{"gene":"PF3D7_1121000","run_date":"2026-09-08T15:29:32+00:00","timeline":{"discoveries":[{"year":2016,"finding":"DHHC3 (PF3D7_1121000 ortholog in P. berghei) co-localizes with a marker of the inner membrane complex (IMC) in ookinete stage parasites, establishing its subcellular localization.","method":"Gene tagging and co-localization by fluorescence microscopy with IMC marker","journal":"Cellular microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct gene-tagging localization experiment with functional consequence, single lab, two orthogonal methods (tagging + genetic deletion)","pmids":["27084458"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2016,"finding":"DHHC3 (PF3D7_1121000 ortholog in P. berghei) is required for gliding motility in ookinetes and sporozoites; DHHC3-knockout ookinetes and sporozoites are severely impaired in gliding motility, and sporozoites are non-infectious to mice, establishing DHHC3 as a palmitoyl transferase mediator of gliding motility.","method":"Gene deletion (knockout) with gliding motility assay, in vivo infectivity assay, and genetic complementation restoring virulence","journal":"Cellular microbiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined cellular phenotype, genetic complementation fully restoring virulence, multiple orthogonal readouts (motility assay, in vivo infectivity)","pmids":["27084458"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2016,"finding":"DHHC3 (PF3D7_1121000 ortholog in P. berghei) is required for ookinete development and mosquito infectivity; DHHC3-knockout ookinetes are significantly less infectious to mosquitoes.","method":"Gene deletion (knockout) with mosquito infectivity assay","journal":"Cellular microbiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined infectivity phenotype, confirmed by genetic complementation","pmids":["27084458"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2016,"finding":"Double knockout of DHHC3 and DHHC9 in P. berghei produces an enhanced phenotype compared to either single knockout, revealing partial functional overlap between these two palmitoyl transferases.","method":"Double gene deletion with phenotypic comparison to single knockouts","journal":"Cellular microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via double KO, single lab, single study","pmids":["27084458"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2016,"finding":"In P. falciparum, multiple DHHC proteins including members of the 12-protein PfDHHC family are capable of palmitoylating the same substrate in vitro, demonstrating functional redundancy; individual PfDHHC proteins localize to distinct organelles including rhoptries and the inner membrane complex. The localization of PF3D7_1121000 (PfDHHC3) specifically was characterized as part of this subset analysis.","method":"In vitro palmitoyl-transferase activity assay with P. falciparum substrates; endogenous protein localization by tagging; knockout studies","journal":"Cellular microbiology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — the abstract describes the DHHC family broadly and does not explicitly specify which individual findings apply to PfDHHC3 (PF3D7_1121000) versus other family members; specific mechanistic attribution to PF3D7_1121000 is uncertain","pmids":["27060339"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"DHHC3 (PF3D7_1121000) is a palmitoyl transferase that localizes to the inner membrane complex in ookinetes and is essential for gliding motility in both ookinetes and sporozoites of Plasmodium berghei, with its loss rendering ookinetes poorly infectious to mosquitoes and sporozoites completely non-infectious to mice; genetic complementation fully restores virulence, and partial functional overlap with the related palmitoyl transferase DHHC9 is revealed by an enhanced double-knockout phenotype."},"narrative":{"mechanistic_narrative":"DHHC3 (PF3D7_1121000) is a palmitoyl transferase that mediates gliding motility and mosquito-to-vertebrate transmission across the Plasmodium life cycle, characterized largely through its P. berghei ortholog [PMID:27084458]. It localizes to the inner membrane complex (IMC) of ookinetes [PMID:27084458], the structure underlying motility in invasive stages. Genetic deletion in P. berghei severely impairs gliding motility in both ookinetes and sporozoites, renders ookinetes poorly infectious to mosquitoes, and leaves sporozoites non-infectious to mice; genetic complementation fully restores virulence, establishing DHHC3 as a causal mediator of these phenotypes [PMID:27084458]. DHHC3 shares partial functional redundancy with the related palmitoyl transferase DHHC9, as a DHHC3/DHHC9 double knockout produces an enhanced phenotype relative to either single knockout [PMID:27084458]. Beyond its IMC localization, motility requirement, and functional overlap with DHHC9, the specific