{"gene":"QPCT","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2022,"finding":"QPCT/L (glutaminyl cyclase) enzymes modify CD47 on senescent cells, increasing CD47 stability/activity, which suppresses macrophage-mediated efferocytosis (clearance of apoptotic corpses) through the SIRPα-CD47-SHP-1 signaling axis. Senescent cell-mediated efferocytosis suppression (SCES) was reversible by interfering with QPCT/L activity, establishing QPCT as a writer of a CD47 post-translational modification that regulates innate immune recognition.","method":"Direct contact assays, QPCT/L inhibition, SIRPα-CD47-SHP-1 pathway interference, in vitro and in vivo senescent cell models","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional rescue by QPCT/L inhibition with defined pathway placement (SIRPα-CD47-SHP-1), single lab, multiple orthogonal approaches but no in vitro reconstitution of the modification itself","pmids":["36459066"],"is_preprint":false},{"year":2015,"finding":"QPCT inhibition reduces mutant huntingtin (HTT) aggregation and toxicity by inducing upregulation of the molecular chaperone αB-crystallin, and this mechanism also reduces aggregation of diverse proteins. New QPCT inhibitors generated by in silico methods and in vitro screening rescued HD-related phenotypes in cell, Drosophila, and zebrafish models.","method":"siRNA screen in human cells, Drosophila genetic validation, zebrafish HD models, αB-crystallin induction assays, in silico inhibitor design followed by in vitro screening","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — independently validated across multiple model organisms (cell, fly, zebrafish), multiple orthogonal methods including genetic knockdown and pharmacological inhibition, defined molecular mechanism (αB-crystallin induction)","pmids":["25848931"],"is_preprint":false},{"year":2019,"finding":"QPCT binds directly to HRAS and attenuates HRAS ubiquitination, thereby increasing HRAS protein stability and leading to activation of the ERK pathway in renal cell carcinoma cells. NF-κB (p65) positively regulates QPCT transcription by binding to the QPCT promoter, and this binding is blocked by promoter hypermethylation.","method":"Human proteome microarray to identify QPCT-interacting proteins, co-immunoprecipitation, confocal laser microscopy, ChIP assay, ubiquitination assay, QPCT knockdown/overexpression with ERK pathway readout","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and proteome microarray for binding, ubiquitination assay for mechanism, ChIP for upstream regulation; single lab with multiple orthogonal methods","pmids":["31534544"],"is_preprint":false},{"year":1996,"finding":"Glutamine cyclotransferase (QC, QPCT) catalyzes pyroglutamate formation from N-terminal glutaminyl residues in peptides. The second amino acid residue in N-terminal glutaminyl peptides significantly accelerates the reaction, while the third residue provides no further rate enhancement. Substrate binding is the main specificity-determining step. Proline derivatives and N-terminal proline-containing dipeptides inhibit QC activity, consistent with a reaction mechanism involving intermediates structurally similar to L-proline.","method":"In vitro enzyme kinetics with systematic substrate and inhibitor specificity testing using papaya latex QC","journal":"Biological chemistry Hoppe-Seyler","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro biochemical assay with systematic substrate panel establishing catalytic mechanism, but single study on non-human (papaya) ortholog","pmids":["8839986"],"is_preprint":false},{"year":2012,"finding":"Site-directed mutagenesis of human QC (QPCT) at residues F325, I303, and S323 defined key interactions between the enzyme and the inhibitor PBD150 in solution: replacement of F325 or I303 with alanine/asparagine caused ~800-fold reduction in inhibitor potency, while replacement of S323 with alanine or valine caused ~20-fold increased inhibitor activity, establishing these residues as critical for the enzyme-inhibitor binding site.","method":"Site-directed mutagenesis of human QC, in vitro enzyme-inhibitor activity assays, semi-empirical QC/MM calculations","journal":"Chemical biology & drug design","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — active-site mutagenesis with quantitative inhibitor potency readout and computational validation; single lab but multiple mutants tested with orthogonal computational support","pmids":["22967026"],"is_preprint":false},{"year":2014,"finding":"QC (QPCT) and its isoenzyme isoQC are expressed throughout the mouse brain with region-specific and strain-specific patterns. Enzymatic QC/isoQC activity is highest in ventral brain, followed by cortex and