{"gene":"PF3D7_1204300","run_date":"2026-09-08T14:19:06","timeline":{"discoveries":[{"year":2004,"finding":"A cDNA encoding P. falciparum EIF5A was cloned and expressed as a His-tagged fusion protein in E. coli; radioactive incorporation studies with [1,8-3H] spermidine demonstrated that the recombinant protein can serve as a substrate for human deoxyhypusine synthase (DHS), establishing its role as the acceptor protein in hypusine biosynthesis.","method":"cDNA cloning, recombinant protein expression, in vitro radioactive spermidine incorporation assay with human DHS","journal":"Molecular and biochemical parasitology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — direct in vitro enzymatic substrate assay, single lab, single method","pmids":["15279952"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2007,"finding":"Recombinant EIF5A from P. vivax (97% amino acid identity to P. falciparum EIF5A) was expressed and purified, and shown to be modified in vitro by a truncated recombinant DHS from P. falciparum NF54, confirming EIF5A as the direct substrate of plasmodial DHS in the first step of hypusine biosynthesis.","method":"Recombinant protein expression, Nickel affinity chromatography purification, in vitro DHS modification assay, Western blot with anti-eIF5A antiserum","journal":"Bioorganic & medicinal chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — reconstituted in vitro enzymatic modification, single lab, single study","pmids":["17591443"],"is_preprint":false,"attribution":[{"species":"Plasmodium vivax","strain":""},{"species":"Plasmodium falciparum","strain":"NF54"}]},{"year":2009,"finding":"Recombinant DOHH from P. falciparum was shown by in vitro enzymatic assay to hydroxylate deoxyhypusine in EIF5A, completing the two-step hypusine modification of EIF5A (DHS acting first, DOHH acting second).","method":"In vitro DOHH hydroxylase activity assay with EIF5A substrate; enzymatic studies documented via MINT interaction database","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — direct in vitro enzymatic assay establishing pathway position of EIF5A modification, single lab","pmids":["19740108"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2008,"finding":"Mass spectrometry identification of protein spots from 2D-DIGE analysis of schizont-stage P. falciparum revealed that EIF5A is represented by more than one isoform with different expression patterns, indicating it undergoes post-translational modifications during intra-erythrocytic development.","method":"2D differential gel electrophoresis (2D-DIGE), mass spectrometry protein identification, synchronized culture time-course","journal":"Genome biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — proteomic identification of multiple isoforms consistent with PTM, single lab, no direct characterization of specific modification","pmids":["19091060"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2009,"finding":"Treatment of P. falciparum in vitro cultures with 10 µM SAM486A (an AdoMETDC inhibitor that depletes spermidine) suppressed EIF5A protein levels as detected by 2D gel electrophoresis and Western blot, establishing that intracellular spermidine availability is required upstream of EIF5A hypusination in the parasite.","method":"In vitro P. falciparum culture drug treatment, 2D gel electrophoresis, Western blot, intracellular polyamine quantification","journal":"Amino acids","confidence":"Low","confidence_rationale":"Tier 3 / Weak — indirect pathway evidence via upstream enzyme inhibition and Western blot, single lab","pmids":["19949824"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2012,"finding":"In vivo silencing of P. berghei EIF5A via expressed shRNA in transgenic schizonts resulted in absence of hypusinated EIF5A (confirmed by Western blot) and reduced parasitemia, demonstrating that hypusinated EIF5A is required for proliferation of the malaria parasite during blood-stage infection; the hypusine pathway was also linked to host iNOS induction.","method":"shRNA-mediated gene silencing in transgenic Plasmodium schizonts, murine infection model, RT-PCR, Western blot","journal":"BMC microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vivo knockdown with defined proliferation phenotype and Western blot confirmation, single lab","pmids":["22694849"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":"ANKA"},{"species":"Plasmodium falciparum","strain":""}]},{"year":2016,"finding":"Targeted gene disruption of EIF5A in P. berghei was not achievable (full knockout not obtained); instead, only episome-carrying parasites were recovered, and knock-in of the endogenous EIF5A gene yielded viable recombinant parasites, indicating EIF5A is essential for asexual blood-stage development.","method":"Targeted gene disruption and knock-in strategy in Plasmodium berghei, selection and genotyping of transgenic parasites","journal":"FEBS open bio","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — failed knockout implying essentiality, single lab, standard reverse genetics approach","pmids":["27516964"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2019,"finding":"Attenuation of PfDHS (the enzyme that catalyzes the first step of EIF5A hypusination) by glmS