protein substrates palmitoylated by DHHC3 have not been defined in the available corpus.","teleology":[{"year":2016,"claim":"Establishing where a candidate palmitoyl transferase acts was the first step: DHHC3 was shown to occupy the inner membrane complex of ookinetes, placing it at the motility apparatus.","evidence":"Gene tagging and fluorescence co-localization with an IMC marker in P. berghei ookinetes","pmids":["27084458"],"confidence":"Medium","gaps":["Localization shown in ookinetes but not resolved across all invasive stages","No identification of which IMC proteins DHHC3 associates with or palmitoylates"],"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2016,"claim":"Whether DHHC3 is functionally required was answered by deletion: loss abolishes gliding motility and blocks transmission at two life-cycle transitions, with complementation confirming causality.","evidence":"Gene knockout with gliding motility assay, mosquito and mouse infectivity assays, and genetic complementation in P. berghei","pmids":["27084458"],"confidence":"High","gaps":["The palmitoylation substrates whose modification drives motility are not identified","Mechanistic link between palmitoyl transferase activity and IMC/motor function not established","Direct demonstration of enzymatic activity for the P. berghei ortholog not shown"],"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2016,"claim":"Genetic epistasis addressed whether DHHC3 acts alone: a DHHC3/DHHC9 double knockout exceeds either single knockout, revealing partial functional overlap between the two palmitoyl transferases.","evidence":"Double gene deletion with phenotypic comparison to single knockouts in P. berghei","pmids":["27084458"],"confidence":"Medium","gaps":["Shared substrates between DHHC3 and DHHC9 not defined","Degree and molecular basis of the redundancy not characterized"],"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2016,"claim":"In a parallel P. falciparum survey of the DHHC family, PfDHHC3 (PF3D7_1121000) localization was characterized within a set where multiple DHHC enzymes palmitoylate the same substrate in vitro, hinting at redundancy, though substrate assignments specific to PfDHHC3 were not resolved.","evidence":"In vitro palmitoyl-transferase assays, endogenous tagging localization, and knockout studies across the PfDHHC family in P. falciparum","pmids":["27060339"],"confidence":"Low","gaps":["The abstract treats the DHHC family broadly and does not isolate which findings apply specifically to PF3D7_1121000","No substrate uniquely assigned to PfDHHC3","Enzymatic activity of PfDHHC3 not individually demonstrated"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"The direct palmitoylation substrates of DHHC3 and the molecular pathway connecting its enzymatic activity to gliding motility remain unidentified.","evidence":"","pmids":[],"confidence":"Low","gaps":["No DHHC3-specific substrate identified","No structural or biochemical model of DHHC3 activity in Plasmodium","Mechanism of DHHC3/DHHC9 redundancy at the substrate level unknown"],"attribution":[]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":["DHHC9 (PARTIAL FUNCTIONAL OVERLAP IN P. BERGHEI)"],"other_free_text":["DHHC3 knockout ookinetes are poorly infectious to mosquitoes and knockout sporozoites are non-infectious to mice; virulence is fully restored by genetic complementation (P. berghei)","DHHC3/DHHC9 double knockout shows an enhanced phenotype over single knockouts, indicating partial redundancy (P. berghei)","Substrate(s) palmitoylated by DHHC3 not identified in the available corpus"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"23638681","id":"PMC_23638681","title":"Global analysis of apicomplexan protein S-acyl transferases reveals an enzyme essential for invasion.","date":"2013","source":"Traffic (Copenhagen, Denmark)","url":"https://pubmed.ncbi.nlm.nih.gov/23638681","citation_count":62,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["curated_ref"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"27060339","id":"PMC_27060339","title":"Study of Plasmodium falciparum DHHC palmitoyl transferases identifies a role for PfDHHC9 in gametocytogenesis.","date":"2016","source":"Cellular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/27060339","citation_count":19,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["curated_ref"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"27084458","id":"PMC_27084458","title":"Palmitoyl transferases have critical roles in the development of mosquito and liver stages of Plasmodium.","date":"2016","source":"Cellular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/27084458","citation_count":18,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["DHHC3"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4526,"output_tokens":1369,"usd":0.017056,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6272,"output_tokens":2158,"usd":0.042655,"stage2_stop_reason":"end_turn"},"total_usd":0.0,"stage1_batch_id":"msgbatch_01FCDwJBogPrvFL5RpW1bgoz","stage2_batch_id":"msgbatch_017MJf5R7pwT6SSC5ZnYgqis","note":"batch pricing = 50% of standard","skipped":true},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2016,\n      \"finding\": \"DHHC3 (PF3D7_1121000 ortholog in P. berghei) co-localizes with a marker of the inner membrane complex (IMC) in ookinete stage parasites, establishing its subcellular localization.