{"gene":"PF3D7_1412900","run_date":"2026-09-08T14:19:07","timeline":{"discoveries":[{"year":2015,"finding":"The structure of the human SUMO E1 ubiquitin fold domain in complex with E2 (Ubc9) was solved by X-ray crystallography, and the interface guided in silico modeling, mutagenesis, and in vitro biochemical studies identifying surface residues on the P. falciparum SUMO E1 and E2 enzymes that explain species-specific E1–E2 interactions distinct from the human system.","method":"X-ray crystallography, in silico modeling, site-directed mutagenesis, in vitro biochemical assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus mutagenesis plus in vitro biochemical validation in a single rigorous study","pmids":["26697886"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2015,"finding":"The P. falciparum SUMO E2 conjugating enzyme (PF3D7_1412900, Pf-Ubc9) participates in a SUMOylation pathway that plays a protective role in the parasite's response to oxidative stress during red blood cell stages, as evidenced by susceptibility of trophozoite-stage parasites to iron-induced oxidative stress when SUMOylation is disrupted.","method":"In vitro oxidative stress assay with iron treatment; biochemical characterization of SUMOylation activity","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, single method linking SUMOylation pathway activity to oxidative stress response","pmids":["26697886"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2022,"finding":"A unidirectional cross-species interaction was demonstrated in which Pf-SUMO interacts with human E2 (Hs-Ubc9), but Hs-SUMO1 failed to interact with Pf-E2 (PF3D7_1412900). Surface-accessible aspartates of Pf-SUMO and critical N-terminal residues of Pf-Ubc9 govern the specificity of SUMO–E2 interactions; mutating Pf-Ubc9 N-terminal residues to corresponding Hs-Ubc9 residues restored electrostatic, π–π, and hydrophobic interactions enabling cross-species interaction.","method":"Biochemical and biophysical binding assays, site-directed mutagenesis","journal":"Biophysical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal biochemical/biophysical methods plus mutagenesis in a single lab study","pmids":["35331687"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"PF3D7_1412900 (Pf-Ubc9) is the SUMO E2-conjugating enzyme of P. falciparum whose interaction with the SUMO E1 activating enzyme is governed by species-specific surface residues (including critical N-terminal residues of Pf-Ubc9 and surface-accessible aspartates of Pf-SUMO), exhibits a unidirectional cross-species interaction profile distinct from the human system, and participates in a SUMOylation pathway that protects the parasite against oxidative stress during intraerythrocytic stages."},"narrative":{"mechanistic_narrative":"PF3D7_1412900 (Pf-Ubc9) is the SUMO E2-conjugating enzyme of Plasmodium falciparum, operating in a SUMOylation pathway that protects intraerythrocytic parasites against oxidative stress, as trophozoite-stage parasites become susceptible to iron-induced oxidative stress when SUMOylation is disrupted [PMID:26697886]. Its engagement with the SUMO E1 activating enzyme is governed by species-specific surface residues: structural analysis of the human SUMO E1–E2 interface guided identification of surface residues on the P. falciparum E1 and E2 enzymes that account for E1–E2 interactions distinct from the human system [PMID:26697886]. The specificity of SUMO–E2 recognition is likewise species-restricted and unidirectional — Pf-SUMO interacts with human Ubc9, but human SUMO1 fails to interact with PF3D7_1412900, a selectivity dictated by critical N-terminal residues of Pf-Ubc9 together with surface-accessible aspartates of Pf-SUMO; mutating these N-terminal residues to their human counterparts restores electrostatic, π–π, and hydrophobic contacts and enables cross-species binding [PMID:35331687]. Beyond these interaction determinants and the oxidative-stress phenotype, no further mechanistic detail for PF3D7_1412900 has been characterized in the available corpus.","teleology":[{"year":2015,"claim":"It was unknown what structural features distinguish the parasite SUMO conjugation machinery from the human system; solving the human E1–E2 interface and mapping it onto the parasite enzymes established that specific surface residues on Pf-E1 and PF3D7_1412900 underlie species-specific E1–E2 interactions.","evidence":"X-ray