{"gene":"METAP2","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":1997,"finding":"Fumagillin covalently and selectively binds and inhibits the metalloprotease MetAP-2 (methionine aminopeptidase 2); this binding is highly specific as fumagillin fails to inhibit the related MetAP-1 in vivo. In the absence of MetAP-1, MetAP-2 function is essential for vegetative growth in yeast.","method":"Affinity purification of fumagillin-binding protein from mammalian cells, identification as MetAP-2, in vivo yeast selectivity assay (MetAP-1 vs MetAP-2)","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — covalent binding demonstrated by biochemical purification and in vivo yeast genetics, replicated across multiple subsequent studies","pmids":["9177176"],"is_preprint":false},{"year":2011,"finding":"MetAP-2 performs N-terminal methionine excision (NME) on the small G protein Rab37 as a specific substrate; accumulation of unprocessed (Met-retaining) Rab37 upon MetAP-2 inhibition suppresses Wnt planar cell polarity (PCP) signaling. A Rab37 point mutant resistant to NME phenocopies MetAP-2 inhibition on Wnt PCP-dependent processes, establishing Rab37 as the downstream effector.","method":"Substrate identification via proteomic N-terminus profiling; Rab37 point mutant (NME-resistant) expression phenocopy assay; TNP-470 inhibition of MetAP-2 in endothelial cells","journal":"Chemistry & biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal substrate identification combined with mutant phenocopy experiment in two orthogonal systems, single lab","pmids":["22035799"],"is_preprint":false},{"year":2016,"finding":"Both MetAP1 and MetAP2 are required in vivo for NME of M[VT]X-type substrates (and possibly M[G]X targets); cell sensitivity to fumagillin-mediated MetAP2 inhibition correlates with the ability to modulate glutathione homeostasis, and MetAP1 protein levels modulate cellular responsiveness to fumagillin.","method":"Large-scale N-terminus profiling (N-terminomics) in fumagillin-sensitive and -insensitive cell lines; proteo-transcriptomic analysis; glutathione status measurement","journal":"Oncotarget","confidence":"High","confidence_rationale":"Tier 1 / Moderate — global N-terminome profiling across multiple cell lines with two orthogonal methods (N-terminomics + proteo-transcriptomics), single lab","pmids":["27542228"],"is_preprint":false},{"year":2016,"finding":"Spiroepoxide-containing MetAP2 inhibitors covalently modify His231 in the MetAP2 active site via ring-opening of the spiroepoxide, as revealed by X-ray crystallography. Inhibitors with the same relative/absolute stereoconfiguration as fumagillin show significantly higher activity. Inhibition of MetAP2 alters N-terminal processing of 14-3-3-γ.","method":"X-ray crystallography of inhibitor-MetAP2 complex; biochemical enzymatic assays against three MetAP isoforms; cell proliferation assays; N-terminal processing assay for 14-3-3-γ","journal":"ACS chemical biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with covalent modification site identified, corroborated by stereochemistry SAR and cellular substrate processing, single lab","pmids":["26686773"],"is_preprint":false},{"year":2010,"finding":"p67/MetAP2 directly binds ERK1/2 MAP kinases and inhibits their activity both in vitro and in vivo; ectopic expression of p67/MetAP2 in oncogenic K-RasV12-transformed NIH3T3 fibroblasts suppresses their transformed phenotype in culture and in athymic nude mice, while siRNA knockdown of p67/MetAP2 activates ERK1/2.","method":"Co-immunoprecipitation and in vitro kinase assay; ectopic overexpression and siRNA knockdown; xenograft tumor model in athymic mice","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction (Co-IP + in vitro kinase inhibition) combined with genetic loss-of-function and in vivo rescue, single lab","pmids":["21033716"],"is_preprint":false},{"year":2021,"finding":"MetAP2 cleaves the initiator methionine from both α-globin and βS-globin; kinetic studies show βS-globin is a fivefold better substrate than α-globin. MetAP2 inhibition or knockdown leads to retention of N-terminal iMet (and acetylated iMet) on both globins, increasing hemoglobin S oxygen affinity and delaying HbS polymerization under hypoxia. Crystal structures of modified HbS variants show stabilization of the high-O2-affinity R2 state.","method":"In vitro kinetic enzymatic assays; MetAP2 knockdown in erythroid progenitor cells; MetAP2 inhibitor treatment of Townes SCD mice; crystal structure of modified HbS; blood rheology assay","journal":"Blood advances","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinetics + crystal structure + in vivo mouse model + cellular knockdown with multiple orthogonal readouts, single study","pmids":["33661300"],"is_preprint":false},{"year":2006,"finding":"MetAP-2 inhibition by PPI-2458 (an irreversible fumagillin-class inhibitor) arrests endothelial cell growth in G1 and inhibits B16F10 melanoma cell proliferation in vitro; in vivo tumor growth inhibition directly correlates with the degree of irreversible MetAP-2 enzyme inhibition (up to 80% inhibition at 100 mg/kg).","method":"Pharmacodynamic assay measuring uninhibited MetAP-2 in tumor tissue; cell cycle analysis; in vivo xenograft tumor model with dose-response correlation","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct pharmacodynamic correlation between enzyme inhibition and anti-proliferative/antitumor effect with dose-response, single lab","pmids":["16525646"],"is_preprint":false},{"year":2005,"finding":"MetAP2 inhibition by fumagillin-class compounds (IDR-803/804/805, CKD-732) causes G1 cell cycle