{"gene":"PKNH_0111000","run_date":"2026-09-08T15:24:04","timeline":{"discoveries":[{"year":2014,"finding":"P. falciparum DegP (PfDegP) complements the growth defect of an E. coli degP null mutant at non-permissive temperatures and confers resistance to oxidative stress, establishing that PfDegP has functional serine protease/chaperone activity capable of substituting for the bacterial ortholog.","method":"Heterologous complementation of E. coli degP null mutant with PfDegP gene; growth assays at non-permissive temperatures and under oxidative stress conditions","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional complementation assay with defined phenotypic readout, single lab, supported by stress-induction data","pmids":["24494818"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2014,"finding":"PfDegP forms a complex with P. falciparum Hsp70 (PfHsp70), iron superoxide dismutase (PfSod), and enolase (PfEno), as well as additional partners (PfOat, PfLDH, PfGpi), demonstrated by co-immunoprecipitation and surface plasmon resonance.","method":"Anti-bait co-immunoprecipitation, surface plasmon resonance, co-localization by fluorescence microscopy, and co-sedimentation through density gradient","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal binding methods (Co-IP, SPR, co-sedimentation, co-localization) in a single lab","pmids":["24494818"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2014,"finding":"PfDegP expression is significantly induced upon heat shock and oxidative stress in P. falciparum culture, indicating transcriptional/translational regulation by stress.","method":"Western blot / immunodetection of DegP protein levels in stressed vs. unstressed parasite cultures","journal":"The FEBS journal","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method (expression quantification), no mechanistic pathway placement","pmids":["24494818"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"finding":"Deletion of the homologous DegP gene (PfDegP) in P. falciparum lowers heme (porphyrin) levels and decreases susceptibility to dihydroartemisinin (DHA), placing PfDegP in the heme metabolism pathway upstream of artemisinin activation.","method":"Genetic deletion (CRISPR-based) of PfDegP in P. falciparum; porphyrin level measurement; DHA susceptibility assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic knockout with two orthogonal phenotypic readouts (porphyrin levels and drug susceptibility), single lab","pmids":["32968076"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"PfDegP (PKNH_0111000 ortholog) is a secretory serine protease with chaperone activity that forms a complex with PfHsp70, PfSod, and PfEno to protect P. falciparum against thermo-oxidative stress; it also supports mitochondrial heme metabolism, such that its deletion lowers porphyrin levels and reduces susceptibility to the heme-activated drug dihydroartemisinin."},"narrative":{"mechanistic_narrative":"PKNH_0111000 (DegP) is inferred from work on its P. falciparum ortholog PfDegP, a serine protease with chaperone activity that defends the parasite against thermo-oxidative stress and supports heme metabolism [PMID:24494818, PMID:32968076]. Heterologous expression of PfDegP rescues the growth defect and oxidative-stress sensitivity of an E. coli degP null mutant at non-permissive temperatures, establishing conserved protease/chaperone function [PMID:24494818]. PfDegP assembles into a multiprotein complex with PfHsp70, iron superoxide dismutase (PfSod), and enolase (PfEno), among other partners, and its expression is induced by heat shock and oxidative stress [PMID:24494818]. Genetic deletion of PfDegP lowers cellular porphyrin (heme) levels and reduces parasite susceptibility to the heme-activated drug dihydroartemisinin, placing it upstream of artemisinin activation in heme metabolism [PMID:32968076]. All direct evidence derives from the P. falciparum ortholog; no experiments on PKNH_0111000 itself are present in the corpus, and no structural, catalytic-mechanism, or substrate-level detail has been characterized.","teleology":[{"year":2014,"claim":"Whether the Plasmodium DegP gene encodes a functional protease/chaperone was unknown; cross-species complementation established that it can substitute for the bacterial ortholog under thermal and oxidative stress.","evidence":"Heterologous complementation of an E. coli degP null mutant with PfDegP, with growth assays at non-permissive temperatures and under oxidative stress","pmids":["24494818"],"confidence":"Medium","gaps":["No direct demonstration of proteolytic or chaperone activity on a defined Plasmodium substrate","Evidence is for the P. falciparum