{"gene":"PF3D7_1033900","run_date":"2026-09-08T12:51:28","timeline":{"discoveries":[{"year":2015,"finding":"X-ray crystallography of the human SUMO E1 ubiquitin fold domain in complex with E2 (Ubc9), combined with in silico modeling, mutagenesis, and in vitro biochemical studies of the P. falciparum SUMO E1 and E2 enzymes, identified surface residues that explain species-specific E1–E2 interactions in the P. falciparum SUMOylation pathway, suggesting the E1–E2 interface is 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 biochemistry in a single study, single lab","pmids":["26697886"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2022,"finding":"Biochemical and biophysical analyses demonstrated that Pf-E2 (Ubc9) exhibits a unidirectional cross-species interaction: Pf-SUMO interacts with human E2, but human SUMO1 fails to interact with Pf-E2. Critical N-terminal residues of Pf-E2 are responsible for this diminished interaction with Hs-SUMO1, and mutating them to the corresponding human Ubc9 residues restores efficient cross-species interaction by recovering electrostatic, π-π, and hydrophobic contacts.","method":"Biochemical binding assays, biophysical analyses, site-directed mutagenesis","journal":"Biophysical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal biochemical/biophysical methods with mutagenesis, single lab","pmids":["35331687"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"PF3D7_1033900 (E2/Ubc9) is the SUMO-conjugating E2 enzyme in P. falciparum whose interaction with the SUMO E1 enzyme is governed by species-specific surface residues; critical N-terminal residues of Pf-E2 restrict its interaction with human SUMO1, while the Pf-SUMO–E2 interface is distinct from the human system and represents a potential target for parasite-specific inhibitors."},"narrative":{"mechanistic_narrative":"PF3D7_1033900 (E2) is the SUMO-conjugating E2 enzyme (Ubc9) of the Plasmodium falciparum SUMOylation pathway, functioning in the enzymatic cascade downstream of the parasite SUMO-activating E1 enzyme [PMID:26697886]. Structural and biochemical characterization of the P. falciparum SUMO E1–E2 interaction identified surface residues that render the E1–E2 interface distinct from its human counterpart, defining species-specific determinants of complex formation [PMID:26697886]. The cross-species compatibility of E2 is asymmetric: Pf-SUMO can engage human E2, but human SUMO1 fails to interact with Pf-E2, a restriction imposed by critical N-terminal residues of Pf-E2 whose mutation to the corresponding human Ubc9 residues restores efficient interaction by recovering electrostatic, π-π, and hydrophobic contacts [PMID:35331687]. Beyond these interface-mapping studies, the catalytic cycle, substrate repertoire, and in vivo role of PF3D7_1033900 in the parasite have not been characterized in the available corpus.","teleology":[{"year":2015,"claim":"Whether the parasite SUMOylation cascade could be selectively targeted was unknown; mapping the SUMO E1–E2 interface established that P. falciparum uses species-specific surface residues distinct from the human enzymes.","evidence":"X-ray crystallography of the human SUMO E1 UFD–E2 complex with in silico modeling, site-directed mutagenesis, and in vitro biochemistry of the P. falciparum E1 and E2 enzymes","pmids":["26697886"],"confidence":"High","gaps":["No structure of the P. falciparum E1–E2 complex itself was solved (interface inferred by modeling from the human structure)","Catalytic mechanism and E2~SUMO thioester chemistry not characterized","No in vivo confirmation that these residues govern SUMOylation in the parasite"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2022,"claim":"The molecular basis for whether parasite and human SUMO machinery are interchangeable was open; biophysical mapping showed a unidirectional cross-species interaction dictated by N-terminal residues of Pf-E2.","evidence":"Biochemical binding assays, biophysical analyses, and site-directed mutagenesis of Pf-E2 and human/parasite SUMO","pmids":["35331687"],"confidence":"Medium","gaps":["Functional consequence of the SUMO–E2 interaction on substrate conjugation not measured","Interaction shown in vitro only; not validated in parasite cells","Whether these interface differences can be exploited pharmacologically not tested"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"The substrate repertoire, catalytic dynamics, and biological role of PF3D7_1033900 in parasite development and viability remain uncharacterized in the available corpus.","evidence":"","pmids":[],"confidence":"Low","gaps":["No SUMO substrates of Pf-E2 identified","No genetic knockdown/knockout phenotype reported","No inhibitor targeting the parasite-specific interface demonstrated"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["P. falciparum SUMO E1–E2 conjugation complex"],"partners":["P. FALCIPARUM SUMO-ACTIVATING E1 ENZYME","PF-SUMO","HUMAN SUMO1 (CROSS-SPECIES INTERACTION ABOLISHED BY PF-E2 N-TERMINAL RESIDUES)"],"other_free_text":["Species-specific N-terminal surface residues of Pf-E2 restrict interaction with human SUMO1; reverting them to human Ubc9 residues restores electrostatic, π-π, and hydrophobic contacts [#1].","The P. falciparum SUMO E1–E2 interface is distinct from the human system and proposed as a parasite-selective drug target [#0]."]