{"gene":"PF3D7_0813800","run_date":"2026-09-08T19:44:17","timeline":{"discoveries":[{"year":2013,"finding":"P. falciparum GMD (PF3D7_0813800) is enzymatically active in vitro, catalyzing the conversion of GDP-mannose toward GDP-fucose as part of the de novo GDP-fucose biosynthesis pathway.","method":"In vitro enzymatic assay of recombinant P. falciparum GMD","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro activity demonstrated, single lab, single method","pmids":["23615908"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":"3D7"}]},{"year":2013,"finding":"Epitope-tagged P. falciparum GMD (PF3D7_0813800) localizes to the cytoplasm of P. falciparum during the intraerythrocytic developmental cycle.","method":"Fluorescence microscopy of epitope-tagged GMD expressed in transgenic 3D7 parasites","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct localization by live fluorescence microscopy, single lab, single method","pmids":["23615908"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":"3D7"}]},{"year":2016,"finding":"Knockout of P. falciparum GMD (PF3D7_0813800) completely abrogates labeling by the fucose-binding lectin UEA-I, confirming GMD is required for the production of fucose-containing glycoconjugates recognized by UEA-I. However, GDP-fucose is still detectable in the null mutant, indicating an alternative (non-GMD) mechanism for maintaining GDP-fucose pools exists in the parasite.","method":"Generation of PfGMD null mutant by gene disruption; UEA-I lectin labeling; LC-MS/MS quantification of GDP-fucose in mutant parasites","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic knockout with two orthogonal readouts (lectin labeling and metabolite quantification), single lab","pmids":["27849032"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2016,"finding":"P. falciparum GMD (PF3D7_0813800) null mutant exhibits normal asexual blood-stage growth and invasion rates, demonstrating that the GDP-fucose de novo biosynthetic pathway is not essential for intraerythrocytic development in culture.","method":"PfGMD null mutant growth and invasion assays in culture","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean genetic knockout with defined phenotypic readout, single lab, single study","pmids":["27849032"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"P. falciparum GMD (PF3D7_0813800) is a cytoplasmic GDP-mannose 4,6-dehydratase that is enzymatically active in vitro and catalyzes the first step of de novo GDP-fucose biosynthesis; it is required for production of UEA-I-reactive fucose-containing glycoconjugates but is dispensable for asexual blood-stage growth and invasion, and an alternative mechanism maintains residual GDP-fucose pools in its absence."},"narrative":{"mechanistic_narrative":"GMD (PF3D7_0813800) is a cytoplasmic GDP-mannose 4,6-dehydratase that catalyzes the first committed step of de novo GDP-fucose biosynthesis in Plasmodium falciparum, converting GDP-mannose toward GDP-fucose as demonstrated by in vitro assay of the recombinant enzyme [PMID:23615908]. Epitope-tagged GMD localizes to the parasite cytoplasm during the intraerythrocytic developmental cycle [PMID:23615908]. Genetic disruption of GMD completely abolishes labeling by the fucose-binding lectin UEA-I, establishing that GMD is required for production of fucose-containing glycoconjugates; however, GDP-fucose remains detectable in the null mutant, indicating an alternative, non-GMD route sustains residual GDP-fucose pools [PMID:27849032]. GMD is dispensable for asexual blood-stage development, as the null mutant shows normal growth and invasion in culture [PMID:27849032]. Beyond these findings, no further mechanistic detail — including structural basis, regulation, or downstream fucosylation targets — has been characterized in the available corpus.","teleology":[{"year":2013,"claim":"Establishing whether P. falciparum encodes a functional entry enzyme for de novo GDP-fucose synthesis, this work showed the recombinant protein is catalytically active on GDP-mannose.","evidence":"In vitro enzymatic assay of recombinant P. falciparum GMD","pmids":["23615908"],"confidence":"Medium","gaps":["Kinetic parameters and structural basis of catalysis not determined","Activity shown in vitro only, not linked to in vivo flux at this stage","Single lab, single method"],"attribution":[{"species":"Plasmodium falciparum","strain":"3D7"}]},{"year":2013,"claim":"To place the enzyme in a subcellular context, tagging showed GMD resides in the parasite cytoplasm during intraerythrocytic development.","evidence":"Fluorescence microscopy of epitope-tagged GMD in transgenic 3D7 parasites","pmids":["23615908"],"confidence":"Medium","gaps":["Localization from a single tagging approach without orthogonal validation","Does not address whether localization changes across stages or is complexed with partners"],"attribution":[{"species":"Plasmodium falciparum","strain":"3D7"}]},{"year":2016,"claim":"To test GMD's cellular role, knockout demonstrated it is required for fucosylated glycoconjugates yet revealed a GMD-independent source of residual GDP-fucose.","evidence":"PfGMD null mutant with UEA-I lectin labeling and LC-MS/MS quantification of GDP-fucose","pmids":["27849032"],"confidence":"High","gaps":["Identity