{"gene":"PF3D7_0806200","run_date":"2026-09-08T12:51:27","timeline":{"discoveries":[{"year":2018,"finding":"P. falciparum DPY19 (PF3D7_0806200) functions as a C-mannosyltransferase: when expressed in a mammalian cell line deficient in C-mannosylation, it modifies TSR domains of TRAP/MIC2 family micronemal adhesins. In vitro, it transfers mannose to a WXXWXXC peptide but, in contrast to C. elegans or mammalian C-mannosyltransferases, is inactive on a short WXXW peptide, indicating a distinct acceptor substrate specificity.","method":"Heterologous expression in C-mannosylation-deficient mammalian cells; in vitro C-mannosyltransferase assay with WXXWXXC and WXXW peptides","journal":"Glycobiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro enzymatic assay combined with cell-based complementation, two orthogonal methods establishing catalytic activity and substrate specificity, single lab","pmids":["29432542"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2022,"finding":"P. falciparum DPY19 (PF3D7_0806200) localizes to the endoplasmic reticulum and acts as a tryptophan C-mannosyltransferase. Genetic deletion (ΔDPY19) abolishes C-glycosylation of TSR-domain proteins including MTRAP (shown to be C-mannosylated in P. falciparum) and CTRP, destabilizes TRAP adhesin family members, impairs gametocyte egress and exflagellation, and abrogates ookinete infectivity of mosquitoes. Genetic complementation of DPY19 restores C-mannosylation activity, ookinete infectivity, and sporozoite production.","method":"CRISPR/Cas9 knockout; genetic complementation; 4D lattice light-sheet microscopy of gametogenesis; mass spectrometry-based detection of C-mannosylation; subcellular localization imaging","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR KO with specific phenotypic readouts at multiple lifecycle stages, genetic complementation restoring activity, direct detection of C-mannosylation on substrate, multiple orthogonal methods in one study","pmids":["35906227"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2019,"finding":"CRISPR/Cas9-mediated disruption of PF3D7_0806200 (DPY19) in P. falciparum demonstrated that it is not essential for asexual blood-stage development; loss of DPY19 causes no detectable growth phenotype, even under ER-stressing conditions.","method":"CRISPR/Cas9 gene disruption; in vitro parasite growth assay; ER stress conditions","journal":"Parasitology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean CRISPR KO with defined negative growth phenotype, single lab, two conditions tested (normal and ER stress)","pmids":["31559936"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"PF3D7_0806200 (DPY19) is a tryptophan C-mannosyltransferase that localizes to the endoplasmic reticulum of P. falciparum, modifies TSR-domain adhesins (including MTRAP and CTRP) with a distinct acceptor specificity (requiring WXXWXXC rather than WXXW), is dispensable for asexual blood-stage growth, but is essential for TSR protein quality control during sexual-stage development, gametocyte egress, exflagellation, and mosquito transmission."},"narrative":{"mechanistic_narrative":"PF3D7_0806200 (DPY19) is a tryptophan C-mannosyltransferase of P. falciparum that catalyzes C-glycosylation of the thrombospondin type-1 repeat (TSR) domains of TRAP/MIC2-family micronemal adhesins [PMID:29432542, PMID:35906227]. When expressed in C-mannosylation-deficient mammalian cells it modifies TSR domains, and in vitro it transfers mannose to a WXXWXXC peptide but is inactive on a short WXXW peptide, defining an acceptor specificity distinct from C. elegans and mammalian C-mannosyltransferases [PMID:29432542]. In the parasite, DPY19 resides in the endoplasmic reticulum, where deletion (ΔDPY19) abolishes C-glycosylation of TSR-domain proteins including MTRAP and CTRP and destabilizes TRAP adhesin family members, implicating the enzyme in TSR-protein quality control [PMID:35906227]. DPY19 is dispensable for asexual blood-stage growth even under ER stress [PMID:31559936], but it is required during sexual development: its loss impairs gametocyte egress and exflagellation and abrogates ookinete infectivity of mosquitoes, and genetic complementation restores C-mannosylation, ookinete infectivity, and sporozoite production [PMID:35906227]. Beyond these findings, no further mechanistic detail on DPY19 has been characterized in the available corpus.","teleology":[{"year":2018,"claim":"Establishing whether PF3D7_0806200 is a functional C-mannosyltransferase and what it recognizes defined the enzyme's catalytic identity and an unexpected acceptor specificity.","evidence":"Heterologous expression in C-mannosylation-deficient mammalian cells plus in vitro assay with WXXWXXC versus WXXW peptides","pmids":["29432542"],"confidence":"High","gaps":["Endogenous substrate repertoire in the parasite not defined by the peptide assay","Structural basis for the WXXWXXC preference over WXXW not determined","Catalytic residues and mannose-donor requirements not mapped"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2019,"claim":"Testing whether DPY19 is required for asexual replication showed the enzyme is dispensable at this stage, narrowing where its function is critical.","evidence":"CRISPR/Cas9 gene disruption with in vitro growth assays under normal and ER-stress conditions","pmids":["31559936"],"confidence":"Medium","gaps":["Does not address sexual-stage or transmission phenotypes","No direct assessment of C-mannosylation status in the knockout in this study"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2022,"claim":"Linking DPY19 to ER localization, TSR-protein C-glycosylation, and sexual-stage biology established its physiological role in adhesin quality control and mosquito transmission.","evidence":"CRISPR/Cas9 knockout and genetic complementation, 4D lattice light-sheet imaging of gametogenesis, mass spectrometry of C-mannosylation, and subcellular localization","pmids":["35906227"],"confidence":"High","gaps":["Mechanism by which loss of C-mannosylation destabilizes TRAP-family proteins not resolved","How defective TSR modification mechanistically blocks gametocyte egress and exflagellation not defined","Full inventory of endogenous DPY19 substrates beyond MTRAP and CTRP unknown"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"The structural and mechanistic basis for DPY19's distinct acceptor specificity and how its modification enforces adhesin stability during transmission remain open.