crystallography of the human SUMO E1–E2 complex with in silico modeling, mutagenesis, and in vitro biochemical assays on the P. falciparum enzymes","pmids":["26697886"],"confidence":"High","gaps":["No direct crystal structure of PF3D7_1412900 itself was reported","Downstream SUMO substrates conjugated by Pf-Ubc9 not identified","Functional consequence of disrupting the specific E1–E2 interface in living parasites not tested"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2015,"claim":"The cellular role of the parasite SUMOylation pathway was unclear; linking pathway activity to survival under iron-induced oxidative stress established a protective function for SUMOylation in intraerythrocytic trophozoites.","evidence":"In vitro iron-induced oxidative stress assay coupled with biochemical characterization of SUMOylation activity","pmids":["26697886"],"confidence":"Medium","gaps":["Single lab, single method linking pathway activity to the phenotype","The specific contribution of PF3D7_1412900 versus other pathway components not isolated genetically","SUMOylation targets responsible for oxidative-stress protection unknown"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2022,"claim":"Whether SUMO–E2 recognition is interchangeable across species was unresolved; demonstrating a unidirectional cross-species interaction and pinpointing the governing residues established that PF3D7_1412900 N-terminal residues and Pf-SUMO surface aspartates dictate binding specificity.","evidence":"Biochemical and biophysical binding assays with site-directed mutagenesis, including humanizing Pf-Ubc9 N-terminal residues to restore cross-species binding","pmids":["35331687"],"confidence":"Medium","gaps":["Single lab study without independent confirmation","Physiological role of the SUMO–E2 specificity in parasite biology not tested in vivo","Whether altered specificity affects substrate conjugation not addressed"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"The SUMO substrates conjugated by PF3D7_1412900 and the in vivo genetic requirement for the enzyme during the parasite life cycle remain unidentified.","evidence":"","pmids":[],"confidence":"Low","gaps":["No SUMO substrate repertoire defined for PF3D7_1412900","No genetic knockout or knockdown phenotype reported","No structural model of PF3D7_1412900 itself in complex with Pf-SUMO or Pf-E1"],"attribution":[]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":["PF-SUMO","P. FALCIPARUM SUMO E1 ACTIVATING ENZYME"],"other_free_text":["PF3D7_1412900 (Pf-Ubc9) is the SUMO E2-conjugating enzyme of P. falciparum.","Species-specific E1–E2 interaction determined by surface residues on the parasite E1 and E2 enzymes [#0].","SUMO–E2 recognition is unidirectional across species: Pf-SUMO binds human Ubc9, but human SUMO1 does not bind PF3D7_1412900; specificity set by Pf-Ubc9 N-terminal residues and Pf-SUMO surface aspartates [#2].","SUMOylation pathway involving PF3D7_1412900 is protective against iron-induced oxidative stress in trophozoite-stage parasites [#1]."]}},"prefetch_data":{},"corpus_meta":[{"pmid":"28577368","id":"PMC_28577368","title":"Inhibitors of ubiquitin E3 ligase as potential new antimalarial drug leads.","date":"2017","source":"BMC pharmacology & toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/28577368","citation_count":23,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["ubiquitin-conjugating enzyme E2"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"26697886","id":"PMC_26697886","title":"Characterization and Structural Insights into Selective E1-E2 Interactions in the Human and Plasmodium falciparum SUMO Conjugation Systems.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26697886","citation_count":14,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["ubiquitin-conjugating enzyme E2"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"35331687","id":"PMC_35331687","title":"Implications of critical node-dependent unidirectional cross-talk of Plasmodium SUMO pathway proteins.","date":"2022","source":"Biophysical journal","url":"https://pubmed.ncbi.nlm.nih.gov/35331687","citation_count":1,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PfE2"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4477,"output_tokens":1009,"usd":0.014283,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5764,"output_tokens":2227,"usd":0.042248,"stage2_stop_reason":"end_turn"},"total_usd":0.056531,"stage1_batch_id":"msgbatch_011BPjN2BL33F8cJXD1r7V7T","stage2_batch_id":"msgbatch_01Qwg6vP7qxkpL6Gsc7tajsb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"The structure of the human SUMO E1 ubiquitin fold domain in complex with E2 (Ubc9) was solved by X-ray crystallography, and the interface guided in silico modeling, mutagenesis, and in vitro biochemical studies identifying surface residues on the P. falciparum SUMO E1 and E2 enzymes that explain species-specific E1–E2 interactions distinct from the human system.