arrest and intracellular accumulation of p21(WAF1/Cip1) in endothelial cells, and induces apoptosis at higher concentrations.","method":"Cell cycle analysis (FACS); p21 western blot; apoptosis assay in HUVEC and SNU-398 cells","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell cycle and molecular marker analyses across multiple inhibitors and cell types, single lab","pmids":["15523682"],"is_preprint":false},{"year":2004,"finding":"The MetAP-2 enzymatic inhibitory activity of reversible triazole-based inhibitors is dependent on the divalent metal cofactor: compounds identified using cobalt(II)-activated MetAP-2 are ~40-fold less potent against manganese-activated MetAP-2, and these reversible inhibitors fail to inhibit endothelial cell proliferation in cell-based assays.","method":"Biochemical enzymatic assay with cobalt vs manganese cofactor substitution; HUVEC proliferation assay; aortic ring explant angiogenesis model","journal":"Angiogenesis","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with cofactor swap and multiple cell-based assays, single lab","pmids":["15516829"],"is_preprint":false},{"year":2019,"finding":"MetAP2 inhibition in brown adipocytes enhances norepinephrine-induced lipolysis and energy expenditure, and prolongs β-adrenergic-stimulated UCP1 gene expression in norepinephrine-desensitized brown adipocytes, indicating direct action on β-adrenergic signaling in this cell type.","method":"Metabolomic analysis of brown adipose tissue in DIO mice; lipolysis and energy expenditure assays in brown adipocytes; UCP1 gene expression measurement; multiple chemical scaffolds tested","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — metabolomics + cell-based functional assays + multiple inhibitor scaffolds, single lab","pmids":["31048375"],"is_preprint":false},{"year":2020,"finding":"CHD1L acts upstream of METAP2, regulating its expression; ectopic CHD1L overexpression increases METAP2 protein levels and promotes epithelial ovarian cancer cell invasion/metastasis, while CHD1L knockdown reduces both METAP2 expression and cell invasion.","method":"Real-time PCR, western blotting, CHD1L overexpression/shRNA knockdown in ovarian cancer cell lines; invasion assay","journal":"International journal of medical sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — expression correlation with functional assay but no direct mechanistic link between CHD1L and METAP2 transcriptional regulation established, single lab","pmids":["32922205"],"is_preprint":false},{"year":2026,"finding":"SNHG5 (lncRNA) acts as a competitive endogenous RNA (ceRNA) for miR-377-3p, thereby upregulating METAP2 expression; elevated METAP2 increases IL-8 secretion and endothelial apoptosis in sepsis-induced coronary artery endothelial cells. Silencing METAP2 reduces IL-8 secretion and apoptosis.","method":"Dual-luciferase reporter assay; loss-of-function/gain-of-function assays; rescue experiments with miR-377-3p mimics/inhibitors; cecal ligation and puncture mouse model","journal":"Mediators of inflammation","confidence":"Low","confidence_rationale":"Tier 3 / Weak — ceRNA mechanism validated by luciferase assay and rescue experiments but the direct catalytic role of METAP2 in IL-8 secretion is not mechanistically resolved, single lab","pmids":["41769044"],"is_preprint":false},{"year":2024,"finding":"MetAP2 co-translationally cleaves the N-terminal methionine preceding second-position threonine and valine residues, thereby exposing position-3 arginine or lysine residues that are recognized exclusively by the E3 ligase UBR4 (but not UBR1 or UBR2) to trigger protein degradation via a new Arg/N-degron pathway.","method":"Reporter assays for N-degron activity; CRISPR-Cas9 knockout of UBR4, UBR1, UBR2; MetAP2 inhibitor treatment; bioinformatic identification of endogenous substrates","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO of multiple N-recognins with reporter assays and bioinformatic validation, preprint not yet peer-reviewed","pmids":["bio_10.1101_2024.10.03.616566"],"is_preprint":true},{"year":2026,"finding":"MetAP2 inhibition by nitroxoline analogs activates ATF4-mediated integrated stress responses through non-canonical mTORC1 signaling, implicating MetAP2 protein processing in mTORC1 nutrient sensing.","method":"In vitro MetAP2 enzymatic inhibition assay; cancer cell proliferation assay; ATF4 reporter assay; mTORC1 pathway analysis","journal":"Bioorganic & medicinal chemistry letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — cellular mechanistic assays showing ATF4 activation and mTORC1 involvement but pathway placement is partially inferential, single lab","pmids":["41912098"],"is_preprint":false}],"current_model":"METAP2 is a cobalt/manganese-dependent metalloprotease that co-translationally cleaves the initiator methionine from nascent proteins (N-terminal methionine excision, NME), acting on substrates including Rab37, α-globin, βS-globin, and proteins with M[VT/G]X N-termini in concert with MetAP1; it is selectively and covalently inhibited by fumagillin (via His231 in the active site), which blocks angiogenesis, induces G1 arrest with p21 accumulation, and suppresses tumor growth, while additionally MetAP2 directly binds and inhibits ERK1/2 MAP kinases and, upon N-terminal methionine removal, generates position-3 Arg/Lys degrons recognized exclusively by the E3 ligase UBR4 to mediate protein decay."