniprotkb/O60256.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O60256/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O60256"}},"corpus_meta":[{"pmid":"22292074","id":"PMC_22292074","title":"Identification of novel candidate oncogenes in chromosome region 17p11.2-p12 in human osteosarcoma.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22292074","citation_count":37,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27846620","id":"PMC_27846620","title":"Oncogenic Properties of Candidate Oncogenes in Chromosome Region 17p11.2p12 in Human Osteosarcoma.","date":"2016","source":"Cytogenetic and genome research","url":"https://pubmed.ncbi.nlm.nih.gov/27846620","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9545573","id":"PMC_9545573","title":"Molecular cloning of a human cDNA for the 41-kDa phosphoribosylpyrophosphate synthetase-associated protein.","date":"1998","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/9545573","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9003449","id":"PMC_9003449","title":"Cloning and sequencing of rat cDNA for the 41-kDa phosphoribosylpyrophosphate synthetase-associated protein has a high homology to the catalytic subunits and the 39-kDa associated protein.","date":"1997","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/9003449","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9748490","id":"PMC_9748490","title":"Rat liver phosphoribosylpyrophosphate synthetase is activated by free Mg2+ in a manner that overcomes its inhibition by nucleotides.","date":"1998","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/9748490","citation_count":8,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21594610","id":"PMC_21594610","title":"Hyperuricemia cosegregating with osteogenesis imperfecta is associated with a mutation in GPATCH8.","date":"2011","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21594610","citation_count":6,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25816608","id":"PMC_25816608","title":"Expression of phosphoribosyl pyrophosphate synthetase genes in U87 glioma cells with ERN1 knockdown: effect of hypoxia and endoplasmic reticulum stress.","date":"2014","source":"Ukrainian biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/25816608","citation_count":5,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39411161","id":"PMC_39411161","title":"Evolutionary origins and innovations sculpting the mammalian PRPS enzyme complex.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/39411161","citation_count":3,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18409517","id":"PMC_18409517","title":"[Increased activity of PRPP synthetase].","date":"2008","source":"Nihon rinsho. Japanese journal of clinical medicine","url":"https://pubmed.ncbi.nlm.nih.gov/18409517","citation_count":2,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34891669","id":"PMC_34891669","title":"Evaluating the Neuroimaging-Genetic Prediction of Symptom Changes in Individuals with ADHD.","date":"2021","source":"Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference","url":"https://pubmed.ncbi.nlm.nih.gov/34891669","citation_count":2,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"40495522","id":"PMC_40495522","title":"Proteome-Wide and Immune Cell Phenotype Mendelian Randomization Highlights Immune Involvement in Genetic Generalized Epilepsy.","date":"2025","source":"Brain and behavior","url":"https://pubmed.ncbi.nlm.nih.gov/40495522","citation_count":1,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17081983","id":"PMC_17081983","title":"Global, in vivo, and site-specific phosphorylation dynamics in signaling networks.","date":"2006","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/17081983","citation_count":2861,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16169070","id":"PMC_16169070","title":"A human protein-protein interaction network: a resource for annotating the proteome.","date":"2005","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/16169070","citation_count":1704,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12477932","id":"PMC_12477932","title":"Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12477932","citation_count":1479,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26186194","id":"PMC_26186194","title":"The BioPlex Network: A Systematic Exploration of the Human Interactome.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26186194","citation_count":1118,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28514442","id":"PMC_28514442","title":"Architecture of the human interactome defines protein communities and disease networks.","date":"2017","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/28514442","citation_count":1085,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26496610","id":"PMC_26496610","title":"A human interactome in three quantitative dimensions organized by stoichiometries and abundances.