ortholog, not PKNH_0111000 directly","Complementation does not distinguish protease from chaperone contribution"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2014,"claim":"The cellular partners of DegP were undefined; orthogonal binding assays showed it forms a complex with PfHsp70, PfSod, and PfEno plus additional partners, embedding it in a stress-response protein network.","evidence":"Anti-bait co-immunoprecipitation, surface plasmon resonance, co-localization microscopy, and density-gradient co-sedimentation in P. falciparum","pmids":["24494818"],"confidence":"Medium","gaps":["Stoichiometry and architecture of the complex not resolved","Whether partners are substrates, regulators, or chaperone clients not distinguished","Functional consequence of complex assembly not tested by perturbation"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2014,"claim":"Whether DegP responds to stress was untested; immunodetection showed its protein levels are induced by heat shock and oxidative stress, consistent with a stress-defense role.","evidence":"Western blot quantification of DegP in stressed versus unstressed P. falciparum cultures","pmids":["24494818"],"confidence":"Low","gaps":["Single lab, single method (expression quantification) with no mechanistic pathway placement","Transcriptional versus post-translational basis of induction not resolved","Regulatory signaling upstream of induction unknown"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"claim":"The connection between DegP and drug response was unknown; genetic deletion linked it to heme metabolism and to activation of dihydroartemisinin.","evidence":"CRISPR-based deletion of PfDegP in P. falciparum with porphyrin-level measurement and DHA susceptibility assays","pmids":["32968076"],"confidence":"Medium","gaps":["Molecular step by which DegP influences porphyrin/heme levels not defined","Whether the effect is via protease activity, chaperone function, or its complex partners unknown","Direct evidence remains from the P. falciparum ortholog, not PKNH_0111000"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"No experiment in the corpus addresses PKNH_0111000 directly, its catalytic mechanism, substrate repertoire, or subcellular localization; the mechanistic model rests entirely on the P. falciparum ortholog.","evidence":"","pmids":[],"confidence":"Low","gaps":["No direct functional data on PKNH_0111000 itself","No identified proteolytic substrates","No structural model of the protease or its complex"],"attribution":[]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["PfDegP–PfHsp70–PfSod–PfEno complex (also including PfOat, PfLDH, PfGpi) [#1]"],"partners":["PFHSP70 [#1]","PFSOD (IRON SUPEROXIDE DISMUTASE) [#1]","PFENO (ENOLASE) [#1]","PFOAT [#1]","PFLDH [#1]","PFGPI [#1]"],"other_free_text":["All direct evidence derives from the P. falciparum ortholog PfDegP; PKNH_0111000 is treated as the orthologous gene but was not itself experimentally assayed in the corpus.","Deletion of PfDegP reduces susceptibility to dihydroartemisinin via lowered porphyrin/heme levels [#3]."]}},"prefetch_data":{},"corpus_meta":[{"pmid":"32968076","id":"PMC_32968076","title":"Genetic screens reveal a central role for heme metabolism in artemisinin susceptibility.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/32968076","citation_count":53,"is_preprint":false,"source_species":["Pk"],"role":"primary","match_terms":["PfDegP"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"24494818","id":"PMC_24494818","title":"A secretory multifunctional serine protease, DegP of Plasmodium falciparum, plays an important role in thermo-oxidative stress, parasite growth and development.","date":"2014","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/24494818","citation_count":16,"is_preprint":false,"source_species":["Pk"],"role":"primary","match_terms":["DegP","serine protease DegP","PfDegP"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"34066964","id":"PMC_34066964","title":"Computational Design of Novel Allosteric Inhibitors for Plasmodium falciparum DegP.","date":"2021","source":"Molecules (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/34066964","citation_count":6,"is_preprint":false,"source_species":["Pk"],"role":"primary","match_terms":["DegP","serine protease DegP","PfDegP"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"27491850","id":"PMC_27491850","title":"In-silico studies on DegP protein of Plasmodium falciparum in search of anti-malarials.","date":"2016","source":"Journal of molecular