},"narrative":{"mechanistic_narrative":"METAP2 is a divalent-metal-dependent methionine aminopeptidase that co-translationally removes the initiator methionine from nascent polypeptides (N-terminal methionine excision, NME), a processing step that controls the maturation, stability, and signaling competence of its substrates [PMID:22035799, PMID:27542228, PMID:33661300]. It acts in concert with MetAP1 on M[VT]X-type N-termini, and the two enzymes are jointly required for processing of these substrates in vivo, with cellular sensitivity to METAP2 inhibition tracking MetAP1 levels and glutathione homeostasis [PMID:27542228]. Characterized substrates include the small G protein Rab37, whose NME is required for Wnt planar cell polarity signaling [PMID:22035799], and both α-globin and βS-globin, where loss of methionine excision retains the iMet, raises hemoglobin S oxygen affinity, and delays HbS polymerization — with βS-globin a fivefold better substrate than α-globin [PMID:33661300]. Beyond simple maturation, METAP2-mediated methionine removal exposes position-3 Arg/Lys residues that constitute Arg/N-degrons recognized specifically by the E3 ligase UBR4 (not UBR1 or UBR2), coupling NME to regulated protein degradation [PMID:bio_10.1101_2024.10.03.616566]. METAP2 is the covalent target of fumagillin-class inhibitors, which alkylate active-site His231; this inhibition arrests endothelial cells in G1 with accumulation of p21, suppresses angiogenesis and tumor growth in proportion to the degree of enzyme inhibition, and at higher doses induces apoptosis [PMID:9177176, PMID:26686773, PMID:16525646, PMID:15523682]. Inhibitor potency is cofactor-dependent, differing markedly between cobalt- and manganese-activated enzyme [PMID:15516829]. Independent of its peptidase role, METAP2 (p67) directly binds and inhibits ERK1/2 MAP kinases, and its loss activates ERK signaling and de-represses K-Ras-driven transformation [PMID:21033716].","teleology":[{"year":1997,"claim":"Establishing the molecular target of the anti-angiogenic natural product fumagillin answered why this compound blocks endothelial growth: it identified METAP2 as a covalently inhibited, selectively targeted metalloprotease distinct from MetAP1.","evidence":"Affinity purification of the fumagillin-binding protein from mammalian cells and in vivo yeast selectivity genetics","pmids":["9177176"],"confidence":"High","gaps":["Did not define the physiological substrates whose processing matters for the anti-angiogenic phenotype","Active-site residue alkylated not yet mapped"]},{"year":2005,"claim":"Defining the cell-cycle consequence of METAP2 inhibition explained the anti-proliferative mechanism: fumagillin-class compounds drive G1 arrest with p21 accumulation and apoptosis at higher doses.","evidence":"FACS cell-cycle analysis, p21 western blot, and apoptosis assays in HUVEC and SNU-398 cells across multiple inhibitors","pmids":["15523682"],"confidence":"Medium","gaps":["Link between enzymatic NME activity and p21 induction not mechanistically resolved","Direct substrate driving G1 arrest unidentified"]},{"year":2006,"claim":"Pharmacodynamic correlation tied antitumor efficacy directly to enzyme inhibition, confirming METAP2 catalytic activity as the relevant target in vivo.","evidence":"Tumor-tissue measurement of uninhibited METAP2 with dose-response xenograft correlation using irreversible inhibitor PPI-2458","pmids":["16525646"],"confidence":"Medium","gaps":["Does not identify the substrate(s) mediating tumor growth inhibition","Endothelial vs tumor-cell-intrinsic contribution not separated"]},{"year":2004,"claim":"Showing inhibitor potency depends on the bound divalent metal clarified that METAP2 enzymatic activity is cofactor-conditioned and that reversible active-site engagement is insufficient for cellular efficacy.","evidence":"Biochemical assay with cobalt vs manganese cofactor swap plus HUVEC proliferation and aortic ring angiogenesis assays","pmids":["15516829"],"confidence":"Medium","gaps":["Physiological metal cofactor in cells not established","Why reversible inhibitors fail in cells while covalent ones succeed not fully explained"]},{"year":2010,"claim":"Identifying a direct METAP2-ERK1/2 interaction revealed a non-catalytic signaling function: METAP2 restrains MAP kinase activity and suppresses oncogenic Ras transformation.","evidence":"Co-IP and in vitro kinase assays with ectopic expression, siRNA knockdown, and xenografts in K-RasV12-transformed fibroblasts","pmids":["21033716"],"confidence":"Medium","gaps":["Whether ERK inhibition requires peptidase activity unresolved","Structural basis of the METAP2-ERK interaction unknown"]},{"year":2011,"claim":"Identifying Rab37 as an NME substrate connected METAP2 catalysis to a defined downstream pathway, showing methionine excision is required for Wnt planar cell polarity signaling.","evidence":"N-terminus proteomic profiling, an NME-resistant Rab37 mutant phenocopy, and TNP-470 inhibition in endothelial cells","pmids":["22035799"],"confidence":"High","gaps":["Generality of NME substrate dependence for other phenotypes not addressed","How retained Met disrupts Rab37 function biochemically not detailed"]},{"year":2016,"claim":"Global N-terminome profiling defined the substrate sequence rules and the cooperative requirement for MetAP1, and linked fumagillin sensitivity to MetAP1 levels and glutathione status.","evidence":"N-terminomics across fumagillin-sensitive/insensitive cell lines, proteo-transcriptomics, and glutathione measurement","pmids":["27542228"],"confidence":"High","gaps":["Mechanistic basis of the glutathione-sensitivity correlation unresolved","Division of labor between MetAP1 and MetAP2 per substrate incomplete"]},{"year":2016,"claim":"Crystallographic mapping of the covalent adduct to His231 explained inhibitor selectivity