{"gene":"PF3D7_1409300","run_date":"2026-09-08T14:19:07","timeline":{"discoveries":[{"year":2016,"finding":"P. falciparum DDI1 (PF3D7_1409300) is implicated in the DNA damage response; genome-wide transcriptional profiling after MMS-induced DNA damage provided evidence that DDI1 is among the DNA repair genes whose expression is induced in wild-type parasites but fails to be induced in mutator strains (Dd2, W2) carrying point mutations in DNA repair genes, placing DDI1 within the parasite's double-strand break and excision repair response network.","method":"Genome-wide transcriptional profiling (DNA microarray) after methyl methanesulphonate (MMS) treatment; genome sequencing of mutator strains to identify point mutations in DNA repair genes","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3–4 / Weak — transcriptional inference only; no direct biochemical assay of DDI1 protein activity; single lab, single method","pmids":["27033103"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":"Dd2"},{"species":"Plasmodium falciparum","strain":"W2"},{"species":"Plasmodium falciparum","strain":""}]},{"year":2025,"finding":"Computational modeling indicates that artemisinin (ART) and its derivatives (artemether, arteether, artemiside, artesunate) bind to PfDdi1 (PF3D7_1409300) at three key loops (Loop 1: GLN266–ILE269; Loop 2: ILE323–TYR326; Loop 3: ALA292–GLY294), with free binding energies ranging from −20.75 kcal/mol (AET) to −34.24 kcal/mol (ATS); the abstract also references prior in vitro studies showing ART and dihydroartemisinin inhibit PfDdi1 activity, suggesting these loops are potential binding/inhibition sites. PfDdi1 is described as functioning in the ubiquitin-proteasome system (UPS) involved in the unfolded protein response.","method":"Computational molecular docking and molecular dynamics simulation; referenced in vitro inhibition assays (from prior studies, not this paper)","journal":"Cell biochemistry and biophysics","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational prediction only in this paper; referenced in vitro data not described in detail; no mutagenesis or structural validation in this study","pmids":["40113723"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"PfDdi1 (PF3D7_1409300) is a DNA damage-inducible protein in P. falciparum that participates in the DNA damage response and the ubiquitin-proteasome/unfolded protein response pathway; computational and preliminary in vitro data suggest artemisinin and its derivatives can inhibit PfDdi1 by binding to specific loop regions, but its precise enzymatic mechanism and direct molecular interactions remain uncharacterised by rigorous experimental studies."},"narrative":{"mechanistic_narrative":"PF3D7_1409300 (DDI1) is a DNA damage-inducible protein of Plasmodium falciparum implicated in the parasite's DNA damage response: genome-wide transcriptional profiling after methyl methanesulphonate treatment placed DDI1 among DNA repair genes whose expression is induced in wild-type parasites but fails to be induced in mutator strains (Dd2, W2) carrying point mutations in DNA repair genes [PMID:27033103]. DDI1 is described as functioning within the ubiquitin-proteasome system associated with the unfolded protein response, and computational docking indicates artemisinin and its derivatives bind three loop regions of the protein [PMID:40113723]. Beyond this transcriptional and computational evidence, the direct enzymatic activity, molecular partners, and mechanism of PF3D7_1409300 have not been characterized by rigorous experimental studies in the available corpus.","teleology":[{"year":2016,"claim":"To learn which parasite genes constitute the DNA damage response, transcriptional profiling after DNA-damaging treatment tested whether DDI1 is part of the repair network, establishing its inducibility as a DNA damage-responsive gene.","evidence":"Genome-wide DNA microarray profiling after MMS treatment, with genome sequencing of mutator strains (Dd2, W2) to identify DNA repair gene mutations","pmids":["27033103"],"confidence":"Low","gaps":["Transcriptional inference only; no direct assay of DDI1 protein activity","Does not establish DDI1's biochemical role in repair","Single lab, single method"],"attribution":[{"species":"Plasmodium falciparum","strain":"Dd2"},{"species":"Plasmodium falciparum","strain":"W2"},{"species":"Plasmodium falciparum","strain":""}]},{"year":2025,"claim":"To assess DDI1 as an antimalarial drug target, computational modeling asked whether artemisinin and derivatives engage the protein, identifying three candidate loop-binding sites and framing DDI1 within the ubiquitin-proteasome/unfolded protein response system.","evidence":"Molecular docking and molecular dynamics simulation of artemisinin derivatives against PfDdi1, referencing prior in vitro inhibition data","pmids":["40113723"],"confidence":"Low","gaps":["Computational prediction only; no mutagenesis or structural validation in this study","Referenced in vitro inhibition data not described in detail here","Direct enzymatic activity of DDI1 not demonstrated"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"The direct enzymatic mechanism, physiological substrates, and molecular interaction partners of PF3D7_1409300 remain