of the alternative GDP-fucose-generating mechanism not defined","Fucosylated substrate glycoconjugates not molecularly identified"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2016,"claim":"To assess essentiality, the null mutant showed normal asexual growth and invasion, establishing the de novo GDP-fucose pathway is dispensable for blood-stage development in culture.","evidence":"Growth and invasion assays of the PfGMD null mutant in culture","pmids":["27849032"],"confidence":"Medium","gaps":["Does not address requirement in sexual/mosquito or liver stages","In vitro culture only; in vivo relevance untested"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"The molecular identity of the alternative GDP-fucose source and the biological function of GMD-dependent fucosylation in the parasite remain unknown.","evidence":"","pmids":[],"confidence":"Medium","gaps":["Salvage or alternative enzymatic route sustaining residual GDP-fucose unidentified","Downstream fucosylated targets and their functional consequences uncharacterized","Role, if any, in non-blood life-cycle stages untested"],"attribution":[]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":[],"other_free_text":["Required for UEA-I-reactive fucose-containing glycoconjugates [#2]","GDP-fucose still detectable in null mutant, indicating a GMD-independent alternative source [#2]","Dispensable for asexual blood-stage growth and invasion in culture [#3]"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"23615908","id":"PMC_23615908","title":"Biosynthesis of GDP-fucose and other sugar nucleotides in the blood stages of Plasmodium falciparum.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23615908","citation_count":36,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["GDP-mannose 4,6-dehydratase","GMD","GDP"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"27849032","id":"PMC_27849032","title":"The disruption of GDP-fucose de novo biosynthesis suggests the presence of a novel fucose-containing glycoconjugate in Plasmodium asexual blood stages.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27849032","citation_count":13,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["GDP-mannose 4,6-dehydratase","GMD","GDP"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"26520586","id":"","title":"Sugar activation and glycosylation in Plasmodium.","date":"2015","source":"Malaria journal","url":"https://pubmed.ncbi.nlm.nih.gov/26520586","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["GMD"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4827,"output_tokens":1042,"usd":0.015055,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5842,"output_tokens":1975,"usd":0.039293,"stage2_stop_reason":"end_turn"},"total_usd":0.054348,"stage1_batch_id":"msgbatch_01SRp5hyRc82zNjddxyCCXGk","stage2_batch_id":"msgbatch_01K3BTmBazRo3pRrMvyaPMTY","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"P. falciparum GMD (PF3D7_0813800) is enzymatically active in vitro, catalyzing the conversion of GDP-mannose toward GDP-fucose as part of the de novo GDP-fucose biosynthesis pathway.\",\n      \"method\": \"In vitro enzymatic assay of recombinant P. falciparum GMD\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro activity demonstrated, single lab, single method\",\n      \"pmids\": [\"23615908\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"}]\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Epitope-tagged P. falciparum GMD (PF3D7_0813800) localizes to the cytoplasm of P. falciparum during the intraerythrocytic developmental cycle.\",\n      \"method\": \"Fluorescence microscopy of epitope-tagged GMD expressed in transgenic 3D7 parasites\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct localization by live fluorescence microscopy, single lab, single method\",\n      \"pmids\": [\"23615908\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"}]\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Knockout of P. falciparum GMD (PF3D7_0813800) completely abrogates labeling by the fucose-binding lectin UEA-I, confirming GMD is required for the production of fucose-containing glycoconjugates recognized by UEA-I. However, GDP-fucose is still detectable in the null mutant, indicating an alternative (non-GMD) mechanism for maintaining GDP-fucose pools exists in the parasite.\",\n      \"method\": \"Generation of PfGMD null mutant by gene disruption; UEA-I lectin labeling; LC-MS/MS quantification of GDP-fucose in mutant parasites\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with two orthogonal readouts (lectin labeling and metabolite quantification), single lab\",\n      \"pmids\": [\"27849032\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"P. falciparum GMD (PF3D7_0813800) null mutant exhibits normal asexual blood-stage growth and invasion rates, demonstrating that the GDP-fucose de novo biosynthetic pathway is not essential for intraerythrocytic development in culture.