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model or catalytic mechanism reported","Full substrate set and the step at which unmodified TSR proteins are degraded unresolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":["MTRAP (TSR-DOMAIN SUBSTRATE)","CTRP (TSR-DOMAIN SUBSTRATE)"],"other_free_text":["C-mannosylates TSR domains of TRAP/MIC2-family micronemal adhesins with acceptor specificity for WXXWXXC but not WXXW, distinct from C. elegans and mammalian enzymes [#0]","Dispensable for asexual blood-stage growth, including under ER stress [#2]","Required for gametocyte egress, exflagellation, ookinete infectivity of mosquitoes, and sporozoite production; complementation restores these functions [#1]","Loss abolishes C-glycosylation and destabilizes TRAP adhesin family members, implicating a TSR-protein quality-control role [#1]"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"26520586","id":"PMC_26520586","title":"Sugar activation and glycosylation in Plasmodium.","date":"2015","source":"Malaria journal","url":"https://pubmed.ncbi.nlm.nih.gov/26520586","citation_count":37,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["curated_ref"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"29432542","id":"PMC_29432542","title":"Apicomplexan C-Mannosyltransferases Modify Thrombospondin Type I-containing Adhesins of the TRAP Family.","date":"2018","source":"Glycobiology","url":"https://pubmed.ncbi.nlm.nih.gov/29432542","citation_count":21,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["DPY19"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"35906227","id":"PMC_35906227","title":"Tryptophan C-mannosylation is critical for Plasmodium falciparum transmission.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/35906227","citation_count":17,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["DPY19"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"31559936","id":"PMC_31559936","title":"A Plasmodium falciparum C-mannosyltransferase is dispensable for parasite asexual blood stage development.","date":"2019","source":"Parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/31559936","citation_count":14,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PfDPY19"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4559,"output_tokens":1126,"usd":0.015284,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5880,"output_tokens":2032,"usd":0.0401,"stage2_stop_reason":"end_turn"},"total_usd":0.055384,"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\": 2018,\n      \"finding\": \"P. falciparum DPY19 (PF3D7_0806200) functions as a C-mannosyltransferase: when expressed in a mammalian cell line deficient in C-mannosylation, it modifies TSR domains of TRAP/MIC2 family micronemal adhesins. In vitro, it transfers mannose to a WXXWXXC peptide but, in contrast to C. elegans or mammalian C-mannosyltransferases, is inactive on a short WXXW peptide, indicating a distinct acceptor substrate specificity.\",\n      \"method\": \"Heterologous expression in C-mannosylation-deficient mammalian cells; in vitro C-mannosyltransferase assay with WXXWXXC and WXXW peptides\",\n      \"journal\": \"Glycobiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro enzymatic assay combined with cell-based complementation, two orthogonal methods establishing catalytic activity and substrate specificity, single lab\",\n      \"pmids\": [\"29432542\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"P. falciparum DPY19 (PF3D7_0806200) localizes to the endoplasmic reticulum and acts as a tryptophan C-mannosyltransferase. Genetic deletion (ΔDPY19) abolishes C-glycosylation of TSR-domain proteins including MTRAP (shown to be C-mannosylated in P. falciparum) and CTRP, destabilizes TRAP adhesin family members, impairs gametocyte egress and exflagellation, and abrogates ookinete infectivity of mosquitoes. Genetic complementation of DPY19 restores C-mannosylation activity, ookinete infectivity, and sporozoite production.\",\n      \"method\": \"CRISPR/Cas9 knockout; genetic complementation; 4D lattice light-sheet microscopy of gametogenesis; mass spectrometry-based detection of C-mannosylation; subcellular localization imaging\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR KO with specific phenotypic readouts at multiple lifecycle stages, genetic complementation restoring activity, direct detection of C-mannosylation on substrate, multiple orthogonal methods in one study\",\n      \"pmids\": [\"35906227\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CRISPR/Cas9-mediated disruption of PF3D7_0806200 (DPY19) in P. falciparum demonstrated that it is not essential for asexual blood-stage development; loss of DPY19 causes no detectable growth phenotype, even under ER-stressing conditions.