and stereochemistry, and added 14-3-3-γ as a processing target.","evidence":"X-ray crystallography of inhibitor-METAP2 complex, enzymatic assays across three MetAP isoforms, and a 14-3-3-γ N-terminal processing assay","pmids":["26686773"],"confidence":"High","gaps":["Functional consequence of altered 14-3-3-γ processing not established"]},{"year":2021,"claim":"Demonstrating METAP2 processes α- and βS-globin connected NME to hemoglobin biophysics, showing retained iMet raises HbS oxygen affinity and delays sickling polymerization.","evidence":"In vitro kinetics, erythroid progenitor knockdown, Townes SCD mouse inhibitor treatment, modified HbS crystal structures, and blood rheology","pmids":["33661300"],"confidence":"High","gaps":["Therapeutic window for selective globin modification in vivo not defined","Whether MetAP1 contributes to globin processing not tested"]},{"year":2024,"claim":"Coupling METAP2 NME to the UBR4 N-recognin established that methionine excision generates Arg/Lys position-3 degrons, defining a new branch of the Arg/N-degron pathway.","evidence":"N-degron reporter assays, CRISPR knockout of UBR4/UBR1/UBR2, METAP2 inhibitor treatment, and bioinformatic substrate prediction (preprint)","pmids":["bio_10.1101_2024.10.03.616566"],"confidence":"Medium","gaps":["Not yet peer-reviewed","Endogenous substrates degraded via this route require biochemical validation","Why UBR4 alone recognizes these degrons unexplained"]},{"year":2026,"claim":"Cellular studies linked METAP2 inhibition to ATF4-mediated integrated stress responses via non-canonical mTORC1 signaling, implicating its protein processing in nutrient sensing.","evidence":"In vitro enzymatic inhibition, ATF4 reporter, and mTORC1 pathway analysis with nitroxoline analogs","pmids":["41912098"],"confidence":"Low","gaps":["Pathway placement is partially inferential","Specific substrate connecting METAP2 to mTORC1 not identified"]},{"year":null,"claim":"It remains unresolved how METAP2's catalytic NME function and its non-catalytic ERK-binding activity are integrated, and which endogenous substrates mediate its angiogenic, metabolic, and degron-generating roles.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structure of METAP2 bound to a physiological protein substrate","Catalytic vs scaffolding contributions to phenotypes not dissected","In vivo substrate repertoire incomplete"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,2,3,5,12]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,5,8]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,2]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,2,5,12]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,1]}],"complexes":[],"partners":["METAP1","ERK1/2","UBR4","RAB37"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P50579","full_name":"Methionine aminopeptidase 2","aliases":["Initiation factor 2-associated 67 kDa glycoprotein","p67","p67eIF2","Peptidase M"],"length_aa":478,"mass_kda":52.9,"function":"Cotranslationally removes the N-terminal methionine from nascent proteins. The N-terminal methionine is often cleaved when the second residue in the primary sequence is small and uncharged (Met-Ala-, Cys, Gly, Pro, Ser, Thr, or Val). The catalytic activity of human METAP2 toward Met-Val peptides is consistently two orders of magnitude higher than that of METAP1, suggesting that it is responsible for processing proteins containing N-terminal Met-Val and Met-Thr sequences in vivo Protects eukaryotic initiation factor EIF2S1 from translation-inhibiting phosphorylation by inhibitory kinases such as EIF2AK2/PKR and EIF2AK1/HCR. Plays a critical role in the regulation of protein synthesis","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P50579/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/METAP2","classification":"Common Essential","n_dependent_lines":860,"n_total_lines":1208,"dependency_fraction":0.7119205298013245},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000111142","cell_line_id":"CID001767","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleolus_gc","grade":1},{"compartment":"nucleoplasm","grade":1}],"interactors":[{"gene":"RPL35","stoichiometry":10.0},{"gene":"RPL21","stoichiometry":10.0},{"gene":"RPL13A;RPL13A","stoichiometry":10.0},{"gene":"RPL31","stoichiometry":10.0},{"gene":"RPL13","stoichiometry":10.0},{"gene":"RPS16","stoichiometry":10.0},{"gene":"RPS28","stoichiometry":10.0},{"gene":"RPS25","stoichiometry":10.0},{"gene":"RPL27","stoichiometry":10.0},{"gene":"RPS15","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/target/CID001767","total_profiled":1310},"omim":[{"mim_id":"601870","title":"METHIONINE AMINOPEPTIDASE 2; METAP2","url":"https://www.omim.org/entry/601870"},{"mim_id":"190080","title":"MYC PROTOONCOGENE, bHLH TRANSCRIPTION FACTOR; MYC","url":"https://www.omim.org/entry/190080"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/METAP2"},"hgnc":{"alias_symbol":["MNPEP","p67","MAP2"],"prev_symbol":[]},"alphafold":{"accession":"P50579","domains":[{"cath_id":"3.90.230.10","chopping":"153-372_450-470","consensus_level":"high","plddt":98.6074,"start":153,"end":470},{"cath_id":"1.10.10.10","chopping":"380-444","consensus_level":"medium","plddt":98.3515,"start":380,"end":444}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P50579","model_url":"https://alphafold.ebi.ac.uk/files/AF-P50579-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P50579-F1-predicted_aligned_error_v6.png","plddt_mean":85.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=METAP2","jax_strain_url":"https://www.jax.org/strain/search?query=METAP2"},"sequence":{"accession":"P50579","fasta_url":"https://rest.uniprot.org/uniprotkb/P50579.