{"gene":"PF3D7_0507400","run_date":"2026-09-08T16:26:55","timeline":{"discoveries":[{"year":2020,"finding":"SUB1-ProM (PF3D7_0507400) is a stand-alone propeptide-like protein whose core structure, predicted by template-based modelling and ab initio structure prediction, is most similar to the X-ray crystal structure of the propeptide of SUB1. Recombinant P. falciparum SUB1-ProM was shown to be a fast-binding, potent inhibitor of P. falciparum SUB1, but not of SUB2 or other proteases tested, establishing it as a selective endogenous inhibitor of SUB1.","method":"Template-based modelling and ab initio structure prediction; in vitro inhibition assay with recombinant protein; selectivity profiling against SUB2 and other proteases","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical reconstitution with recombinant protein, structural prediction, and selectivity profiling in a single focused study","pmids":["31942933"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"finding":"SUB1-ProM (PF3D7_0507400) is expressed in the parasitophorous vacuole (PV) of blood-stage P. falciparum, as determined by mass spectrometry and immunofluorescence, placing it in the same compartment as its target protease SUB1.","method":"Mass spectrometry; immunofluorescence microscopy","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal localization methods (MS and IFA) in a single lab study, no functional consequence of localization directly demonstrated","pmids":["31942933"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"finding":"The gene encoding SUB1-ProM (PF3D7_0507400) lies in a highly syntenic locus adjacent to three of the four subtilisin-like genes in the Plasmodium genome, suggesting a conserved genomic and functional relationship with the subtilase family.","method":"Comparative genomics / synteny analysis","journal":"The Biochemical journal","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational/genomic observation only, no direct functional experiment","pmids":["31942933"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"SUB1-ProM (PF3D7_0507400) is a stand-alone subtilisin propeptide-like protein expressed in the parasitophorous vacuole of blood-stage P. falciparum that acts as a fast-binding, potent, and selective endogenous inhibitor of the essential egress protease SUB1, likely regulating its activity in the parasitophorous vacuole prior to or during parasite egress."},"narrative":{"mechanistic_narrative":"SUB1-ProM (PF3D7_0507400) is a stand-alone subtilisin propeptide-like protein of blood-stage Plasmodium falciparum that functions as a selective endogenous inhibitor of the egress protease SUB1 [PMID:31942933]. Its core fold, predicted by template-based modelling and ab initio structure prediction, most closely resembles the X-ray crystal structure of the SUB1 propeptide, and recombinant SUB1-ProM acts as a fast-binding, potent inhibitor of P. falciparum SUB1 while sparing SUB2 and other proteases tested, establishing selectivity for SUB1 [PMID:31942933]. Consistent with this inhibitory role, SUB1-ProM localizes to the parasitophorous vacuole, the same compartment as its target protease [PMID:31942933]. Beyond this in vitro inhibitory activity and localization, the physiological consequence of SUB1-ProM function during parasite egress has not been characterized in the available corpus.","teleology":[{"year":2020,"claim":"Whether PF3D7_0507400 encodes a functional protein rather than a genomic curiosity was unknown; showing it folds like a subtilisin propeptide and selectively inhibits SUB1 established it as a bona fide endogenous protease inhibitor.","evidence":"Template-based and ab initio structure prediction plus in vitro inhibition assay with recombinant protein and selectivity profiling against SUB2 and other proteases","pmids":["31942933"],"confidence":"High","gaps":["No experimental structure of SUB1-ProM or of the SUB1-ProM:SUB1 complex","Inhibitory activity shown only in vitro; effect on SUB1 activity or egress in living parasites not demonstrated","Kinetic mechanism and binding stoichiometry not fully resolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"claim":"For an inhibitor to regulate SUB1 physiologically it must reach the same compartment; localizing SUB1-ProM to the parasitophorous vacuole placed it alongside its target protease.","evidence":"Mass spectrometry and immunofluorescence microscopy in blood-stage P. falciparum","pmids":["31942933"],"confidence":"Medium","gaps":["Co-localization or physical interaction with SUB1 in situ not directly shown","No functional consequence of PV localization demonstrated","Timing of expression relative to the egress program not established"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"claim":"Whether the