hippocampus. In cortex, activity arises predominantly from isoQC expression. Both enzymes catalyze pyroglutamate formation from glutamine precursors at the N-terminus of peptide hormones, neuropeptides, and chemokines, and QC is also involved in pathogenic pGlu modification of amyloid peptides in neurodegeneration.","method":"Enzymatic activity assays and immunohistochemistry with specific antibodies across nine mouse strains and multiple brain regions; unbiased stereology for cell counting","journal":"International journal of developmental neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct enzymatic activity measurements combined with immunohistochemistry across multiple strains; localization tied to functional enzyme activity","pmids":["24886834"],"is_preprint":false},{"year":2015,"finding":"Qpct is a maternally imprinted gene in mice (expressed from the maternal allele only in placenta). ChIP assay demonstrated that histone H3K4me3 modification is associated with maternal activation of Qpct expression. Qpct is expressed during early embryonic development in brain regions and shows peak expression in the labyrinth layer of the placenta at E15.5.","method":"Allele-specific expression analysis, ChIP assay for H3K4me3, in situ hybridization/expression profiling across developmental stages","journal":"Molecules and cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP for epigenetic mark and allele-specific expression analysis; single lab with two orthogonal methods establishing imprinting and its epigenetic basis","pmids":["26447138"],"is_preprint":false},{"year":2021,"finding":"QPCT expression is regulated by CCCTC-binding factor (CTCF) and promotes sunitinib resistance in renal cell carcinoma by promoting angiogenesis, with PIK3CA identified as a downstream effector. This extends the previously reported QPCT-HRAS-ERK axis for sunitinib resistance.","method":"Analysis of sunitinib-resistant vs. -responsive RCC tissues and plasma, molecular pathway analysis of CTCF-QPCT-PIK3CA axis","journal":"International journal of oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pathway placement inferred from tissue analyses without full mechanistic reconstitution of CTCF-QPCT binding or PIK3CA activation","pmids":["34036385"],"is_preprint":false},{"year":2023,"finding":"QPCT knockdown in acute myeloid leukemia (AML) cells promotes cell proliferation, inhibits apoptosis, and impairs myeloid differentiation, while QPCT upregulation by the HDAC inhibitor Apicidin mediates anti-leukemic effects. Rescue assay confirmed that QPCT depletion alleviates Apicidin's anti-leukemic effects, placing QPCT downstream of Apicidin in this pathway.","method":"QPCT knockdown/overexpression in AML cell lines, Apicidin treatment, proliferation/apoptosis/differentiation assays, rescue experiments","journal":"Cancer biology & therapy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, genetic loss-of-function with defined cellular phenotype but no molecular mechanism identified for how QPCT mediates these effects downstream of Apicidin","pmids":["37381175"],"is_preprint":false}],"current_model":"QPCT (glutaminyl cyclase) is a secretory enzyme that catalyzes pyroglutamate (pGlu) formation from N-terminal glutamine residues on substrate peptides (hormones, neuropeptides, chemokines, and amyloid peptides), with substrate binding as the key specificity-determining step and active-site residues F325, I303, and S323 critical for inhibitor interactions; it also modifies CD47 on senescent cells to suppress macrophage efferocytosis via SIRPα-CD47-SHP-1 signaling, promotes mutant huntingtin aggregation (reversible by inducing αB-crystallin upon QPCT inhibition), and stabilizes HRAS by attenuating its ubiquitination to activate ERK signaling in renal cell carcinoma."},"narrative":{"mechanistic_narrative":"QPCT is a glutaminyl cyclase that catalyzes the conversion of N-terminal glutaminyl residues into pyroglutamate (pGlu) on substrate peptides, including peptide hormones, neuropeptides, chemokines, and amyloid peptides [PMID:24886834]. Catalysis proceeds through an intermediate structurally resembling L-proline, with substrate binding — particularly the identity of the second N-terminal residue — serving as the principal specificity-determining step [PMID:8839986]. Active-site residues F325, I303, and S323 govern enzyme-inhibitor interactions, with F325 and I303 substitutions sharply reducing potency of the inhibitor PBD150 [PMID:22967026]. Beyond its canonical catalytic role, QPCT acts as a writer of a CD47 post-translational modification on senescent cells that stabilizes CD47 and suppresses macrophage efferocytosis via the SIRPα-CD47-SHP-1 axis [PMID:36459066], and QPCT inhibition