uncharacterized by direct experimental evidence.","evidence":"","pmids":[],"confidence":"Low","gaps":["No biochemical demonstration of DDI1 enzymatic activity","No validated protein interaction partners in the corpus","No structural or genetic knockout data defining function"],"attribution":[]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":[],"other_free_text":["DNA damage-inducible: expression induced in wild-type P. falciparum after MMS treatment but not in mutator strains Dd2/W2 [#0]","Computationally predicted binding of artemisinin and derivatives at three loops (GLN266-ILE269, ILE323-TYR326, ALA292-GLY294) [#1]","Direct enzymatic activity, substrates, and molecular partners of PF3D7_1409300 not experimentally characterized in the available corpus"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"3088783","id":"PMC_3088783","title":"Rapid repeated DNA replication during microgametogenesis and DNA synthesis in young zygotes of Plasmodium berghei.","date":"1986","source":"Transactions of the Royal Society of Tropical Medicine and Hygiene","url":"https://pubmed.ncbi.nlm.nih.gov/3088783","citation_count":61,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["DNA"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"2440713","id":"PMC_2440713","title":"Plasmodium species: flow cytometry and microfluorometry assessments of DNA content and synthesis.","date":"1987","source":"Experimental parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/2440713","citation_count":57,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["DNA"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"27033103","id":"PMC_27033103","title":"DNA damage regulation and its role in drug-related phenotypes in the malaria parasites.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27033103","citation_count":56,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["DNA"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"4971014","id":"PMC_4971014","title":"DNA, RNA , and protein synthesis in erythrocytic forms of Plasmodium knowlesi.","date":"1968","source":"The American journal of tropical medicine and hygiene","url":"https://pubmed.ncbi.nlm.nih.gov/4971014","citation_count":56,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["DNA"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"15948708","id":"PMC_15948708","title":"DNA-[adenine] methylation in lower eukaryotes.","date":"2005","source":"Biochemistry. Biokhimiia","url":"https://pubmed.ncbi.nlm.nih.gov/15948708","citation_count":42,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["DNA"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"2892060","id":"PMC_2892060","title":"From Laveran's discovery to DNA probes: new trends in diagnosis of malaria.","date":"1987","source":"Lancet (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/2892060","citation_count":31,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["DNA"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"40113723","id":"PMC_40113723","title":"Computational Analysis of Plasmodium falciparum DNA Damage Inducible Protein 1 (PfDdi1): Insights into Binding of Artemisinin and its Derivatives and Implications for Antimalarial Drug Design.","date":"2025","source":"Cell biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/40113723","citation_count":4,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["DDI1","DNA damage-inducible protein 1","PfDDI1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":5066,"output_tokens":861,"usd":0.014056,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5578,"output_tokens":1546,"usd":0.03327,"stage2_stop_reason":"end_turn"},"total_usd":0.047326,"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\": 2016,\n      \"finding\": \"P. falciparum DDI1 (PF3D7_1409300) is implicated in the DNA damage response; genome-wide transcriptional profiling after MMS-induced DNA damage provided evidence that DDI1 is among the DNA repair genes whose expression is induced in wild-type parasites but fails to be induced in mutator strains (Dd2, W2) carrying point mutations in DNA repair genes, placing DDI1 within the parasite's double-strand break and excision repair response network.\",\n      \"method\": \"Genome-wide transcriptional profiling (DNA microarray) after methyl methanesulphonate (MMS) treatment; genome sequencing of mutator strains to identify point mutations in DNA repair genes\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3–4 / Weak — transcriptional inference only; no direct biochemical assay of DDI1 protein activity; single lab, single method\",\n      \"pmids\": [\"27033103\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"Dd2\"},\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"W2\"},\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Computational modeling indicates that artemisinin (ART) and its derivatives (artemether, arteether, artemiside, artesunate) bind to PfDdi1 (PF3D7_1409300) at three key loops (Loop 1: GLN266–ILE269; Loop 2: ILE323–TYR326; Loop 3: ALA292–GLY294), with free binding energies ranging from −20.75 kcal/mol (AET) to −34.24 kcal/mol (ATS); the abstract also references prior in vitro studies showing ART and dihydroartemisinin inhibit PfDdi1 activity, suggesting these loops are potential binding/inhibition sites. PfDdi1 is described as functioning in the ubiquitin-proteasome system (UPS) involved in the unfolded protein response.