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P50579/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P50579"}},"corpus_meta":[{"pmid":"9177176","id":"PMC_9177176","title":"The anti-angiogenic agent fumagillin covalently binds and inhibits the methionine aminopeptidase, MetAP-2.","date":"1997","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/9177176","citation_count":554,"is_preprint":false},{"pmid":"22229417","id":"PMC_22229417","title":"The development of MetAP-2 inhibitors in cancer treatment.","date":"2012","source":"Current medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22229417","citation_count":54,"is_preprint":false},{"pmid":"23161775","id":"PMC_23161775","title":"MicroRNA profiling in pediatric pilocytic astrocytoma reveals biologically relevant targets, including PBX3, NFIB, and METAP2.","date":"2012","source":"Neuro-oncology","url":"https://pubmed.ncbi.nlm.nih.gov/23161775","citation_count":48,"is_preprint":false},{"pmid":"10636239","id":"PMC_10636239","title":"Design and synthesis of highly potent fumagillin analogues from homology modeling for a human MetAP-2.","date":"2000","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/10636239","citation_count":46,"is_preprint":false},{"pmid":"15523682","id":"PMC_15523682","title":"Novel inhibitors targeted to methionine aminopeptidase 2 (MetAP2) strongly inhibit the growth of cancers in xenografted nude model.","date":"2005","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/15523682","citation_count":40,"is_preprint":false},{"pmid":"15516829","id":"PMC_15516829","title":"Small molecule inhibitors of methionine aminopeptidase type 2 (MetAP-2).","date":"2004","source":"Angiogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/15516829","citation_count":38,"is_preprint":false},{"pmid":"27542228","id":"PMC_27542228","title":"MetAP1 and MetAP2 drive cell selectivity for a potent anti-cancer agent in synergy, by controlling glutathione redox 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In the absence of MetAP-1, MetAP-2 function is essential for vegetative growth in yeast.\",\n      \"method\": \"Affinity purification of fumagillin-binding protein from mammalian cells, identification as MetAP-2, in vivo yeast selectivity assay (MetAP-1 vs MetAP-2)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — covalent binding demonstrated by biochemical purification and in vivo yeast genetics, replicated across multiple subsequent studies\",\n      \"pmids\": [\"9177176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MetAP-2 performs N-terminal methionine excision (NME) on the small G protein Rab37 as a specific substrate; accumulation of unprocessed (Met-retaining) Rab37 upon MetAP-2 inhibition suppresses Wnt planar cell polarity (PCP) signaling. A Rab37 point mutant resistant to NME phenocopies MetAP-2 inhibition on Wnt PCP-dependent processes, establishing Rab37 as the downstream effector.\",\n      \"method\": \"Substrate identification via proteomic N-terminus profiling; Rab37 point mutant (NME-resistant) expression phenocopy assay; TNP-470 inhibition of MetAP-2 in endothelial cells\",\n      \"journal\": \"Chemistry & biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal substrate identification combined with mutant phenocopy experiment in two orthogonal systems, single lab\",\n      \"pmids\": [\"22035799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Both MetAP1 and MetAP2 are required in vivo for NME of M[VT]X-type substrates (and possibly M[G]X targets); cell sensitivity to fumagillin-mediated MetAP2 inhibition correlates with the ability to modulate glutathione homeostasis, and MetAP1 protein levels modulate cellular responsiveness to fumagillin.\",\n      \"method\": \"Large-scale N-terminus profiling (N-terminomics) in fumagillin-sensitive and -insensitive cell lines; proteo-transcriptomic analysis; glutathione status measurement\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — global N-terminome profiling across multiple cell lines with two orthogonal methods (N-terminomics + proteo-transcriptomics), single lab\",\n      \"pmids\": [\"27542228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Spiroepoxide-containing MetAP2 inhibitors covalently modify His231 in the MetAP2 active site via ring-opening of the spiroepoxide, as revealed by X-ray crystallography. Inhibitors with the same relative/absolute stereoconfiguration as fumagillin show significantly higher activity. Inhibition of MetAP2 alters N-terminal processing of 14-3-3-γ.\",\n      \"method\": \"X-ray crystallography of inhibitor-MetAP2 complex; biochemical enzymatic assays against three MetAP isoforms; cell proliferation assays; N-terminal processing assay for 14-3-3-γ\",\n      \"journal\": \"ACS chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with covalent modification site identified, corroborated by stereochemistry SAR and cellular substrate processing, single lab\",\n      \"pmids\": [\"26686773\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"p67/MetAP2 directly binds ERK1/2 MAP kinases and inhibits their activity both in vitro and in vivo; ectopic expression of p67/MetAP2 in oncogenic K-RasV12-transformed NIH3T3 fibroblasts suppresses their transformed phenotype in culture and in athymic nude mice, while siRNA knockdown of p67/MetAP2 activates ERK1/2.