reduces aggregation of mutant huntingtin and other aggregation-prone proteins by inducing the chaperone αB-crystallin [PMID:25848931]. In renal cell carcinoma, QPCT binds HRAS directly, attenuates its ubiquitination to stabilize the protein, and activates ERK signaling, with QPCT transcription driven by NF-κB (p65) [PMID:31534544]. QPCT additionally functions in cancer cell phenotypes including sunitinib resistance and myeloid differentiation [PMID:34036385, PMID:37381175].","teleology":[{"year":1996,"claim":"Established the core catalytic activity and specificity logic of glutaminyl cyclase, defining how the enzyme selects and converts N-terminal glutaminyl peptides.","evidence":"In vitro enzyme kinetics with systematic substrate and inhibitor panels using papaya latex QC","pmids":["8839986"],"confidence":"Medium","gaps":["Single study on a non-human (papaya) ortholog","Physiological human substrates not defined here","No structural model of the active site"]},{"year":2012,"claim":"Defined the human QC active-site residues responsible for inhibitor binding, providing the molecular basis for rational inhibitor design.","evidence":"Site-directed mutagenesis of human QC with inhibitor potency readouts and semi-empirical QC/MM calculations","pmids":["22967026"],"confidence":"Medium","gaps":["Residue roles defined for inhibitor PBD150, not for natural substrates","No co-crystal structure","Single lab"]},{"year":2014,"claim":"Mapped QPCT/isoQC enzymatic activity across brain regions and tied the enzyme to pGlu modification of hormones, neuropeptides, chemokines, and pathogenic amyloid peptides.","evidence":"Enzymatic activity assays and immunohistochemistry across nine mouse strains and brain regions","pmids":["24886834"],"confidence":"Medium","gaps":["Does not separate QPCT from isoQC contributions in all regions functionally","Causal link to neurodegeneration not tested here","Human brain not assessed"]},{"year":2015,"claim":"Connected QPCT activity to protein aggregation pathology, showing that inhibiting QPCT suppresses mutant huntingtin toxicity via chaperone induction.","evidence":"siRNA screen in human cells with genetic validation in Drosophila and zebrafish HD models, plus in silico inhibitor design","pmids":["25848931"],"confidence":"High","gaps":["Mechanistic link between QC catalysis and αB-crystallin induction not fully resolved","Direct QPCT substrate driving the effect not identified","Effect in mammalian HD disease models not shown"]},{"year":2015,"claim":"Revealed genomic imprinting and epigenetic control of Qpct, indicating dosage-sensitive developmental regulation distinct from its enzymatic function.","evidence":"Allele-specific expression analysis and ChIP for H3K4me3 with developmental expression profiling in mice","pmids":["26447138"],"confidence":"Medium","gaps":["Functional consequence of imprinting for QPCT activity unknown","Mouse-specific; human conservation untested","No link to enzymatic phenotypes"]},{"year":2019,"claim":"Identified a non-enzymatic protein-stabilizing role for QPCT in cancer, where direct HRAS binding attenuates ubiquitination to drive ERK signaling, plus its NF-κB-driven transcriptional control.","evidence":"Proteome microarray, reciprocal Co-IP, ubiquitination assay, ChIP, and knockdown/overexpression with ERK readout in RCC cells","pmids":["31534544"],"confidence":"Medium","gaps":["Whether HRAS stabilization requires QC catalytic activity is unresolved","Single lab","Direct ubiquitination mechanism not fully reconstituted"]},{"year":2021,"claim":"Extended QPCT's oncogenic role to sunitinib resistance via a CTCF-QPCT-PIK3CA angiogenic axis in RCC.","evidence":"Analysis of sunitinib-resistant vs. -responsive RCC tissues and plasma with pathway analysis","pmids":["34036385"],"confidence":"Low","gaps":["CTCF-QPCT binding and PIK3CA activation not mechanistically reconstituted","Pathway inferred from tissue correlation","Single lab"]},{"year":2022,"claim":"Established QPCT/L as a writer of a CD47 modification that controls innate immune recognition of senescent cells through the SIRPα-CD47-SHP-1 axis.","evidence":"Direct contact efferocytosis assays with QPCT/L inhibition and pathway interference in senescent cell models in vitro and in vivo","pmids":["36459066"],"confidence":"Medium","gaps":["The CD47 modification itself was not reconstituted in vitro","Direct identification of the modified residue/pGlu mark not shown","Single lab"]},{"year":2023,"claim":"Implicated QPCT in myeloid differentiation and as a downstream effector of an HDAC inhibitor's anti-leukemic action.","evidence":"QPCT knockdown/overexpression and rescue in AML cell lines with Apicidin treatment and proliferation/apoptosis/differentiation