gene bears an evolutionary relationship to the subtilase machinery it inhibits was addressed by mapping its genomic context, linking it to the subtilisin family.","evidence":"Comparative genomics / synteny analysis showing the locus adjacent to three of the four Plasmodium subtilisin-like genes","pmids":["31942933"],"confidence":"Low","gaps":["Computational synteny only; no functional experiment ties the genomic arrangement to co-regulation or function","Conservation across other Plasmodium species not experimentally tested"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"Whether SUB1-ProM regulates SUB1 activity in vivo and is required for or modulates parasite egress remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No genetic knockout or knockdown phenotype reported","No demonstration that SUB1-ProM inhibits SUB1 within the parasitophorous vacuole in living parasites","Regulation of SUB1-ProM expression and its temporal relationship to egress unknown"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":["SUB1 (TARGET PROTEASE SELECTIVELY INHIBITED BY SUB1-PROM)"],"other_free_text":["Core fold predicted to resemble the SUB1 propeptide by template-based and ab initio modelling [#0]","Fast-binding, potent inhibitor of P. falciparum SUB1 with selectivity against SUB2 and other proteases [#0]","Gene lies in a syntenic locus adjacent to three of the four Plasmodium subtilisin-like genes [#2]"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"31942933","id":"PMC_31942933","title":"A malaria parasite subtilisin propeptide-like protein is a potent inhibitor of the egress protease SUB1.","date":"2020","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/31942933","citation_count":7,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["SUB1-ProM"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"30941868","id":"","title":"The Plasmodium berghei serine protease PbSUB1 plays an important role in male gamete egress.","date":"2019","source":"Cellular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/30941868","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["SUB1-ProM"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":3839,"output_tokens":879,"usd":0.012351,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5569,"output_tokens":1813,"usd":0.036585,"stage2_stop_reason":"end_turn"},"total_usd":0.048936,"stage1_batch_id":"msgbatch_01NE1MTa8x1hW7Lo4tAaNzY1","stage2_batch_id":"msgbatch_0141vaQdeFvbo2q39AinvXM9","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2020,\n      \"finding\": \"SUB1-ProM (PF3D7_0507400) is a stand-alone propeptide-like protein whose core structure, predicted by template-based modelling and ab initio structure prediction, is most similar to the X-ray crystal structure of the propeptide of SUB1. Recombinant P. falciparum SUB1-ProM was shown to be a fast-binding, potent inhibitor of P. falciparum SUB1, but not of SUB2 or other proteases tested, establishing it as a selective endogenous inhibitor of SUB1.\",\n      \"method\": \"Template-based modelling and ab initio structure prediction; in vitro inhibition assay with recombinant protein; selectivity profiling against SUB2 and other proteases\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical reconstitution with recombinant protein, structural prediction, and selectivity profiling in a single focused study\",\n      \"pmids\": [\"31942933\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SUB1-ProM (PF3D7_0507400) is expressed in the parasitophorous vacuole (PV) of blood-stage P. falciparum, as determined by mass spectrometry and immunofluorescence, placing it in the same compartment as its target protease SUB1.\",\n      \"method\": \"Mass spectrometry; immunofluorescence microscopy\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal localization methods (MS and IFA) in a single lab study, no functional consequence of localization directly demonstrated\",\n      \"pmids\": [\"31942933\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The gene encoding SUB1-ProM (PF3D7_0507400) lies in a highly syntenic locus adjacent to three of the four subtilisin-like genes in the Plasmodium genome, suggesting a conserved genomic and functional relationship with the subtilase family.\",\n      \"method\": \"Comparative genomics / synteny analysis\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational/genomic observation only, no direct functional experiment\",\n      \"pmids\": [\"31942933\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    }\n  ],\n  \"current_model\": \"SUB1-ProM (PF3D7_0507400) is a stand-alone subtilisin propeptide-like protein expressed in the parasitophorous vacuole of blood-stage P. falciparum that acts as a fast-binding, potent, and selective endogenous inhibitor of the essential egress protease SUB1, likely regulating its activity in the parasitophorous vacuole prior to or during parasite egress.