\",\n      \"method\": \"Co-immunoprecipitation and in vitro kinase assay; ectopic overexpression and siRNA knockdown; xenograft tumor model in athymic mice\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction (Co-IP + in vitro kinase inhibition) combined with genetic loss-of-function and in vivo rescue, single lab\",\n      \"pmids\": [\"21033716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MetAP2 cleaves the initiator methionine from both α-globin and βS-globin; kinetic studies show βS-globin is a fivefold better substrate than α-globin. MetAP2 inhibition or knockdown leads to retention of N-terminal iMet (and acetylated iMet) on both globins, increasing hemoglobin S oxygen affinity and delaying HbS polymerization under hypoxia. Crystal structures of modified HbS variants show stabilization of the high-O2-affinity R2 state.\",\n      \"method\": \"In vitro kinetic enzymatic assays; MetAP2 knockdown in erythroid progenitor cells; MetAP2 inhibitor treatment of Townes SCD mice; crystal structure of modified HbS; blood rheology assay\",\n      \"journal\": \"Blood advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinetics + crystal structure + in vivo mouse model + cellular knockdown with multiple orthogonal readouts, single study\",\n      \"pmids\": [\"33661300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"MetAP-2 inhibition by PPI-2458 (an irreversible fumagillin-class inhibitor) arrests endothelial cell growth in G1 and inhibits B16F10 melanoma cell proliferation in vitro; in vivo tumor growth inhibition directly correlates with the degree of irreversible MetAP-2 enzyme inhibition (up to 80% inhibition at 100 mg/kg).\",\n      \"method\": \"Pharmacodynamic assay measuring uninhibited MetAP-2 in tumor tissue; cell cycle analysis; in vivo xenograft tumor model with dose-response correlation\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct pharmacodynamic correlation between enzyme inhibition and anti-proliferative/antitumor effect with dose-response, single lab\",\n      \"pmids\": [\"16525646\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"MetAP2 inhibition by fumagillin-class compounds (IDR-803/804/805, CKD-732) causes G1 cell cycle arrest and intracellular accumulation of p21(WAF1/Cip1) in endothelial cells, and induces apoptosis at higher concentrations.\",\n      \"method\": \"Cell cycle analysis (FACS); p21 western blot; apoptosis assay in HUVEC and SNU-398 cells\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell cycle and molecular marker analyses across multiple inhibitors and cell types, single lab\",\n      \"pmids\": [\"15523682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The MetAP-2 enzymatic inhibitory activity of reversible triazole-based inhibitors is dependent on the divalent metal cofactor: compounds identified using cobalt(II)-activated MetAP-2 are ~40-fold less potent against manganese-activated MetAP-2, and these reversible inhibitors fail to inhibit endothelial cell proliferation in cell-based assays.\",\n      \"method\": \"Biochemical enzymatic assay with cobalt vs manganese cofactor substitution; HUVEC proliferation assay; aortic ring explant angiogenesis model\",\n      \"journal\": \"Angiogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with cofactor swap and multiple cell-based assays, single lab\",\n      \"pmids\": [\"15516829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MetAP2 inhibition in brown adipocytes enhances norepinephrine-induced lipolysis and energy expenditure, and prolongs β-adrenergic-stimulated UCP1 gene expression in norepinephrine-desensitized brown adipocytes, indicating direct action on β-adrenergic signaling in this cell type.\",\n      \"method\": \"Metabolomic analysis of brown adipose tissue in DIO mice; lipolysis and energy expenditure assays in brown adipocytes; UCP1 gene expression measurement; multiple chemical scaffolds tested\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — metabolomics + cell-based functional assays + multiple inhibitor scaffolds, single lab\",\n      \"pmids\": [\"31048375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CHD1L acts upstream of METAP2, regulating its expression; ectopic CHD1L overexpression increases METAP2 protein levels and promotes epithelial ovarian cancer cell invasion/metastasis, while CHD1L knockdown reduces both METAP2 expression and cell invasion.\",\n      \"method\": \"Real-time PCR, western blotting, CHD1L overexpression/shRNA knockdown in ovarian cancer cell lines; invasion assay\",\n      \"journal\": \"International journal of medical sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — expression correlation with functional assay but no direct mechanistic link between CHD1L and METAP2 transcriptional regulation established, single lab\",\n      \"pmids\": [\"32922205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SNHG5 (lncRNA) acts as a competitive endogenous RNA (ceRNA) for miR-377-3p, thereby upregulating METAP2 expression; elevated METAP2 increases IL-8 secretion and endothelial apoptosis in sepsis-induced coronary artery endothelial cells. Silencing METAP2 reduces IL-8 secretion and apoptosis.\",\n      \"method\": \"Dual-luciferase reporter assay; loss-of-function/gain-of-function assays; rescue experiments with miR-377-3p mimics/inhibitors; cecal ligation and puncture mouse model\",\n      \"journal\": \"Mediators of inflammation\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — ceRNA mechanism validated by luciferase assay and rescue experiments but the direct catalytic role of METAP2 in IL-8 secretion is not mechanistically resolved, single lab\",\n      \"pmids\": [\"41769044\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MetAP2 co-translationally cleaves the N-terminal methionine preceding second-position threonine and valine residues, thereby exposing position-3 arginine or lysine residues that are recognized exclusively by the E3 ligase UBR4 (but not UBR1 or UBR2) to trigger protein degradation via a new Arg/N-degron pathway.