assays","pmids":["37381175"],"confidence":"Low","gaps":["No molecular mechanism for how QPCT mediates these effects","Whether catalytic activity is required is untested","Single lab"]},{"year":null,"claim":"Whether QPCT's diverse non-canonical roles (CD47 modification, HRAS stabilization, huntingtin aggregation, leukemic differentiation) all depend on its glutaminyl cyclase catalytic activity, and the identity of the relevant physiological substrates, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No direct demonstration that catalysis underlies the CD47 or HRAS effects","Endogenous human substrates largely undefined","No structural model linking active site to specific peptide targets"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[3,5]},{"term_id":"GO:0016853","term_label":"isomerase activity","supporting_discovery_ids":[3]}],"localization":[],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[3,5]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2]}],"complexes":[],"partners":["HRAS"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q16769","full_name":"Glutaminyl-peptide cyclotransferase","aliases":["Glutaminyl cyclase","QC","sQC","Glutaminyl-tRNA cyclotransferase","Glutamyl cyclase","EC"],"length_aa":361,"mass_kda":40.9,"function":"Responsible for the biosynthesis of pyroglutamyl peptides. Has a bias against acidic and tryptophan residues adjacent to the N-terminal glutaminyl residue and a lack of importance of chain length after the second residue. Also catalyzes N-terminal pyroglutamate formation. In vitro, catalyzes pyroglutamate formation of N-terminally truncated form of APP amyloid-beta peptides [Glu-3]-amyloid-beta. May be involved in the N-terminal pyroglutamate formation of several amyloid-related plaque-forming peptides","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q16769/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/QPCT","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/QPCT","total_profiled":1310},"omim":[{"mim_id":"621526","title":"GLUTAMINYL-PEPTIDE CYCLOTRANSFERASE-LIKE PROTEIN; QPCTL","url":"https://www.omim.org/entry/621526"},{"mim_id":"607065","title":"GLUTAMINYL-PEPTIDE CYCLOTRANSFERASE; QPCT","url":"https://www.omim.org/entry/607065"},{"mim_id":"104760","title":"AMYLOID BETA A4 PRECURSOR PROTEIN; APP","url":"https://www.omim.org/entry/104760"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"adrenal gland","ntpm":162.3},{"tissue":"epididymis","ntpm":98.2}],"url":"https://www.proteinatlas.org/search/QPCT"},"hgnc":{"alias_symbol":["QC","GCT"],"prev_symbol":[]},"alphafold":{"accession":"Q16769","domains":[{"cath_id":"3.40.630.10","chopping":"38-358","consensus_level":"high","plddt":97.5869,"start":38,"end":358}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q16769","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q16769-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q16769-F1-predicted_aligned_error_v6.png","plddt_mean":92.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=QPCT","jax_strain_url":"https://www.jax.org/strain/search?query=QPCT"},"sequence":{"accession":"Q16769","fasta_url":"https://rest.uniprot.org/uniprotkb/Q16769.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q16769/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q16769"}},"corpus_meta":[{"pmid":"27458135","id":"PMC_27458135","title":"mito-QC illuminates mitophagy and mitochondrial architecture in vivo.","date":"2016","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/27458135","citation_count":427,"is_preprint":false},{"pmid":"9037047","id":"PMC_9037047","title":"Triplet repeat polymorphism in the transmembrane region of the MICA gene: a strong association of six GCT repetitions with Behçet disease.","date":"1997","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/9037047","citation_count":338,"is_preprint":false},{"pmid":"8464127","id":"PMC_8464127","title":"Relationship between parental trinucleotide GCT repeat length and severity of myotonic dystrophy in offspring.","date":"1993","source":"JAMA","url":"https://pubmed.ncbi.nlm.nih.gov/8464127","citation_count":163,"is_preprint":false},{"pmid":"29048505","id":"PMC_29048505","title":"Outcome of patients with intracranial non-germinomatous germ cell tumors-lessons from the SIOP-CNS-GCT-96 trial.","date":"2017","source":"Neuro-oncology","url":"https://pubmed.ncbi.nlm.nih.gov/29048505","citation_count":163,"is_preprint":false},{"pmid":"8155902","id":"PMC_8155902","title":"The granular convoluted tubule (GCT) cell of rodent submandibular glands.","date":"1994","source":"Microscopy research and technique","url":"https://pubmed.ncbi.nlm.nih.gov/8155902","citation_count":152,"is_preprint":false},{"pmid":"1407566","id":"PMC_1407566","title":"Anticipation in myotonic dystrophy. 