\",\n      \"method\": \"Gene tagging and co-localization by fluorescence microscopy with IMC marker\",\n      \"journal\": \"Cellular microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct gene-tagging localization experiment with functional consequence, single lab, two orthogonal methods (tagging + genetic deletion)\",\n      \"pmids\": [\"27084458\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"DHHC3 (PF3D7_1121000 ortholog in P. berghei) is required for gliding motility in ookinetes and sporozoites; DHHC3-knockout ookinetes and sporozoites are severely impaired in gliding motility, and sporozoites are non-infectious to mice, establishing DHHC3 as a palmitoyl transferase mediator of gliding motility.\",\n      \"method\": \"Gene deletion (knockout) with gliding motility assay, in vivo infectivity assay, and genetic complementation restoring virulence\",\n      \"journal\": \"Cellular microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined cellular phenotype, genetic complementation fully restoring virulence, multiple orthogonal readouts (motility assay, in vivo infectivity)\",\n      \"pmids\": [\"27084458\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"DHHC3 (PF3D7_1121000 ortholog in P. berghei) is required for ookinete development and mosquito infectivity; DHHC3-knockout ookinetes are significantly less infectious to mosquitoes.\",\n      \"method\": \"Gene deletion (knockout) with mosquito infectivity assay\",\n      \"journal\": \"Cellular microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined infectivity phenotype, confirmed by genetic complementation\",\n      \"pmids\": [\"27084458\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Double knockout of DHHC3 and DHHC9 in P. berghei produces an enhanced phenotype compared to either single knockout, revealing partial functional overlap between these two palmitoyl transferases.\",\n      \"method\": \"Double gene deletion with phenotypic comparison to single knockouts\",\n      \"journal\": \"Cellular microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via double KO, single lab, single study\",\n      \"pmids\": [\"27084458\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In P. falciparum, multiple DHHC proteins including members of the 12-protein PfDHHC family are capable of palmitoylating the same substrate in vitro, demonstrating functional redundancy; individual PfDHHC proteins localize to distinct organelles including rhoptries and the inner membrane complex. The localization of PF3D7_1121000 (PfDHHC3) specifically was characterized as part of this subset analysis.\",\n      \"method\": \"In vitro palmitoyl-transferase activity assay with P. falciparum substrates; endogenous protein localization by tagging; knockout studies\",\n      \"journal\": \"Cellular microbiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — the abstract describes the DHHC family broadly and does not explicitly specify which individual findings apply to PfDHHC3 (PF3D7_1121000) versus other family members; specific mechanistic attribution to PF3D7_1121000 is uncertain\",\n      \"pmids\": [\"27060339\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    }\n  ],\n  \"current_model\": \"DHHC3 (PF3D7_1121000) is a palmitoyl transferase that localizes to the inner membrane complex in ookinetes and is essential for gliding motility in both ookinetes and sporozoites of Plasmodium berghei, with its loss rendering ookinetes poorly infectious to mosquitoes and sporozoites completely non-infectious to mice; genetic complementation fully restores virulence, and partial functional overlap with the related palmitoyl transferase DHHC9 is revealed by an enhanced double-knockout phenotype.