\",\n      \"method\": \"Computational molecular docking and molecular dynamics simulation; referenced in vitro inhibition assays (from prior studies, not this paper)\",\n      \"journal\": \"Cell biochemistry and biophysics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational prediction only in this paper; referenced in vitro data not described in detail; no mutagenesis or structural validation in this study\",\n      \"pmids\": [\"40113723\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    }\n  ],\n  \"current_model\": \"PfDdi1 (PF3D7_1409300) is a DNA damage-inducible protein in P. falciparum that participates in the DNA damage response and the ubiquitin-proteasome/unfolded protein response pathway; computational and preliminary in vitro data suggest artemisinin and its derivatives can inhibit PfDdi1 by binding to specific loop regions, but its precise enzymatic mechanism and direct molecular interactions remain uncharacterised by rigorous experimental studies.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PF3D7_1409300 (DDI1) is a DNA damage-inducible protein of Plasmodium falciparum implicated in the parasite's DNA damage response: genome-wide transcriptional profiling after methyl methanesulphonate treatment placed DDI1 among DNA repair genes whose expression is induced in wild-type parasites but fails to be induced in mutator strains (Dd2, W2) carrying point mutations in DNA repair genes [#0]. DDI1 is described as functioning within the ubiquitin-proteasome system associated with the unfolded protein response, and computational docking indicates artemisinin and its derivatives bind three loop regions of the protein [#1]. Beyond this transcriptional and computational evidence, the direct enzymatic activity, molecular partners, and mechanism of PF3D7_1409300 have not been characterized by rigorous experimental studies in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"To learn which parasite genes constitute the DNA damage response, transcriptional profiling after DNA-damaging treatment tested whether DDI1 is part of the repair network, establishing its inducibility as a DNA damage-responsive gene.\",\n      \"evidence\": \"Genome-wide DNA microarray profiling after MMS treatment, with genome sequencing of mutator strains (Dd2, W2) to identify DNA repair gene mutations\",\n      \"pmids\": [\"27033103\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Transcriptional inference only; no direct assay of DDI1 protein activity\",\n        \"Does not establish DDI1's biochemical role in repair\",\n        \"Single lab, single method\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"Dd2\"},\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"W2\"},\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"To assess DDI1 as an antimalarial drug target, computational modeling asked whether artemisinin and derivatives engage the protein, identifying three candidate loop-binding sites and framing DDI1 within the ubiquitin-proteasome/unfolded protein response system.\",\n      \"evidence\": \"Molecular docking and molecular dynamics simulation of artemisinin derivatives against PfDdi1, referencing prior in vitro inhibition data\",\n      \"pmids\": [\"40113723\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Computational prediction only; no mutagenesis or structural validation in this study\",\n        \"Referenced in vitro inhibition data not described in detail here\",\n        \"Direct enzymatic activity of DDI1 not demonstrated\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct enzymatic mechanism, physiological substrates, and molecular interaction partners of PF3D7_1409300 remain uncharacterized by direct experimental evidence.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No biochemical demonstration of DDI1 enzymatic activity\",\n        \"No validated protein interaction partners in the corpus\",\n        \"No structural or genetic knockout data defining function\"\n      ],\n      \"attribution\": []\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"GO:0006281\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0006511\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0030968\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": [\n      \"DNA damage-inducible: expression induced in wild-type P. falciparum after MMS treatment but not in mutator strains Dd2/W2 [#0]\",\n      \"Computationally predicted binding of artemisinin and derivatives at three loops (GLN266-ILE269, ILE323-TYR326, ALA292-GLY294) [#1]\",\n      \"Direct enzymatic activity, substrates, and molecular partners of PF3D7_1409300 not experimentally characterized in the available corpus\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1409300","name":null,"product":"DNA damage-inducible protein 1","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1033200","name":null,"product":"DNA damage-inducible protein 1, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1349100","name":null,"product":"DNA damage-inducible protein 1, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"DDI1","evaluation":null}