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Complex relationships between clinical findings and structure of the GCT repeat.","date":"1992","source":"Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/1407566","citation_count":134,"is_preprint":false},{"pmid":"6968234","id":"PMC_6968234","title":"The fractionation, characterization, and subcellular localization of colony-stimulating activities released by the human monocyte-like cell line, GCT.","date":"1980","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/6968234","citation_count":92,"is_preprint":false},{"pmid":"21736653","id":"PMC_21736653","title":"OsIAA23-mediated auxin signaling defines postembryonic maintenance of QC in rice.","date":"2011","source":"The Plant journal : for cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/21736653","citation_count":89,"is_preprint":false},{"pmid":"10725100","id":"PMC_10725100","title":"Solution structure of an LNA hybridized to DNA: NMR study of the d(CT(L)GCT(L)T(L)CT(L)GC):d(GCAGAAGCAG) duplex containing four locked nucleotides.","date":"2000","source":"Bioconjugate chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10725100","citation_count":88,"is_preprint":false},{"pmid":"36459066","id":"PMC_36459066","title":"Senescent cells suppress macrophage-mediated corpse removal via upregulation of the CD47-QPCT/L axis.","date":"2022","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/36459066","citation_count":85,"is_preprint":false},{"pmid":"15525219","id":"PMC_15525219","title":"QA/QC: challenges and pitfalls facing the microarray community and regulatory agencies.","date":"2004","source":"Expert review of molecular diagnostics","url":"https://pubmed.ncbi.nlm.nih.gov/15525219","citation_count":78,"is_preprint":false},{"pmid":"25848931","id":"PMC_25848931","title":"siRNA screen identifies QPCT as a druggable target for Huntington's disease.","date":"2015","source":"Nature chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/25848931","citation_count":74,"is_preprint":false},{"pmid":"9151375","id":"PMC_9151375","title":"Benign giant cell tumor of bone with osteosarcomatous transformation (\"dedifferentiated\" primary malignant GCT): report of two cases.","date":"1997","source":"Skeletal radiology","url":"https://pubmed.ncbi.nlm.nih.gov/9151375","citation_count":71,"is_preprint":false},{"pmid":"33685343","id":"PMC_33685343","title":"Mt-Keima detects PINK1-PRKN mitophagy in vivo with greater sensitivity than mito-QC.","date":"2021","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/33685343","citation_count":62,"is_preprint":false},{"pmid":"6975643","id":"PMC_6975643","title":"Hydrophobic adsorption chromatography of colony-stimulating activities and erythroid-enhancing activity from the human monocyte-like cell line, GCT.","date":"1981","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/6975643","citation_count":51,"is_preprint":false},{"pmid":"33533276","id":"PMC_33533276","title":"2020 White Paper on Recent Issues in Bioanalysis: Vaccine Assay Validation, qPCR Assay Validation, QC for CAR-T Flow Cytometry, NAb Assay Harmonization and ELISpot Validation (Part 3 - 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Senescent cell-mediated efferocytosis suppression (SCES) was reversible by interfering with QPCT/L activity, establishing QPCT as a writer of a CD47 post-translational modification that regulates innate immune recognition.\",\n      \"method\": \"Direct contact assays, QPCT/L inhibition, SIRPα-CD47-SHP-1 pathway interference, in vitro and in vivo senescent cell models\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional rescue by QPCT/L inhibition with defined pathway placement (SIRPα-CD47-SHP-1), single lab, multiple orthogonal approaches but no in vitro reconstitution of the modification itself\",\n      \"pmids\": [\"36459066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"QPCT inhibition reduces mutant huntingtin (HTT) aggregation and toxicity by inducing upregulation of the molecular chaperone αB-crystallin, and this mechanism also reduces aggregation of diverse proteins. New QPCT inhibitors generated by in silico methods and in vitro screening rescued HD-related phenotypes in cell, Drosophila, and zebrafish models.\",\n      \"method\": \"siRNA screen in human cells, Drosophila genetic validation, zebrafish HD models, αB-crystallin induction assays, in silico inhibitor design followed by in vitro screening\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — independently validated across multiple model organisms (cell, fly, zebrafish), multiple orthogonal methods including genetic knockdown and pharmacological inhibition, defined molecular mechanism (αB-crystallin induction)\",\n      \"pmids\": [\"25848931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"QPCT binds directly to HRAS and attenuates HRAS ubiquitination, thereby increasing HRAS protein stability and leading to activation of the ERK pathway in renal cell carcinoma cells. NF-κB (p65) positively regulates QPCT transcription by binding to the QPCT promoter, and this binding is blocked by promoter hypermethylation.