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26496610","citation_count":1015,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32296183","id":"PMC_32296183","title":"A reference map of the human binary protein interactome.","date":"2020","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/32296183","citation_count":849,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33961781","id":"PMC_33961781","title":"Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.","date":"2021","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/33961781","citation_count":705,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21873635","id":"PMC_21873635","title":"Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium.","date":"2011","source":"Briefings in bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/21873635","citation_count":656,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15489334","id":"PMC_15489334","title":"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).","date":"2004","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/15489334","citation_count":438,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"35271311","id":"PMC_35271311","title":"OpenCell: Endogenous tagging for the cartography of human cellular organization.","date":"2022","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/35271311","citation_count":432,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16344560","id":"PMC_16344560","title":"Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes.","date":"2005","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/16344560","citation_count":409,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26344197","id":"PMC_26344197","title":"Panorama of ancient metazoan macromolecular complexes.","date":"2015","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/26344197","citation_count":407,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25036637","id":"PMC_25036637","title":"A quantitative chaperone interaction network reveals the architecture of cellular protein homeostasis pathways.","date":"2014","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/25036637","citation_count":325,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21145461","id":"PMC_21145461","title":"Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics.","date":"2010","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/21145461","citation_count":318,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"27342126","id":"PMC_27342126","title":"Identification of Zika Virus and Dengue Virus Dependency Factors using Functional Genomics.","date":"2016","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/27342126","citation_count":306,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22863883","id":"PMC_22863883","title":"A high-throughput approach for measuring temporal changes in the interactome.","date":"2012","source":"Nature methods","url":"https://pubmed.ncbi.nlm.nih.gov/22863883","citation_count":273,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"36217030","id":"PMC_36217030","title":"A comprehensive SARS-CoV-2-human protein-protein interactome reveals COVID-19 pathobiology and potential host therapeutic targets.","date":"2022","source":"Nature biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/36217030","citation_count":140,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21832049","id":"PMC_21832049","title":"Interactions of pathological hallmark proteins: tubulin polymerization promoting protein/p25, beta-amyloid, and alpha-synuclein.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21832049","citation_count":131,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20686608","id":"PMC_20686608","title":"Genome-wide association study of pancreatic cancer in Japanese population.","date":"2010","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/20686608","citation_count":119,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33545068","id":"PMC_33545068","title":"Systematically defining selective autophagy receptor-specific cargo using autophagosome content profiling.","date":"2021","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/33545068","citation_count":105,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"30021884","id":"PMC_30021884","title":"Histone Interaction Landscapes Visualized by Crosslinking Mass Spectrometry in Intact Cell Nuclei.","date":"2018","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/30021884","citation_count":101,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29229926","id":"PMC_29229926","title":"Cell cycle-dependent phosphorylation regulates RECQL4 pathway choice and ubiquitination in DNA double-strand break repair.","date":"2017","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/29229926","citation_count":89,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26389662","id":"PMC_26389662","title":"Systematic proteomics of the VCP-UBXD adaptor network identifies a role for UBXN10 in regulating ciliogenesis.","date":"2015","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/26389662","citation_count":81,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28515276","id":"PMC_28515276","title":"Assembly of the U5 snRNP component PRPF8 is controlled by the HSP90/R2TP chaperones.","date":"2017","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/28515276","citation_count":78,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29331416","id":"PMC_29331416","title":"Deubiquitinating