\",\n      \"method\": \"CRISPR/Cas9 gene disruption; in vitro parasite growth assay; ER stress conditions\",\n      \"journal\": \"Parasitology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean CRISPR KO with defined negative growth phenotype, single lab, two conditions tested (normal and ER stress)\",\n      \"pmids\": [\"31559936\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    }\n  ],\n  \"current_model\": \"PF3D7_0806200 (DPY19) is a tryptophan C-mannosyltransferase that localizes to the endoplasmic reticulum of P. falciparum, modifies TSR-domain adhesins (including MTRAP and CTRP) with a distinct acceptor specificity (requiring WXXWXXC rather than WXXW), is dispensable for asexual blood-stage growth, but is essential for TSR protein quality control during sexual-stage development, gametocyte egress, exflagellation, and mosquito transmission.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PF3D7_0806200 (DPY19) is a tryptophan C-mannosyltransferase of P. falciparum that catalyzes C-glycosylation of the thrombospondin type-1 repeat (TSR) domains of TRAP/MIC2-family micronemal adhesins [#0, #1]. When expressed in C-mannosylation-deficient mammalian cells it modifies TSR domains, and in vitro it transfers mannose to a WXXWXXC peptide but is inactive on a short WXXW peptide, defining an acceptor specificity distinct from C. elegans and mammalian C-mannosyltransferases [#0]. In the parasite, DPY19 resides in the endoplasmic reticulum, where deletion (ΔDPY19) abolishes C-glycosylation of TSR-domain proteins including MTRAP and CTRP and destabilizes TRAP adhesin family members, implicating the enzyme in TSR-protein quality control [#1]. DPY19 is dispensable for asexual blood-stage growth even under ER stress [#2], but it is required during sexual development: its loss impairs gametocyte egress and exflagellation and abrogates ookinete infectivity of mosquitoes, and genetic complementation restores C-mannosylation, ookinete infectivity, and sporozoite production [#1]. Beyond these findings, no further mechanistic detail on DPY19 has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2018,\n      \"claim\": \"Establishing whether PF3D7_0806200 is a functional C-mannosyltransferase and what it recognizes defined the enzyme's catalytic identity and an unexpected acceptor specificity.\",\n      \"evidence\": \"Heterologous expression in C-mannosylation-deficient mammalian cells plus in vitro assay with WXXWXXC versus WXXW peptides\",\n      \"pmids\": [\"29432542\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Endogenous substrate repertoire in the parasite not defined by the peptide assay\",\n        \"Structural basis for the WXXWXXC preference over WXXW not determined\",\n        \"Catalytic residues and mannose-donor requirements not mapped\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Testing whether DPY19 is required for asexual replication showed the enzyme is dispensable at this stage, narrowing where its function is critical.\",\n      \"evidence\": \"CRISPR/Cas9 gene disruption with in vitro growth assays under normal and ER-stress conditions\",\n      \"pmids\": [\"31559936\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Does not address sexual-stage or transmission phenotypes\",\n        \"No direct assessment of C-mannosylation status in the knockout in this study\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linking DPY19 to ER localization, TSR-protein C-glycosylation, and sexual-stage biology established its physiological role in adhesin quality control and mosquito transmission.\",\n      \"evidence\": \"CRISPR/Cas9 knockout and genetic complementation, 4D lattice light-sheet imaging of gametogenesis, mass spectrometry of C-mannosylation, and subcellular localization\",\n      \"pmids\": [\"35906227\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which loss of C-mannosylation destabilizes TRAP-family proteins not resolved\",\n        \"How defective TSR modification mechanistically blocks gametocyte egress and exflagellation not defined\",\n        \"Full inventory of endogenous DPY19 substrates beyond MTRAP and CTRP unknown\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural and mechanistic basis for DPY19's distinct acceptor specificity and how its modification enforces adhesin stability during transmission remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural model or catalytic mechanism reported\",\n        \"Full substrate set and the step at which unmodified TSR proteins are degraded unresolved\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0018537\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0018101\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"MTRAP (TSR-domain substrate)\",\n      \"CTRP (TSR-domain substrate)\"\n    ],\n    \"other_free_text\": [\n      \"C-mannosylates TSR domains of TRAP/MIC2-family micronemal adhesins with acceptor specificity for WXXWXXC but not WXXW, distinct from C. elegans and mammalian enzymes [#0]\",\n      \"Dispensable for asexual blood-stage growth, including under ER stress [#2]\",\n      \"Required for gametocyte egress, exflagellation, ookinete infectivity of mosquitoes, and sporozoite production; complementation restores these functions [#1]\",\n      \"Loss abolishes C-glycosylation and destabilizes TRAP adhesin family members, implicating a TSR-protein quality-control role [#1]\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_0806200","name":null,"product":"Dpy-19-like C-mannosyltransferase","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1224500","name":null,"product":"Dpy-19-like C-mannosyltransferase, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_0112700","name":null,"product":"Dpy-19-like C-mannosyltransferase, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"DPY19","evaluation":null}