\",\n      \"method\": \"Human proteome microarray to identify QPCT-interacting proteins, co-immunoprecipitation, confocal laser microscopy, ChIP assay, ubiquitination assay, QPCT knockdown/overexpression with ERK pathway readout\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and proteome microarray for binding, ubiquitination assay for mechanism, ChIP for upstream regulation; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"31534544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Glutamine cyclotransferase (QC, QPCT) catalyzes pyroglutamate formation from N-terminal glutaminyl residues in peptides. The second amino acid residue in N-terminal glutaminyl peptides significantly accelerates the reaction, while the third residue provides no further rate enhancement. Substrate binding is the main specificity-determining step. Proline derivatives and N-terminal proline-containing dipeptides inhibit QC activity, consistent with a reaction mechanism involving intermediates structurally similar to L-proline.\",\n      \"method\": \"In vitro enzyme kinetics with systematic substrate and inhibitor specificity testing using papaya latex QC\",\n      \"journal\": \"Biological chemistry Hoppe-Seyler\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro biochemical assay with systematic substrate panel establishing catalytic mechanism, but single study on non-human (papaya) ortholog\",\n      \"pmids\": [\"8839986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Site-directed mutagenesis of human QC (QPCT) at residues F325, I303, and S323 defined key interactions between the enzyme and the inhibitor PBD150 in solution: replacement of F325 or I303 with alanine/asparagine caused ~800-fold reduction in inhibitor potency, while replacement of S323 with alanine or valine caused ~20-fold increased inhibitor activity, establishing these residues as critical for the enzyme-inhibitor binding site.\",\n      \"method\": \"Site-directed mutagenesis of human QC, in vitro enzyme-inhibitor activity assays, semi-empirical QC/MM calculations\",\n      \"journal\": \"Chemical biology & drug design\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — active-site mutagenesis with quantitative inhibitor potency readout and computational validation; single lab but multiple mutants tested with orthogonal computational support\",\n      \"pmids\": [\"22967026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"QC (QPCT) and its isoenzyme isoQC are expressed throughout the mouse brain with region-specific and strain-specific patterns. Enzymatic QC/isoQC activity is highest in ventral brain, followed by cortex and hippocampus. In cortex, activity arises predominantly from isoQC expression. Both enzymes catalyze pyroglutamate formation from glutamine precursors at the N-terminus of peptide hormones, neuropeptides, and chemokines, and QC is also involved in pathogenic pGlu modification of amyloid peptides in neurodegeneration.\",\n      \"method\": \"Enzymatic activity assays and immunohistochemistry with specific antibodies across nine mouse strains and multiple brain regions; unbiased stereology for cell counting\",\n      \"journal\": \"International journal of developmental neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct enzymatic activity measurements combined with immunohistochemistry across multiple strains; localization tied to functional enzyme activity\",\n      \"pmids\": [\"24886834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Qpct is a maternally imprinted gene in mice (expressed from the maternal allele only in placenta). ChIP assay demonstrated that histone H3K4me3 modification is associated with maternal activation of Qpct expression. Qpct is expressed during early embryonic development in brain regions and shows peak expression in the labyrinth layer of the placenta at E15.5.\",\n      \"method\": \"Allele-specific expression analysis, ChIP assay for H3K4me3, in situ hybridization/expression profiling across developmental stages\",\n      \"journal\": \"Molecules and cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP for epigenetic mark and allele-specific expression analysis; single lab with two orthogonal methods establishing imprinting and its epigenetic basis\",\n      \"pmids\": [\"26447138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"QPCT expression is regulated by CCCTC-binding factor (CTCF) and promotes sunitinib resistance in renal cell carcinoma by promoting angiogenesis, with PIK3CA identified as a downstream effector. This extends the previously reported QPCT-HRAS-ERK axis for sunitinib resistance.