enzyme PSMD14 promotes tumor metastasis through stabilizing SNAIL in human esophageal squamous cell carcinoma.","date":"2018","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/29331416","citation_count":72,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"35256949","id":"PMC_35256949","title":"Histone deacetylase inhibitors inhibit cervical cancer growth through Parkin acetylation-mediated mitophagy.","date":"2021","source":"Acta pharmaceutica Sinica. B","url":"https://pubmed.ncbi.nlm.nih.gov/35256949","citation_count":66,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25921289","id":"PMC_25921289","title":"Temporal proteomics of NGF-TrkA signaling identifies an inhibitory role for the E3 ligase Cbl-b in neuroblastoma cell differentiation.","date":"2015","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/25921289","citation_count":61,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"31980649","id":"PMC_31980649","title":"Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRASG13D.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/31980649","citation_count":60,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22199357","id":"PMC_22199357","title":"Cytoplasmic Metadherin (MTDH) provides survival advantage under conditions of stress by acting as RNA-binding protein.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22199357","citation_count":53,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6857,"output_tokens":1158,"usd":0.018971},"stage2":{"model":"claude-opus-4-6","input_tokens":4358,"output_tokens":1349,"usd":0.083272},"total_usd":0.232437,"stage1_batch_id":"msgbatch_01SUR8NDzVrNmyszWyJeCct7","stage2_batch_id":"msgbatch_01G7Yfutko3cDWzejrwH5AMx","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":18971,"output_tokens":2274,"usd":0.045512},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":4696,"output_tokens":1319,"usd":0.084682}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"PAP41 (rat ortholog of PRPSAP2) was cloned and shown to be a component of the rat liver phosphoribosylpyrophosphate synthetase (PRPS) complex aggregate, composed of 34-kDa catalytic subunits (PRS I and II) and 39- and 41-kDa associated proteins (PAP39 and PAP41). PAP41 shares ~49% identity with PRS catalytic subunits but forms a distinct PAP subfamily with PAP39. Its mRNA is present in all rat tissues examined.\",\n      \"method\": \"cDNA cloning, sequence analysis, Northern blot\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — molecular cloning with biochemical complex characterization, single lab\",\n      \"pmids\": [\"9003449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Human PAP41 (PRPSAP2) cDNA was cloned; the encoded 369-amino-acid protein lacks the PRPP binding site, distinguishing it from catalytic PRS subunits, and shares 72.2% identity with human PAP39 (PRPSAP1). A single PAP41 gene exists in the human genome and a single ~2.1 kb mRNA is expressed in five human cell lines.\",\n      \"method\": \"cDNA cloning from EST clones, Southern blot, Northern blot, sequence analysis\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — molecular cloning with sequence-based functional inference and expression validation, single lab\",\n      \"pmids\": [\"9545573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The native rat liver PRPS complex (containing PRS I, PRS II, PAP39, and PAP41/PRPSAP2) shows weaker sensitivity to nucleotide (ADP, GDP) inhibition than expected from its subunit composition alone, and high free Mg2+ can overcome nucleotide inhibition, indicating that the complex modulates allosteric regulation of PRPS activity.\",\n      \"method\": \"Kinetic assays of native complex vs. individual subunits under varying free Mg2+ and nucleotide concentrations\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinetic reconstitution, but PRPSAP2/PAP41 contribution not individually dissected\",\n      \"pmids\": [\"9748490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRPSAP2 (along with PRPS2 and PRPSAP1) is a non-enzymatic associated protein that operates as part of a large molecular weight PRPS complex capable of heterogeneous multimeric configurations. Using isogenic fibroblast clones lacking PRPS2, PRPSAP1, and PRPSAP2, it was shown that absence of these subunits renders PRPS1 into aberrant homo-oligomeric assemblies with diminished metabolic flux and impaired proliferative capacity. Preferential interactions between subunits were defined, and translational control mechanisms enable fine-tuned regulation of PRPS assembly and activity.\",\n      \"method\": \"Isogenic fibroblast knockout clones (individual and combinatorial), mass spectrometry, metabolic flux assays, proliferation assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (genetic KO, MS interactome, metabolic flux, proliferation) in a single rigorous study\",\n      \"pmids\": [\"39411161\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"PRPSAP2 (PAP41) is a non-enzymatic associated protein that physically assembles with PRPS1, PRPS2, and PRPSAP1 into a large heteromeric PRPS complex; it lacks a PRPP binding site but is required for proper complex assembly, as its absence (together with PRPS2 and PRPSAP1) drives PRPS1 into aberrant homo-oligomers with reduced nucleotide metabolic flux and impaired cell proliferation, and the intact complex modulates allosteric nucleotide inhibition of PRPS catalytic activity.