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DHHC3 (PF3D7_1121000) is a palmitoyl transferase that mediates gliding motility and mosquito-to-vertebrate transmission across the Plasmodium life cycle, characterized largely through its P. berghei ortholog [#1]. It localizes to the inner membrane complex (IMC) of ookinetes [#0], the structure underlying motility in invasive stages. Genetic deletion in P. berghei severely impairs gliding motility in both ookinetes and sporozoites, renders ookinetes poorly infectious to mosquitoes, and leaves sporozoites non-infectious to mice; genetic complementation fully restores virulence, establishing DHHC3 as a causal mediator of these phenotypes [#1, #2]. DHHC3 shares partial functional redundancy with the related palmitoyl transferase DHHC9, as a DHHC3/DHHC9 double knockout produces an enhanced phenotype relative to either single knockout [#3]. Beyond its IMC localization, motility requirement, and functional overlap with DHHC9, the specific protein substrates palmitoylated by DHHC3 have not been defined in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Establishing where a candidate palmitoyl transferase acts was the first step: DHHC3 was shown to occupy the inner membrane complex of ookinetes, placing it at the motility apparatus.\",\n      \"evidence\": \"Gene tagging and fluorescence co-localization with an IMC marker in P. berghei ookinetes\",\n      \"pmids\": [\"27084458\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Localization shown in ookinetes but not resolved across all invasive stages\",\n        \"No identification of which IMC proteins DHHC3 associates with or palmitoylates\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Whether DHHC3 is functionally required was answered by deletion: loss abolishes gliding motility and blocks transmission at two life-cycle transitions, with complementation confirming causality.\",\n      \"evidence\": \"Gene knockout with gliding motility assay, mosquito and mouse infectivity assays, and genetic complementation in P. berghei\",\n      \"pmids\": [\"27084458\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The palmitoylation substrates whose modification drives motility are not identified\",\n        \"Mechanistic link between palmitoyl transferase activity and IMC/motor function not established\",\n        \"Direct demonstration of enzymatic activity for the P. berghei ortholog not shown\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Genetic epistasis addressed whether DHHC3 acts alone: a DHHC3/DHHC9 double knockout exceeds either single knockout, revealing partial functional overlap between the two palmitoyl transferases.\",\n      \"evidence\": \"Double gene deletion with phenotypic comparison to single knockouts in P. berghei\",\n      \"pmids\": [\"27084458\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Shared substrates between DHHC3 and DHHC9 not defined\",\n        \"Degree and molecular basis of the redundancy not characterized\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"In a parallel P. falciparum survey of the DHHC family, PfDHHC3 (PF3D7_1121000) localization was characterized within a set where multiple DHHC enzymes palmitoylate the same substrate in vitro, hinting at redundancy, though substrate assignments specific to PfDHHC3 were not resolved.\",\n      \"evidence\": \"In vitro palmitoyl-transferase assays, endogenous tagging localization, and knockout studies across the PfDHHC family in P. falciparum\",\n      \"pmids\": [\"27060339\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"The abstract treats the DHHC family broadly and does not isolate which findings apply specifically to PF3D7_1121000\",\n        \"No substrate uniquely assigned to PfDHHC3\",\n        \"Enzymatic activity of PfDHHC3 not individually demonstrated\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct palmitoylation substrates of DHHC3 and the molecular pathway connecting its enzymatic activity to gliding motility remain unidentified.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No DHHC3-specific substrate identified\",\n        \"No structural or biochemical model of DHHC3 activity in Plasmodium\",\n        \"Mechanism of DHHC3/DHHC9 redundancy at the substrate level unknown\"\n      ],\n      \"attribution\": []\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016409\", \"supporting_discovery_ids\": [1, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0070258\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0071976\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"DHHC9 (partial functional overlap in P. berghei)\"],\n    \"other_free_text\": [\n      \"DHHC3 knockout ookinetes are poorly infectious to mosquitoes and knockout sporozoites are non-infectious to mice; virulence is fully restored by genetic complementation (P. berghei)\",\n      \"DHHC3/DHHC9 double knockout shows an enhanced phenotype over single knockouts, indicating partial redundancy (P. berghei)\",\n      \"Substrate(s) palmitoylated by DHHC3 not identified in the available corpus\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1121000","name":null,"product":"palmitoyltransferase DHHC3","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_0927300","name":null,"product":"palmitoyltransferase DHHC3","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_0918700","name":null,"product":"palmitoyltransferase DHHC3, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"DHHC3","evaluation":null}