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SUB1-ProM (PF3D7_0507400) is a stand-alone subtilisin propeptide-like protein of blood-stage Plasmodium falciparum that functions as a selective endogenous inhibitor of the egress protease SUB1 [#0]. Its core fold, predicted by template-based modelling and ab initio structure prediction, most closely resembles the X-ray crystal structure of the SUB1 propeptide, and recombinant SUB1-ProM acts as a fast-binding, potent inhibitor of P. falciparum SUB1 while sparing SUB2 and other proteases tested, establishing selectivity for SUB1 [#0]. Consistent with this inhibitory role, SUB1-ProM localizes to the parasitophorous vacuole, the same compartment as its target protease [#1]. Beyond this in vitro inhibitory activity and localization, the physiological consequence of SUB1-ProM function during parasite egress has not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2020,\n      \"claim\": \"Whether PF3D7_0507400 encodes a functional protein rather than a genomic curiosity was unknown; showing it folds like a subtilisin propeptide and selectively inhibits SUB1 established it as a bona fide endogenous protease inhibitor.\",\n      \"evidence\": \"Template-based and ab initio structure prediction plus in vitro inhibition assay with recombinant protein and selectivity profiling against SUB2 and other proteases\",\n      \"pmids\": [\"31942933\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No experimental structure of SUB1-ProM or of the SUB1-ProM:SUB1 complex\",\n        \"Inhibitory activity shown only in vitro; effect on SUB1 activity or egress in living parasites not demonstrated\",\n        \"Kinetic mechanism and binding stoichiometry not fully resolved\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"For an inhibitor to regulate SUB1 physiologically it must reach the same compartment; localizing SUB1-ProM to the parasitophorous vacuole placed it alongside its target protease.\",\n      \"evidence\": \"Mass spectrometry and immunofluorescence microscopy in blood-stage P. falciparum\",\n      \"pmids\": [\"31942933\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Co-localization or physical interaction with SUB1 in situ not directly shown\",\n        \"No functional consequence of PV localization demonstrated\",\n        \"Timing of expression relative to the egress program not established\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Whether the gene bears an evolutionary relationship to the subtilase machinery it inhibits was addressed by mapping its genomic context, linking it to the subtilisin family.\",\n      \"evidence\": \"Comparative genomics / synteny analysis showing the locus adjacent to three of the four Plasmodium subtilisin-like genes\",\n      \"pmids\": [\"31942933\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Computational synteny only; no functional experiment ties the genomic arrangement to co-regulation or function\",\n        \"Conservation across other Plasmodium species not experimentally tested\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether SUB1-ProM regulates SUB1 activity in vivo and is required for or modulates parasite egress remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No genetic knockout or knockdown phenotype reported\",\n        \"No demonstration that SUB1-ProM inhibits SUB1 within the parasitophorous vacuole in living parasites\",\n        \"Regulation of SUB1-ProM expression and its temporal relationship to egress unknown\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0004867\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0030414\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0020003\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [\"SUB1 (target protease selectively inhibited by SUB1-ProM)\"],\n    \"other_free_text\": [\n      \"Core fold predicted to resemble the SUB1 propeptide by template-based and ab initio modelling [#0]\",\n      \"Fast-binding, potent inhibitor of P. falciparum SUB1 with selectivity against SUB2 and other proteases [#0]\",\n      \"Gene lies in a syntenic locus adjacent to three of the four Plasmodium subtilisin-like genes [#2]\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_0507400","name":null,"product":"subtilisin propeptide-like protein","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1107000","name":null,"product":"subtilisin propeptide-like protein, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1026200","name":null,"product":"subtilisin propeptide-like protein, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"SUB1-ProM","evaluation":null}