\",\n      \"method\": \"Reporter assays for N-degron activity; CRISPR-Cas9 knockout of UBR4, UBR1, UBR2; MetAP2 inhibitor treatment; bioinformatic identification of endogenous substrates\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO of multiple N-recognins with reporter assays and bioinformatic validation, preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2024.10.03.616566\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"MetAP2 inhibition by nitroxoline analogs activates ATF4-mediated integrated stress responses through non-canonical mTORC1 signaling, implicating MetAP2 protein processing in mTORC1 nutrient sensing.\",\n      \"method\": \"In vitro MetAP2 enzymatic inhibition assay; cancer cell proliferation assay; ATF4 reporter assay; mTORC1 pathway analysis\",\n      \"journal\": \"Bioorganic & medicinal chemistry letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — cellular mechanistic assays showing ATF4 activation and mTORC1 involvement but pathway placement is partially inferential, single lab\",\n      \"pmids\": [\"41912098\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"METAP2 is a cobalt/manganese-dependent metalloprotease that co-translationally cleaves the initiator methionine from nascent proteins (N-terminal methionine excision, NME), acting on substrates including Rab37, α-globin, βS-globin, and proteins with M[VT/G]X N-termini in concert with MetAP1; it is selectively and covalently inhibited by fumagillin (via His231 in the active site), which blocks angiogenesis, induces G1 arrest with p21 accumulation, and suppresses tumor growth, while additionally MetAP2 directly binds and inhibits ERK1/2 MAP kinases and, upon N-terminal methionine removal, generates position-3 Arg/Lys degrons recognized exclusively by the E3 ligase UBR4 to mediate protein decay.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"METAP2 is a divalent-metal-dependent methionine aminopeptidase that co-translationally removes the initiator methionine from nascent polypeptides (N-terminal methionine excision, NME), a processing step that controls the maturation, stability, and signaling competence of its substrates [#1, #2, #5]. It acts in concert with MetAP1 on M[VT]X-type N-termini, and the two enzymes are jointly required for processing of these substrates in vivo, with cellular sensitivity to METAP2 inhibition tracking MetAP1 levels and glutathione homeostasis [#2]. Characterized substrates include the small G protein Rab37, whose NME is required for Wnt planar cell polarity signaling [#1], and both \\u03b1-globin and \\u03b2S-globin, where loss of methionine excision retains the iMet, raises hemoglobin S oxygen affinity, and delays HbS polymerization \\u2014 with \\u03b2S-globin a fivefold better substrate than \\u03b1-globin [#5]. Beyond simple maturation, METAP2-mediated methionine removal exposes position-3 Arg/Lys residues that constitute Arg/N-degrons recognized specifically by the E3 ligase UBR4 (not UBR1 or UBR2), coupling NME to regulated protein degradation [#12]. METAP2 is the covalent target of fumagillin-class inhibitors, which alkylate active-site His231; this inhibition arrests endothelial cells in G1 with accumulation of p21, suppresses angiogenesis and tumor growth in proportion to the degree of enzyme inhibition, and at higher doses induces apoptosis [#0, #3, #6, #7]. Inhibitor potency is cofactor-dependent, differing markedly between cobalt- and manganese-activated enzyme [#8]. Independent of its peptidase role, METAP2 (p67) directly binds and inhibits ERK1/2 MAP kinases, and its loss activates ERK signaling and de-represses K-Ras-driven transformation [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Establishing the molecular target of the anti-angiogenic natural product fumagillin answered why this compound blocks endothelial growth: it identified METAP2 as a covalently inhibited, selectively targeted metalloprotease distinct from MetAP1.\",\n      \"evidence\": \"Affinity purification of the fumagillin-binding protein from mammalian cells and in vivo yeast selectivity genetics\",\n      \"pmids\": [\"9177176\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the physiological substrates whose processing matters for the anti-angiogenic phenotype\", \"Active-site residue alkylated not yet mapped\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defining the cell-cycle consequence of METAP2 inhibition explained the anti-proliferative mechanism: fumagillin-class compounds drive G1 arrest with p21 accumulation and apoptosis at higher doses.\",\n      \"evidence\": \"FACS cell-cycle analysis, p21 western blot, and apoptosis assays in HUVEC and SNU-398 cells across multiple inhibitors\",\n      \"pmids\": [\"15523682\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Link between enzymatic NME activity and p21 induction not mechanistically resolved\", \"Direct substrate driving G1 arrest unidentified\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Pharmacodynamic correlation tied antitumor efficacy directly to enzyme inhibition, confirming METAP2 catalytic activity as the relevant target in vivo.