\",\n      \"method\": \"X-ray crystallography, in silico modeling, site-directed mutagenesis, in vitro biochemical assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus mutagenesis plus in vitro biochemical validation in a single rigorous study\",\n      \"pmids\": [\"26697886\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The P. falciparum SUMO E2 conjugating enzyme (PF3D7_1412900, Pf-Ubc9) participates in a SUMOylation pathway that plays a protective role in the parasite's response to oxidative stress during red blood cell stages, as evidenced by susceptibility of trophozoite-stage parasites to iron-induced oxidative stress when SUMOylation is disrupted.\",\n      \"method\": \"In vitro oxidative stress assay with iron treatment; biochemical characterization of SUMOylation activity\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, single method linking SUMOylation pathway activity to oxidative stress response\",\n      \"pmids\": [\"26697886\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A unidirectional cross-species interaction was demonstrated in which Pf-SUMO interacts with human E2 (Hs-Ubc9), but Hs-SUMO1 failed to interact with Pf-E2 (PF3D7_1412900). Surface-accessible aspartates of Pf-SUMO and critical N-terminal residues of Pf-Ubc9 govern the specificity of SUMO–E2 interactions; mutating Pf-Ubc9 N-terminal residues to corresponding Hs-Ubc9 residues restored electrostatic, π–π, and hydrophobic interactions enabling cross-species interaction.\",\n      \"method\": \"Biochemical and biophysical binding assays, site-directed mutagenesis\",\n      \"journal\": \"Biophysical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal biochemical/biophysical methods plus mutagenesis in a single lab study\",\n      \"pmids\": [\"35331687\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    }\n  ],\n  \"current_model\": \"PF3D7_1412900 (Pf-Ubc9) is the SUMO E2-conjugating enzyme of P. falciparum whose interaction with the SUMO E1 activating enzyme is governed by species-specific surface residues (including critical N-terminal residues of Pf-Ubc9 and surface-accessible aspartates of Pf-SUMO), exhibits a unidirectional cross-species interaction profile distinct from the human system, and participates in a SUMOylation pathway that protects the parasite against oxidative stress during intraerythrocytic stages.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PF3D7_1412900 (Pf-Ubc9) is the SUMO E2-conjugating enzyme of Plasmodium falciparum, operating in a SUMOylation pathway that protects intraerythrocytic parasites against oxidative stress, as trophozoite-stage parasites become susceptible to iron-induced oxidative stress when SUMOylation is disrupted [#1]. Its engagement with the SUMO E1 activating enzyme is governed by species-specific surface residues: structural analysis of the human SUMO E1–E2 interface guided identification of surface residues on the P. falciparum E1 and E2 enzymes that account for E1–E2 interactions distinct from the human system [#0]. The specificity of SUMO–E2 recognition is likewise species-restricted and unidirectional — Pf-SUMO interacts with human Ubc9, but human SUMO1 fails to interact with PF3D7_1412900, a selectivity dictated by critical N-terminal residues of Pf-Ubc9 together with surface-accessible aspartates of Pf-SUMO; mutating these N-terminal residues to their human counterparts restores electrostatic, π–π, and hydrophobic contacts and enables cross-species binding [#2]. Beyond these interaction determinants and the oxidative-stress phenotype, no further mechanistic detail for PF3D7_1412900 has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"It was unknown what structural features distinguish the parasite SUMO conjugation machinery from the human system; solving the human E1–E2 interface and mapping it onto the parasite enzymes established that specific surface residues on Pf-E1 and PF3D7_1412900 underlie species-specific E1–E2 interactions.