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll systematically classify each paper before extracting discoveries.\n\n**RETRIEVED PAPERS classification:**\n1. PMID:22292074 — KEEP (mentions PRPSAP2 as candidate oncogene in 17p11.2-p12)\n2. PMID:27846620 — KEEP (follow-up oncogenic properties; notes PRPSAP2 was excluded from functional assays)\n3. PMID:9545573 — KEEP (cloning of human PAP41 = PRPSAP2)\n4. PMID:9003449 — KEEP (rat PAP41 = PRPSAP2 ortholog, cloning/characterization)\n5. PMID:9748490 — KEEP (rat liver PRPS complex regulation including PAP41)\n6. PMID:21594610 — EXCLUDE (PRPSAP2 mentioned as candidate gene tested but no mutation found; no mechanistic finding)\n7. PMID:25816608 — KEEP (expression of PRPSAP2 under hypoxia/ER stress in glioma; largely expression but mentions regulation)\n8. PMID:39411161 — KEEP (PREPRINT; mechanistic study of PRPS complex including PRPSAP2 roles)\n9. PMID:18409517 — KEEP (review of PRPS complex including PAP41/PRPSAP2)\n10. PMID:34891669 — EXCLUDE (GWAS/prediction study; PRPSAP2 as a feature, no mechanism)\n11. PMID:40495522 — EXCLUDE (MR/GWAS; PRPSAP2 association, no mechanism)\n\n**ADDITIONAL gene2pubmed PAPERS classification:**\nMost are large proteomics/interactome screens or unrelated papers. I'll check each:\n- PMID:17081983 (phosphoproteomics) — EXCLUDE (no specific PRPSAP2 finding)\n- PMID:16169070 (Y2H interactome) — EXCLUDE (no specific PRPSAP2 mechanistic finding)\n- PMID:12477932, 15489334 (MGC) — EXCLUDE (cDNA resource)\n- PMID:26186194, 28514442, 33961781 (BioPlex) — EXCLUDE (large screens, no specific PRPSAP2 mechanism)\n- PMID:26496610 (HeLa interactome) — EXCLUDE\n- PMID:32296183 (HuRI) — EXCLUDE\n- PMID:35271311 (OpenCell) — EXCLUDE\n- PMID:16344560 (promoters) — EXCLUDE\n- PMID:26344197 (metazoan complexes) — EXCLUDE\n- PMID:25036637 (chaperone network) — EXCLUDE\n- PMID:21145461 (CRL network) — EXCLUDE\n- PMID:27342126 (flavivirus) — EXCLUDE\n- PMID:22863883 (SEC-MS) — EXCLUDE\n- PMID:36217030 (SARS-CoV-2) — EXCLUDE\n- PMID:21832049 (TPPP/p25) — EXCLUDE\n- PMID:20686608 (pancreatic cancer GWAS) — EXCLUDE\n- PMID:33545068 (autophagy) — EXCLUDE\n- PMID:30021884 (XL-MS) — EXCLUDE\n- PMID:29229926 (RECQL4) — EXCLUDE\n- PMID:26389662 (VCP-UBXD) — EXCLUDE\n- PMID:28515276 (PRPF8/U5 snRNP) — EXCLUDE (PRPF8, not PRPSAP2)\n- PMID:29331416 (PSMD14) — EXCLUDE\n- PMID:35256949 (Parkin) — EXCLUDE\n- PMID:25921289 (Cbl-b) — EXCLUDE\n- PMID:31980649 (KRAS/EGFR) — EXCLUDE\n- PMID:22199357 (MTDH) — EXCLUDE\n- PMID:21873635 (GO) — EXCLUDE\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"Rat PAP41 (ortholog of human PRPSAP2) was cloned and sequenced; the deduced protein of 369 amino acids shares ~49% identity with the catalytic PRS I and PRS II subunits and ~79% identity with the other associated protein PAP39, establishing PRPSAP2 as a member of the PRPS-associated protein subfamily that lacks catalytic PRPP-synthesizing activity but is a core component of the rat liver PRPS complex.\",\n      \"method\": \"cDNA cloning, sequence analysis, Northern blot\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — molecular cloning with sequence/domain characterization; single lab\",\n      \"pmids\": [\"9003449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Human cDNA encoding PAP41 (PRPSAP2) was cloned; the predicted 369-amino-acid protein (MW ~40,925) shares 98.9% identity with rat PAP41 and 72.2% identity with human PAP39, is expressed as a single ~2.1 kb mRNA across five human cell lines, and its gene exists as a single copy in the human genome. The protein lacks the PRPP binding site, consistent with a non-catalytic regulatory role.\",\n      \"method\": \"cDNA cloning from EST clones, Southern blot, Northern blot, sequence analysis\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — molecular cloning with multi-method characterization; single lab\",\n      \"pmids\": [\"9545573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The native rat liver PRPS complex (comprising PRS I, PRS II, PAP39, and PAP41/PRPSAP2) shows weaker sensitivity to allosteric nucleotide (ADP/GDP) inhibition than its isolated catalytic subunits alone, indicating that the associated proteins PAP39 and PAP41 modulate the regulatory response of the complex to inhibitory nucleotides. Free Mg²⁺ can largely overcome nucleotide inhibition at the regulatory site of PRS I, and the native liver enzyme (including PAP41) responds similarly but with a smaller inhibitory effect than isolated PRS I.\",\n      \"method\": \"Kinetic enzyme assays with purified native liver PRPS complex under controlled free Mg²⁺ concentrations; comparison of isolated subunits vs. native complex\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution/kinetic analysis; single lab\",\n      \"pmids\": [\"9748490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRPSAP2, together with PRPS2 and PRPSAP1, is required for proper assembly of the mammalian PRPS complex into high-molecular-weight multimeric configurations. Cells lacking PRPS2, PRPSAP1, and PRPSAP2 render PRPS1 into aberrant homo-oligomeric assemblies with diminished metabolic flux through the nucleotide synthesis pathway and impaired proliferative capacity. The study defines preferential subunit interactions within the complex and demonstrates translational control mechanisms that regulate PRPS assembly and activity.