\",\n      \"evidence\": \"Tumor-tissue measurement of uninhibited METAP2 with dose-response xenograft correlation using irreversible inhibitor PPI-2458\",\n      \"pmids\": [\"16525646\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not identify the substrate(s) mediating tumor growth inhibition\", \"Endothelial vs tumor-cell-intrinsic contribution not separated\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showing inhibitor potency depends on the bound divalent metal clarified that METAP2 enzymatic activity is cofactor-conditioned and that reversible active-site engagement is insufficient for cellular efficacy.\",\n      \"evidence\": \"Biochemical assay with cobalt vs manganese cofactor swap plus HUVEC proliferation and aortic ring angiogenesis assays\",\n      \"pmids\": [\"15516829\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological metal cofactor in cells not established\", \"Why reversible inhibitors fail in cells while covalent ones succeed not fully explained\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identifying a direct METAP2-ERK1/2 interaction revealed a non-catalytic signaling function: METAP2 restrains MAP kinase activity and suppresses oncogenic Ras transformation.\",\n      \"evidence\": \"Co-IP and in vitro kinase assays with ectopic expression, siRNA knockdown, and xenografts in K-RasV12-transformed fibroblasts\",\n      \"pmids\": [\"21033716\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ERK inhibition requires peptidase activity unresolved\", \"Structural basis of the METAP2-ERK interaction unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identifying Rab37 as an NME substrate connected METAP2 catalysis to a defined downstream pathway, showing methionine excision is required for Wnt planar cell polarity signaling.\",\n      \"evidence\": \"N-terminus proteomic profiling, an NME-resistant Rab37 mutant phenocopy, and TNP-470 inhibition in endothelial cells\",\n      \"pmids\": [\"22035799\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of NME substrate dependence for other phenotypes not addressed\", \"How retained Met disrupts Rab37 function biochemically not detailed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Global N-terminome profiling defined the substrate sequence rules and the cooperative requirement for MetAP1, and linked fumagillin sensitivity to MetAP1 levels and glutathione status.\",\n      \"evidence\": \"N-terminomics across fumagillin-sensitive/insensitive cell lines, proteo-transcriptomics, and glutathione measurement\",\n      \"pmids\": [\"27542228\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic basis of the glutathione-sensitivity correlation unresolved\", \"Division of labor between MetAP1 and MetAP2 per substrate incomplete\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Crystallographic mapping of the covalent adduct to His231 explained inhibitor selectivity and stereochemistry, and added 14-3-3-\\u03b3 as a processing target.\",\n      \"evidence\": \"X-ray crystallography of inhibitor-METAP2 complex, enzymatic assays across three MetAP isoforms, and a 14-3-3-\\u03b3 N-terminal processing assay\",\n      \"pmids\": [\"26686773\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of altered 14-3-3-\\u03b3 processing not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrating METAP2 processes \\u03b1- and \\u03b2S-globin connected NME to hemoglobin biophysics, showing retained iMet raises HbS oxygen affinity and delays sickling polymerization.\",\n      \"evidence\": \"In vitro kinetics, erythroid progenitor knockdown, Townes SCD mouse inhibitor treatment, modified HbS crystal structures, and blood rheology\",\n      \"pmids\": [\"33661300\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Therapeutic window for selective globin modification in vivo not defined\", \"Whether MetAP1 contributes to globin processing not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Coupling METAP2 NME to the UBR4 N-recognin established that methionine excision generates Arg/Lys position-3 degrons, defining a new branch of the Arg/N-degron pathway.\",\n      \"evidence\": \"N-degron reporter assays, CRISPR knockout of UBR4/UBR1/UBR2, METAP2 inhibitor treatment, and bioinformatic substrate prediction (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.10.03.616566\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Not yet peer-reviewed\", \"Endogenous substrates degraded via this route require biochemical validation\", \"Why UBR4 alone recognizes these degrons unexplained\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Cellular studies linked METAP2 inhibition to ATF4-mediated integrated stress responses via non-canonical mTORC1 signaling, implicating its protein processing in nutrient sensing.\",\n      \"evidence\": \"In vitro enzymatic inhibition, ATF4 reporter, and mTORC1 pathway analysis with nitroxoline analogs\",\n      \"pmids\": [\"41912098\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Pathway placement is partially inferential\", \"Specific substrate connecting METAP2 to mTORC1 not identified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how METAP2's catalytic NME function and its non-catalytic ERK-binding activity are integrated, and which endogenous substrates mediate its angiogenic, metabolic, and degron-generating roles.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structure of METAP2 bound to a physiological protein substrate\", \"Catalytic vs scaffolding contributions to phenotypes not dissected\", \"In vivo substrate repertoire incomplete\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 2, 3, 5, 12]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 5, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 2, 5, 12]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"MetAP1\",\n      \"ERK1/2\",\n      \"UBR4\",\n      \"Rab37\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}