modeling","url":"https://pubmed.ncbi.nlm.nih.gov/27491850","citation_count":3,"is_preprint":false,"source_species":["Pk"],"role":"primary","match_terms":["DegP","PfDegP"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4869,"output_tokens":1087,"usd":0.015456,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5863,"output_tokens":2342,"usd":0.043932,"stage2_stop_reason":"end_turn"},"total_usd":0.059388,"stage1_batch_id":"msgbatch_01S4WrhSkksYHeZXxqf3za3o","stage2_batch_id":"msgbatch_019VBBeuW6G52X8gZfsFDfb5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2014,\n      \"finding\": \"P. falciparum DegP (PfDegP) complements the growth defect of an E. coli degP null mutant at non-permissive temperatures and confers resistance to oxidative stress, establishing that PfDegP has functional serine protease/chaperone activity capable of substituting for the bacterial ortholog.\",\n      \"method\": \"Heterologous complementation of E. coli degP null mutant with PfDegP gene; growth assays at non-permissive temperatures and under oxidative stress conditions\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional complementation assay with defined phenotypic readout, single lab, supported by stress-induction data\",\n      \"pmids\": [\"24494818\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PfDegP forms a complex with P. falciparum Hsp70 (PfHsp70), iron superoxide dismutase (PfSod), and enolase (PfEno), as well as additional partners (PfOat, PfLDH, PfGpi), demonstrated by co-immunoprecipitation and surface plasmon resonance.\",\n      \"method\": \"Anti-bait co-immunoprecipitation, surface plasmon resonance, co-localization by fluorescence microscopy, and co-sedimentation through density gradient\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal binding methods (Co-IP, SPR, co-sedimentation, co-localization) in a single lab\",\n      \"pmids\": [\"24494818\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PfDegP expression is significantly induced upon heat shock and oxidative stress in P. falciparum culture, indicating transcriptional/translational regulation by stress.\",\n      \"method\": \"Western blot / immunodetection of DegP protein levels in stressed vs. unstressed parasite cultures\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method (expression quantification), no mechanistic pathway placement\",\n      \"pmids\": [\"24494818\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Deletion of the homologous DegP gene (PfDegP) in P. falciparum lowers heme (porphyrin) levels and decreases susceptibility to dihydroartemisinin (DHA), placing PfDegP in the heme metabolism pathway upstream of artemisinin activation.\",\n      \"method\": \"Genetic deletion (CRISPR-based) of PfDegP in P. falciparum; porphyrin level measurement; DHA susceptibility assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic knockout with two orthogonal phenotypic readouts (porphyrin levels and drug susceptibility), single lab\",\n      \"pmids\": [\"32968076\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"PfDegP (PKNH_0111000 ortholog) is a secretory serine protease with chaperone activity that forms a complex with PfHsp70, PfSod, and PfEno to protect P. falciparum against thermo-oxidative stress; it also supports mitochondrial heme metabolism, such that its deletion lowers porphyrin levels and reduces susceptibility to the heme-activated drug dihydroartemisinin.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PKNH_0111000 (DegP) is inferred from work on its P. falciparum ortholog PfDegP, a serine protease with chaperone activity that defends the parasite against thermo-oxidative stress and supports heme metabolism [#0, #3]. Heterologous expression of PfDegP rescues the growth defect and oxidative-stress sensitivity of an E. coli degP null mutant at non-permissive temperatures, establishing conserved protease/chaperone function [#0]. PfDegP assembles into a multiprotein complex with PfHsp70, iron superoxide dismutase (PfSod), and enolase (PfEno), among other partners, and its expression is induced by heat shock and oxidative stress [#1, #2]. Genetic deletion of PfDegP lowers cellular porphyrin (heme) levels and reduces parasite susceptibility to the heme-activated drug dihydroartemisinin, placing it upstream of artemisinin activation in heme metabolism [#3]. All direct evidence derives from the P. falciparum ortholog; no experiments on PKNH_0111000 itself are present in the corpus, and no structural, catalytic-mechanism, or substrate-level detail has been characterized.\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Whether the Plasmodium DegP gene encodes a functional protease/chaperone was unknown; cross-species complementation established that it can substitute for the bacterial ortholog under thermal and oxidative stress.