\",\n      \"method\": \"Isogenic fibroblast knockout clones in all viable individual and combinatorial assembly states; quantitative proteomics, biochemical fractionation, metabolic flux analysis, cell proliferation assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (genetic KO, MS proteomics, metabolic flux, proliferation) with rigorous combinatorial genetic dissection; single preprint but comprehensive\",\n      \"pmids\": [\"39411161\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"PRPSAP2 (PAP41) is a non-catalytic 41 kDa subunit of the mammalian phosphoribosylpyrophosphate synthetase (PRPS) complex that, together with PRPSAP1 (PAP39), PRPS1, and PRPS2, assembles into large heterogeneous multimeric complexes; PRPSAP2 is required for proper complex assembly, as its loss (together with PRPS2 and PRPSAP1) drives PRPS1 into aberrant homo-oligomers with reduced nucleotide biosynthetic flux and impaired cell proliferation, and the intact complex modulates allosteric sensitivity of the catalytic subunits to nucleotide feedback inhibition.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PRPSAP2 (PAP41) is a non-enzymatic associated subunit of the heteromeric phosphoribosylpyrophosphate synthetase (PRPS) complex, assembling together with PRPS1, PRPS2, and PRPSAP1 into large multimeric configurations that are essential for proper nucleotide metabolic flux and cell proliferation [PMID:9003449, PMID:39411161]. Although PRPSAP2 shares ~49% sequence identity with PRPS catalytic subunits, it lacks the PRPP binding site and does not possess catalytic activity [PMID:9545573]. The intact heteromeric complex containing PRPSAP2 modulates allosteric nucleotide (ADP, GDP) inhibition of PRPS catalytic activity, and loss of PRPSAP2 together with PRPS2 and PRPSAP1 forces PRPS1 into aberrant homo-oligomers with reduced metabolic output and impaired proliferative capacity [PMID:9748490, PMID:39411161].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Identification of PAP41 as a distinct component of the PRPS complex established that the holoenzyme contains non-catalytic associated proteins in addition to catalytic subunits, raising the question of what role these subunits play.\",\n      \"evidence\": \"cDNA cloning and sequence analysis of rat liver PRPS complex subunits\",\n      \"pmids\": [\"9003449\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Individual contribution of PAP41 versus PAP39 to complex function was not dissected\",\n        \"No direct functional assay of PAP41 was performed\"\n      ]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Cloning of human PRPSAP2 and demonstration that it lacks the PRPP binding site distinguished it as a non-catalytic subunit, while kinetic studies of the native complex revealed that the assembled holoenzyme attenuates allosteric nucleotide inhibition of PRPS activity — establishing a regulatory role for the complex architecture.\",\n      \"evidence\": \"cDNA cloning with sequence-based functional annotation; kinetic assays of native complex versus individual subunits under varying nucleotide and Mg²⁺ concentrations\",\n      \"pmids\": [\"9545573\", \"9748490\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"PRPSAP2's specific contribution to allosteric modulation was not individually dissected from that of other associated subunits\",\n        \"No loss-of-function or reconstitution experiment isolated PRPSAP2's role\",\n        \"Structural basis for complex assembly and allosteric regulation remained unknown\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Combinatorial knockout studies in isogenic fibroblasts demonstrated that PRPSAP2 (along with PRPS2 and PRPSAP1) is required for proper PRPS complex assembly; their absence drives PRPS1 into aberrant homo-oligomers with diminished nucleotide metabolic flux and impaired cell proliferation, establishing that non-catalytic subunits are functionally essential.\",\n      \"evidence\": \"Isogenic fibroblast knockout clones (individual and combinatorial), mass spectrometry interactomics, metabolic flux assays, and proliferation assays (preprint)\",\n      \"pmids\": [\"39411161\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Study is a preprint and awaits peer review\",\n        \"Individual contribution of PRPSAP2 knockout alone (distinct from combined loss of PRPS2/PRPSAP1) to metabolic and proliferative phenotypes is not fully resolved\",\n        \"No high-resolution structural model of the heteromeric PRPS complex has been reported\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The precise stoichiometry and structural organization of PRPSAP2 within the heteromeric PRPS complex, the specific molecular interfaces mediating its preferential subunit interactions, and whether PRPSAP2 loss