\",\n      \"method\": \"Analysis of sunitinib-resistant vs. -responsive RCC tissues and plasma, molecular pathway analysis of CTCF-QPCT-PIK3CA axis\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pathway placement inferred from tissue analyses without full mechanistic reconstitution of CTCF-QPCT binding or PIK3CA activation\",\n      \"pmids\": [\"34036385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"QPCT knockdown in acute myeloid leukemia (AML) cells promotes cell proliferation, inhibits apoptosis, and impairs myeloid differentiation, while QPCT upregulation by the HDAC inhibitor Apicidin mediates anti-leukemic effects. Rescue assay confirmed that QPCT depletion alleviates Apicidin's anti-leukemic effects, placing QPCT downstream of Apicidin in this pathway.\",\n      \"method\": \"QPCT knockdown/overexpression in AML cell lines, Apicidin treatment, proliferation/apoptosis/differentiation assays, rescue experiments\",\n      \"journal\": \"Cancer biology & therapy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, genetic loss-of-function with defined cellular phenotype but no molecular mechanism identified for how QPCT mediates these effects downstream of Apicidin\",\n      \"pmids\": [\"37381175\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"QPCT (glutaminyl cyclase) is a secretory enzyme that catalyzes pyroglutamate (pGlu) formation from N-terminal glutamine residues on substrate peptides (hormones, neuropeptides, chemokines, and amyloid peptides), with substrate binding as the key specificity-determining step and active-site residues F325, I303, and S323 critical for inhibitor interactions; it also modifies CD47 on senescent cells to suppress macrophage efferocytosis via SIRPα-CD47-SHP-1 signaling, promotes mutant huntingtin aggregation (reversible by inducing αB-crystallin upon QPCT inhibition), and stabilizes HRAS by attenuating its ubiquitination to activate ERK signaling in renal cell carcinoma.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"QPCT is a glutaminyl cyclase that catalyzes the conversion of N-terminal glutaminyl residues into pyroglutamate (pGlu) on substrate peptides, including peptide hormones, neuropeptides, chemokines, and amyloid peptides [#5]. Catalysis proceeds through an intermediate structurally resembling L-proline, with substrate binding — particularly the identity of the second N-terminal residue — serving as the principal specificity-determining step [#3]. Active-site residues F325, I303, and S323 govern enzyme-inhibitor interactions, with F325 and I303 substitutions sharply reducing potency of the inhibitor PBD150 [#4]. Beyond its canonical catalytic role, QPCT acts as a writer of a CD47 post-translational modification on senescent cells that stabilizes CD47 and suppresses macrophage efferocytosis via the SIRPα-CD47-SHP-1 axis [#0], and QPCT inhibition reduces aggregation of mutant huntingtin and other aggregation-prone proteins by inducing the chaperone αB-crystallin [#1]. In renal cell carcinoma, QPCT binds HRAS directly, attenuates its ubiquitination to stabilize the protein, and activates ERK signaling, with QPCT transcription driven by NF-κB (p65) [#2]. QPCT additionally functions in cancer cell phenotypes including sunitinib resistance and myeloid differentiation [#7, #8].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established the core catalytic activity and specificity logic of glutaminyl cyclase, defining how the enzyme selects and converts N-terminal glutaminyl peptides.\",\n      \"evidence\": \"In vitro enzyme kinetics with systematic substrate and inhibitor panels using papaya latex QC\",\n      \"pmids\": [\"8839986\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single study on a non-human (papaya) ortholog\", \"Physiological human substrates not defined here\", \"No structural model of the active site\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined the human QC active-site residues responsible for inhibitor binding, providing the molecular basis for rational inhibitor design.\",\n      \"evidence\": \"Site-directed mutagenesis of human QC with inhibitor potency readouts and semi-empirical QC/MM calculations\",\n      \"pmids\": [\"22967026\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Residue roles defined for inhibitor PBD150, not for natural substrates\", \"No co-crystal structure\", \"Single lab\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Mapped QPCT/isoQC enzymatic activity across brain regions and tied the enzyme to pGlu modification of hormones, neuropeptides, chemokines, and pathogenic amyloid peptides.