\",\n      \"evidence\": \"Heterologous complementation of an E. coli degP null mutant with PfDegP, with growth assays at non-permissive temperatures and under oxidative stress\",\n      \"pmids\": [\"24494818\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No direct demonstration of proteolytic or chaperone activity on a defined Plasmodium substrate\",\n        \"Evidence is for the P. falciparum ortholog, not PKNH_0111000 directly\",\n        \"Complementation does not distinguish protease from chaperone contribution\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"The cellular partners of DegP were undefined; orthogonal binding assays showed it forms a complex with PfHsp70, PfSod, and PfEno plus additional partners, embedding it in a stress-response protein network.\",\n      \"evidence\": \"Anti-bait co-immunoprecipitation, surface plasmon resonance, co-localization microscopy, and density-gradient co-sedimentation in P. falciparum\",\n      \"pmids\": [\"24494818\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Stoichiometry and architecture of the complex not resolved\",\n        \"Whether partners are substrates, regulators, or chaperone clients not distinguished\",\n        \"Functional consequence of complex assembly not tested by perturbation\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Whether DegP responds to stress was untested; immunodetection showed its protein levels are induced by heat shock and oxidative stress, consistent with a stress-defense role.\",\n      \"evidence\": \"Western blot quantification of DegP in stressed versus unstressed P. falciparum cultures\",\n      \"pmids\": [\"24494818\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single lab, single method (expression quantification) with no mechanistic pathway placement\",\n        \"Transcriptional versus post-translational basis of induction not resolved\",\n        \"Regulatory signaling upstream of induction unknown\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"The connection between DegP and drug response was unknown; genetic deletion linked it to heme metabolism and to activation of dihydroartemisinin.\",\n      \"evidence\": \"CRISPR-based deletion of PfDegP in P. falciparum with porphyrin-level measurement and DHA susceptibility assays\",\n      \"pmids\": [\"32968076\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Molecular step by which DegP influences porphyrin/heme levels not defined\",\n        \"Whether the effect is via protease activity, chaperone function, or its complex partners unknown\",\n        \"Direct evidence remains from the P. falciparum ortholog, not PKNH_0111000\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"No experiment in the corpus addresses PKNH_0111000 directly, its catalytic mechanism, substrate repertoire, or subcellular localization; the mechanistic model rests entirely on the P. falciparum ortholog.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No direct functional data on PKNH_0111000 itself\",\n        \"No identified proteolytic substrates\",\n        \"No structural model of the protease or its complex\"\n      ],\n      \"attribution\": []\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0004252\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0051082\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"GO:0006979\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0006783\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0009408\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [\n      \"PfDegP–PfHsp70–PfSod–PfEno complex (also including PfOat, PfLDH, PfGpi) [#1]\"\n    ],\n    \"partners\": [\n      \"PfHsp70 [#1]\",\n      \"PfSod (iron superoxide dismutase) [#1]\",\n      \"PfEno (enolase) [#1]\",\n      \"PfOat [#1]\",\n      \"PfLDH [#1]\",\n      \"PfGpi [#1]\"\n    ],\n    \"other_free_text\": [\n      \"All direct evidence derives from the P. falciparum ortholog PfDegP; PKNH_0111000 is treated as the orthologous gene but was not itself experimentally assayed in the corpus.\",\n      \"Deletion of PfDegP reduces susceptibility to dihydroartemisinin via lowered porphyrin/heme levels [#3].\"\n    ]\n  }\n}","audit_flag":{"gene":"PKNH_0111000","tier":"IDENTITY_CHECK","verdict":"identity unverified","subtype":"names_other_cards","uniprot_band":"","rules_fired":"R12","issue":"No cited paper names this card; 1 of 2 cited papers name other catalogue genes (PF3D7_0818900, PF3D7_1324900). The summary may describe one of those genes."},"strains":[{"strain":"PkH","gene_id":"PKNH_0111000","name":null,"product":"serine protease DegP, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"DegP","evaluation":null}