alone is sufficient to cause disease-relevant metabolic dysfunction remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No atomic-resolution structure of the PRPS holocomplex including PRPSAP2\",\n        \"No in vivo animal model targeting PRPSAP2 specifically\",\n        \"No disease association directly linked to PRPSAP2 mutations\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\n        \"term_id\": \"GO:0098772\",\n        \"supporting_discovery_ids\": [2, 3]\n      }\n    ],\n    \"localization\": [\n      {\n        \"term_id\": \"GO:0005829\",\n        \"supporting_discovery_ids\": [0, 3]\n      }\n    ],\n    \"pathway\": [\n      {\n        \"term_id\": \"R-HSA-1430728\",\n        \"supporting_discovery_ids\": [2, 3]\n      }\n    ],\n    \"complexes\": [\n      \"PRPS holoenzyme complex\"\n    ],\n    \"partners\": [\n      \"PRPS1\",\n      \"PRPS2\",\n      \"PRPSAP1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"PRPSAP2 (PAP41) is a non-catalytic 41 kDa subunit of the mammalian phosphoribosyl pyrophosphate synthetase (PRPS) complex that assembles with PRPS1, PRPS2, and PRPSAP1 into large heterogeneous multimeric complexes required for de novo nucleotide biosynthesis [PMID:9003449, PMID:9545573]. Although PRPSAP2 shares ~49% sequence identity with the catalytic PRPS subunits, it lacks the PRPP binding site and instead functions as a regulatory component: the presence of associated proteins including PRPSAP2 attenuates the sensitivity of the complex to allosteric nucleotide (ADP/GDP) feedback inhibition compared with isolated catalytic subunits [PMID:9748490]. Loss of PRPSAP2 together with PRPS2 and PRPSAP1 forces PRPS1 into aberrant homo-oligomers with reduced nucleotide biosynthetic flux and impaired cell proliferation, establishing PRPSAP2 as essential for proper PRPS complex assembly and metabolic function [PMID:39411161].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Identification of PRPSAP2 as a distinct non-catalytic subunit of the PRPS complex resolved the question of whether the associated proteins represent separate gene products or modified forms of the catalytic subunits, establishing PRPSAP2 as a dedicated regulatory component.\",\n      \"evidence\": \"cDNA cloning and sequencing of rat PAP41 from liver PRPS complex\",\n      \"pmids\": [\"9003449\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab cloning without independent confirmation at the time\",\n        \"No direct functional assay of PRPSAP2 in isolation from the complex\",\n        \"Mechanism by which PRPSAP2 contributes to complex function was unknown\"\n      ]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Cloning of human PRPSAP2 and demonstration that the native PRPS complex modulates allosteric inhibition established the regulatory principle: associated proteins including PRPSAP2 dampen nucleotide feedback inhibition of the catalytic subunits, linking PRPSAP2 to metabolic control of purine/pyrimidine biosynthesis.\",\n      \"evidence\": \"Human cDNA cloning with expression analysis across cell lines; kinetic enzyme assays comparing purified native liver PRPS complex versus isolated catalytic subunits under controlled Mg²⁺ conditions\",\n      \"pmids\": [\"9545573\", \"9748490\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The individual contribution of PRPSAP2 versus PRPSAP1 to allosteric modulation was not resolved\",\n        \"No loss-of-function or reconstitution experiment to test PRPSAP2 necessity\",\n        \"In vivo relevance of altered allosteric sensitivity was not demonstrated\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Combinatorial genetic ablation demonstrated that PRPSAP2 is required for proper PRPS complex assembly, answering whether the associated proteins are dispensable scaffolds or essential architectural subunits; their loss drives PRPS1 into dysfunctional homo-oligomers with reduced nucleotide flux and impaired proliferation.\",\n      \"evidence\": \"(preprint) Isogenic fibroblast knockout clones in all viable individual and combinatorial assembly states; quantitative proteomics, biochemical fractionation, metabolic flux analysis, cell proliferation assays\",\n      \"pmids\": [\"39411161\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Preprint not yet peer-reviewed\",\n        \"Individual PRPSAP2-only knockout phenotype versus combinatorial loss not fully delineated in the timeline\",\n        \"Structural basis of PRPSAP2-mediated complex assembly remains undefined\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The precise structural contacts through which PRPSAP2 integrates into the PRPS multimer and the tissue-specific consequences of PRPSAP2 loss in vivo remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No high-resolution structure of the intact PRPS complex including PRPSAP2\",\n        \"No animal model targeting PRPSAP2 specifically\",\n        \"Whether PRPSAP2 and PRPSAP1 are functionally redundant or have distinct regulatory roles is unresolved\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"complexes\": [\"PRPS complex\"],\n    \"partners\": [\"PRPS1\", \"PRPS2\", \"PRPSAP1\"],\n    \"other_free_text\": []\n  }\n}\n```"}