}},"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":716,"usd":0.012086,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5355,"output_tokens":1734,"usd":0.035063,"stage2_stop_reason":"end_turn"},"total_usd":0.047149,"stage1_batch_id":"msgbatch_01DisAaTypwmC8QwdMBuePHo","stage2_batch_id":"msgbatch_0184zxZTqxiEfdYYfPMfkqjb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"X-ray crystallography of the human SUMO E1 ubiquitin fold domain in complex with E2 (Ubc9), combined with in silico modeling, mutagenesis, and in vitro biochemical studies of the P. falciparum SUMO E1 and E2 enzymes, identified surface residues that explain species-specific E1–E2 interactions in the P. falciparum SUMOylation pathway, suggesting the E1–E2 interface is 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 biochemistry in a single study, single lab\",\n      \"pmids\": [\"26697886\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Biochemical and biophysical analyses demonstrated that Pf-E2 (Ubc9) exhibits a unidirectional cross-species interaction: Pf-SUMO interacts with human E2, but human SUMO1 fails to interact with Pf-E2. Critical N-terminal residues of Pf-E2 are responsible for this diminished interaction with Hs-SUMO1, and mutating them to the corresponding human Ubc9 residues restores efficient cross-species interaction by recovering electrostatic, π-π, and hydrophobic contacts.\",\n      \"method\": \"Biochemical binding assays, biophysical analyses, site-directed mutagenesis\",\n      \"journal\": \"Biophysical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal biochemical/biophysical methods with mutagenesis, single lab\",\n      \"pmids\": [\"35331687\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    }\n  ],\n  \"current_model\": \"PF3D7_1033900 (E2/Ubc9) is the SUMO-conjugating E2 enzyme in P. falciparum whose interaction with the SUMO E1 enzyme is governed by species-specific surface residues; critical N-terminal residues of Pf-E2 restrict its interaction with human SUMO1, while the Pf-SUMO–E2 interface is distinct from the human system and represents a potential target for parasite-specific inhibitors.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PF3D7_1033900 (E2) is the SUMO-conjugating E2 enzyme (Ubc9) of the Plasmodium falciparum SUMOylation pathway, functioning in the enzymatic cascade downstream of the parasite SUMO-activating E1 enzyme [#0]. Structural and biochemical characterization of the P. falciparum SUMO E1–E2 interaction identified surface residues that render the E1–E2 interface distinct from its human counterpart, defining species-specific determinants of complex formation [#0]. The cross-species compatibility of E2 is asymmetric: Pf-SUMO can engage human E2, but human SUMO1 fails to interact with Pf-E2, a restriction imposed by critical N-terminal residues of Pf-E2 whose mutation to the corresponding human Ubc9 residues restores efficient interaction by recovering electrostatic, π-π, and hydrophobic contacts [#1]. Beyond these interface-mapping studies, the catalytic cycle, substrate repertoire, and in vivo role of PF3D7_1033900 in the parasite have not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Whether the parasite SUMOylation cascade could be selectively targeted was unknown; mapping the SUMO E1–E2 interface established that P. falciparum uses species-specific surface residues distinct from the human enzymes.\",\n      \"evidence\": \"X-ray crystallography of the human SUMO E1 UFD–E2 complex with in silico modeling, site-directed mutagenesis, and in vitro biochemistry of the P. falciparum E1 and E2 enzymes\",\n      \"pmids\": [\"26697886\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structure of the P. falciparum E1–E2 complex itself was solved (interface inferred by modeling from the human structure)\",\n        \"Catalytic mechanism and E2~SUMO thioester chemistry not characterized\",\n        \"No in vivo confirmation that these residues govern SUMOylation in the parasite\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The molecular basis for whether parasite and human SUMO machinery are interchangeable was open; biophysical mapping showed a unidirectional cross-species interaction dictated by N-terminal residues of Pf-E2.\",\n      \"evidence\": \"Biochemical binding assays, biophysical analyses, and site-directed mutagenesis of Pf-E2 and human/parasite SUMO\",\n      \"pmids\": [\"35331687\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional consequence of the SUMO–E2 interaction on substrate conjugation not measured\",\n        \"Interaction shown in vitro only; not validated in parasite cells\",\n        \"Whether these interface differences can be exploited pharmacologically not tested\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The substrate repertoire, catalytic dynamics, and biological role of PF3D7_1033900 in parasite development and viability remain uncharacterized in the available corpus.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No SUMO substrates of Pf-E2 identified\",\n        \"No genetic knockdown/knockout phenotype reported\",\n        \"No inhibitor targeting the parasite-specific interface demonstrated\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0061656\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0019789\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"GO:0016925\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [\n      \"P. falciparum SUMO E1–E2 conjugation complex\"\n    ],\n    \"partners\": [\n      \"P. falciparum SUMO-activating E1 enzyme\",\n      \"Pf-SUMO\",\n      \"human SUMO1 (cross-species interaction abolished by Pf-E2 N-terminal residues)\"\n    ],\n    \"other_free_text\": [\n      \"Species-specific N-terminal surface residues of Pf-E2 restrict interaction with human SUMO1; reverting them to human Ubc9 residues restores electrostatic, π-π, and hydrophobic contacts [#1].\",\n      \"The P. falciparum SUMO E1–E2 interface is distinct from the human system and proposed as a parasite-selective drug target [#0].\"\n    ]\n  }\n}","audit_flag":{"gene":"PF3D7_1033900","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_1033900","name":null,"product":"ubiquitin-conjugating enzyme E2, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_0517700","name":null,"product":"ubiquitin-conjugating enzyme E2, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_0619100","name":null,"product":"ubiquitin-conjugating enzyme E2, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"","evaluation":null}