\",\n      \"evidence\": \"Enzymatic activity assays and immunohistochemistry across nine mouse strains and brain regions\",\n      \"pmids\": [\"24886834\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not separate QPCT from isoQC contributions in all regions functionally\", \"Causal link to neurodegeneration not tested here\", \"Human brain not assessed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Connected QPCT activity to protein aggregation pathology, showing that inhibiting QPCT suppresses mutant huntingtin toxicity via chaperone induction.\",\n      \"evidence\": \"siRNA screen in human cells with genetic validation in Drosophila and zebrafish HD models, plus in silico inhibitor design\",\n      \"pmids\": [\"25848931\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic link between QC catalysis and αB-crystallin induction not fully resolved\", \"Direct QPCT substrate driving the effect not identified\", \"Effect in mammalian HD disease models not shown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Revealed genomic imprinting and epigenetic control of Qpct, indicating dosage-sensitive developmental regulation distinct from its enzymatic function.\",\n      \"evidence\": \"Allele-specific expression analysis and ChIP for H3K4me3 with developmental expression profiling in mice\",\n      \"pmids\": [\"26447138\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of imprinting for QPCT activity unknown\", \"Mouse-specific; human conservation untested\", \"No link to enzymatic phenotypes\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified a non-enzymatic protein-stabilizing role for QPCT in cancer, where direct HRAS binding attenuates ubiquitination to drive ERK signaling, plus its NF-κB-driven transcriptional control.\",\n      \"evidence\": \"Proteome microarray, reciprocal Co-IP, ubiquitination assay, ChIP, and knockdown/overexpression with ERK readout in RCC cells\",\n      \"pmids\": [\"31534544\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether HRAS stabilization requires QC catalytic activity is unresolved\", \"Single lab\", \"Direct ubiquitination mechanism not fully reconstituted\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended QPCT's oncogenic role to sunitinib resistance via a CTCF-QPCT-PIK3CA angiogenic axis in RCC.\",\n      \"evidence\": \"Analysis of sunitinib-resistant vs. -responsive RCC tissues and plasma with pathway analysis\",\n      \"pmids\": [\"34036385\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"CTCF-QPCT binding and PIK3CA activation not mechanistically reconstituted\", \"Pathway inferred from tissue correlation\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established QPCT/L as a writer of a CD47 modification that controls innate immune recognition of senescent cells through the SIRPα-CD47-SHP-1 axis.\",\n      \"evidence\": \"Direct contact efferocytosis assays with QPCT/L inhibition and pathway interference in senescent cell models in vitro and in vivo\",\n      \"pmids\": [\"36459066\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The CD47 modification itself was not reconstituted in vitro\", \"Direct identification of the modified residue/pGlu mark not shown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Implicated QPCT in myeloid differentiation and as a downstream effector of an HDAC inhibitor's anti-leukemic action.\",\n      \"evidence\": \"QPCT knockdown/overexpression and rescue in AML cell lines with Apicidin treatment and proliferation/apoptosis/differentiation assays\",\n      \"pmids\": [\"37381175\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No molecular mechanism for how QPCT mediates these effects\", \"Whether catalytic activity is required is untested\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether QPCT's diverse non-canonical roles (CD47 modification, HRAS stabilization, huntingtin aggregation, leukemic differentiation) all depend on its glutaminyl cyclase catalytic activity, and the identity of the relevant physiological substrates, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct demonstration that catalysis underlies the CD47 or HRAS effects\", \"Endogenous human substrates largely undefined\", \"No structural model linking active site to specific peptide targets\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [3, 5]},\n      {\"term_id\": \"GO:0016853\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [3, 5]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"HRAS\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}