\",\n      \"method\": \"PfGMD null mutant growth and invasion assays in culture\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean genetic knockout with defined phenotypic readout, single lab, single study\",\n      \"pmids\": [\"27849032\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"P. falciparum GMD (PF3D7_0813800) is a cytoplasmic GDP-mannose 4,6-dehydratase that is enzymatically active in vitro and catalyzes the first step of de novo GDP-fucose biosynthesis; it is required for production of UEA-I-reactive fucose-containing glycoconjugates but is dispensable for asexual blood-stage growth and invasion, and an alternative mechanism maintains residual GDP-fucose pools in its absence.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"GMD (PF3D7_0813800) is a cytoplasmic GDP-mannose 4,6-dehydratase that catalyzes the first committed step of de novo GDP-fucose biosynthesis in Plasmodium falciparum, converting GDP-mannose toward GDP-fucose as demonstrated by in vitro assay of the recombinant enzyme [#0]. Epitope-tagged GMD localizes to the parasite cytoplasm during the intraerythrocytic developmental cycle [#1]. Genetic disruption of GMD completely abolishes labeling by the fucose-binding lectin UEA-I, establishing that GMD is required for production of fucose-containing glycoconjugates; however, GDP-fucose remains detectable in the null mutant, indicating an alternative, non-GMD route sustains residual GDP-fucose pools [#2]. GMD is dispensable for asexual blood-stage development, as the null mutant shows normal growth and invasion in culture [#3]. Beyond these findings, no further mechanistic detail — including structural basis, regulation, or downstream fucosylation targets — has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Establishing whether P. falciparum encodes a functional entry enzyme for de novo GDP-fucose synthesis, this work showed the recombinant protein is catalytically active on GDP-mannose.\",\n      \"evidence\": \"In vitro enzymatic assay of recombinant P. falciparum GMD\",\n      \"pmids\": [\"23615908\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Kinetic parameters and structural basis of catalysis not determined\",\n        \"Activity shown in vitro only, not linked to in vivo flux at this stage\",\n        \"Single lab, single method\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"}\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"To place the enzyme in a subcellular context, tagging showed GMD resides in the parasite cytoplasm during intraerythrocytic development.\",\n      \"evidence\": \"Fluorescence microscopy of epitope-tagged GMD in transgenic 3D7 parasites\",\n      \"pmids\": [\"23615908\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Localization from a single tagging approach without orthogonal validation\",\n        \"Does not address whether localization changes across stages or is complexed with partners\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"}\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"To test GMD's cellular role, knockout demonstrated it is required for fucosylated glycoconjugates yet revealed a GMD-independent source of residual GDP-fucose.\",\n      \"evidence\": \"PfGMD null mutant with UEA-I lectin labeling and LC-MS/MS quantification of GDP-fucose\",\n      \"pmids\": [\"27849032\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Identity of the alternative GDP-fucose-generating mechanism not defined\",\n        \"Fucosylated substrate glycoconjugates not molecularly identified\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"To assess essentiality, the null mutant showed normal asexual growth and invasion, establishing the de novo GDP-fucose pathway is dispensable for blood-stage development in culture.\",\n      \"evidence\": \"Growth and invasion assays of the PfGMD null mutant in culture\",\n      \"pmids\": [\"27849032\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Does not address requirement in sexual/mosquito or liver stages\",\n        \"In vitro culture only; in vivo relevance untested\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular identity of the alternative GDP-fucose source and the biological function of GMD-dependent fucosylation in the parasite remain unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Salvage or alternative enzymatic route sustaining residual GDP-fucose unidentified\",\n        \"Downstream fucosylated targets and their functional consequences uncharacterized\",\n        \"Role, if any, in non-blood life-cycle stages untested\"\n      ],\n      \"attribution\": []\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008446\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005737\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0042351\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": [\n      \"Required for UEA-I-reactive fucose-containing glycoconjugates [#2]\",\n      \"GDP-fucose still detectable in null mutant, indicating a GMD-independent alternative source [#2]\",\n      \"Dispensable for asexual blood-stage growth and invasion in culture [#3]\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_0813800","name":null,"product":"GDP-mannose 4,6-dehydratase","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1423700","name":null,"product":"GDP-mannose 4,6-dehydratase, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1426500","name":null,"product":"GDP-mannose 4,6-dehydratase, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"GMD","evaluation":null}