\",\n      \"evidence\": \"X-ray crystallography of the human SUMO E1–E2 complex with in silico modeling, mutagenesis, and in vitro biochemical assays on the P. falciparum enzymes\",\n      \"pmids\": [\"26697886\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No direct crystal structure of PF3D7_1412900 itself was reported\",\n        \"Downstream SUMO substrates conjugated by Pf-Ubc9 not identified\",\n        \"Functional consequence of disrupting the specific E1–E2 interface in living parasites not tested\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The cellular role of the parasite SUMOylation pathway was unclear; linking pathway activity to survival under iron-induced oxidative stress established a protective function for SUMOylation in intraerythrocytic trophozoites.\",\n      \"evidence\": \"In vitro iron-induced oxidative stress assay coupled with biochemical characterization of SUMOylation activity\",\n      \"pmids\": [\"26697886\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single lab, single method linking pathway activity to the phenotype\",\n        \"The specific contribution of PF3D7_1412900 versus other pathway components not isolated genetically\",\n        \"SUMOylation targets responsible for oxidative-stress protection unknown\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Whether SUMO–E2 recognition is interchangeable across species was unresolved; demonstrating a unidirectional cross-species interaction and pinpointing the governing residues established that PF3D7_1412900 N-terminal residues and Pf-SUMO surface aspartates dictate binding specificity.\",\n      \"evidence\": \"Biochemical and biophysical binding assays with site-directed mutagenesis, including humanizing Pf-Ubc9 N-terminal residues to restore cross-species binding\",\n      \"pmids\": [\"35331687\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single lab study without independent confirmation\",\n        \"Physiological role of the SUMO–E2 specificity in parasite biology not tested in vivo\",\n        \"Whether altered specificity affects substrate conjugation not addressed\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The SUMO substrates conjugated by PF3D7_1412900 and the in vivo genetic requirement for the enzyme during the parasite life cycle remain unidentified.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No SUMO substrate repertoire defined for PF3D7_1412900\",\n        \"No genetic knockout or knockdown phenotype reported\",\n        \"No structural model of PF3D7_1412900 itself in complex with Pf-SUMO or Pf-E1\"\n      ],\n      \"attribution\": []\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0061656\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"GO:0016925\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0006979\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"Pf-SUMO\",\n      \"P. falciparum SUMO E1 activating enzyme\"\n    ],\n    \"other_free_text\": [\n      \"PF3D7_1412900 (Pf-Ubc9) is the SUMO E2-conjugating enzyme of P. falciparum.\",\n      \"Species-specific E1–E2 interaction determined by surface residues on the parasite E1 and E2 enzymes [#0].\",\n      \"SUMO–E2 recognition is unidirectional across species: Pf-SUMO binds human Ubc9, but human SUMO1 does not bind PF3D7_1412900; specificity set by Pf-Ubc9 N-terminal residues and Pf-SUMO surface aspartates [#2].\",\n      \"SUMOylation pathway involving PF3D7_1412900 is protective against iron-induced oxidative stress in trophozoite-stage parasites [#1].\"\n    ]\n  }\n}","audit_flag":{"gene":"PF3D7_1412900","tier":"IDENTITY_CHECK","verdict":"identity unverified","subtype":"names_other_cards","uniprot_band":"","rules_fired":"R12","issue":"No cited paper names this card; 2 of 2 cited papers name other catalogue genes (PF3D7_0505800, PF3D7_0915100). The summary may describe one of those genes."},"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1412900","name":null,"product":"ubiquitin-conjugating enzyme E2, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1029700","name":null,"product":"ubiquitin-conjugating enzyme E2, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1345400","name":null,"product":"ubiquitin-conjugating enzyme E2, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"","evaluation":null}