riboswitch in transgenic P. falciparum led to a significant reduction of hypusinated EIF5A protein (assessed by hypusination assay) without affecting global protein synthesis, and caused a significant parasite growth defect, supporting that hypusinated EIF5A has a specific rather than global role in translation.","method":"glmS riboswitch conditional knockdown, Western blot, hypusination assay, nascent protein synthesis assay, competitive growth assay in P. falciparum","journal":"PeerJ","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal assays (hypusination, global translation, growth) in conditional knockdown system, single lab","pmids":["31024761"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2025,"finding":"In P. falciparum, spermidine is indispensable for hypusination of EIF5A and thereby for regulating protein translation; depletion of spermidine (via disruption of spermidine biosynthesis) leads to parasite death, demonstrating that EIF5A hypusination is a critical downstream function of spermidine in intraerythrocytic development.","method":"Genetic disruption of spermidine biosynthesis, hypusination assay, parasite viability assay, reactive oxygen species measurement","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — genetic disruption with functional readout of EIF5A hypusination, single study","pmids":["40531988"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2007,"finding":"EIF5A transcription in P. vivax was detected in both trophozoite and ring developmental stages, indicating the gene is expressed throughout the erythrocytic cycle.","method":"Transcription analysis of staged parasite cultures (developmental stage assessment)","journal":"Bioorganic & medicinal chemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, transcription stage-profiling only, no functional consequence established","pmids":["17591443"],"is_preprint":false,"attribution":[{"species":"Plasmodium vivax","strain":""}]},{"year":2004,"finding":"Quantitative real-time PCR of synchronized erythrocytic stages of P. falciparum showed no significant induction or downregulation of EIF5A mRNA across ring, trophozoite, and schizont stages, indicating the gene is constitutively transcribed without major stage-specific variation.","method":"Quantitative real-time PCR on synchronized P. falciparum cultures","journal":"Molecular and biochemical parasitology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method, transcription-level only with no functional consequence","pmids":["15279952"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"P. falciparum EIF5A (PF3D7_1204300) is a 161-amino-acid protein that undergoes an essential two-step post-translational modification: deoxyhypusine synthase (DHS) first transfers an aminobutyl moiety from spermidine to a specific lysine residue of the EIF5A precursor, and deoxyhypusine hydroxylase (DOHH) then hydroxylates this intermediate to generate the unique amino acid hypusine; this hypusination depends on intracellular spermidine availability, is required for parasite proliferation during blood-stage infection (knockdown abolishes the hypusinated form and arrests growth), and appears to regulate translation of specific mRNAs rather than global protein synthesis, while the gene itself is essential—full genetic knockout has not been achieved."},"narrative":{"mechanistic_narrative":"EIF5A (PF3D7_1204300) is a translation factor whose activity in Plasmodium depends on an essential two-step post-translational modification, hypusination, that is required for asexual blood-stage proliferation [PMID:22694849, PMID:31024761]. Recombinant P. falciparum EIF5A serves as the direct acceptor substrate for deoxyhypusine synthase (DHS), which transfers an aminobutyl moiety from spermidine to the EIF5A precursor [PMID:15279952, PMID:17591443], after which P. falciparum DOHH hydroxylates the deoxyhypusine intermediate to complete formation of the mature hypusine residue [PMID:19740108]. This modification depends on intracellular spermidine: pharmacological depletion of spermidine suppresses EIF5A protein levels [PMID:19949824], and genetic disruption of spermidine biosynthesis abolishes hypusination and kills the parasite [PMID:40531988]. Hypusinated EIF5A is functionally required for parasite proliferation—in vivo silencing in P. berghei eliminates the hypusinated form and reduces parasitemia [PMID:22694849], and the gene is refractory to knockout, consistent with essentiality for asexual blood-stage development [PMID:27516964]. Attenuation of the upstream modifying enzyme DHS reduces hypusinated EIF5A and causes a growth defect without affecting global protein synthesis, indicating that hypusinated EIF5A regulates translation of specific mRNAs rather than bulk protein production [PMID:31024761]. Beyond its role as the hypusinated substrate in this pathway, the specific mRNA targets and translational mechanism of EIF5A have not been characterized in the available corpus.","teleology":[{"year":2004,"claim":"Establishing that P. falciparum encodes a bona fide hypusination substrate answered whether the parasite possesses the eIF5A/hypusine axis at all.","evidence":"cDNA cloning, recombinant His-tagged expression, and in vitro [3H]spermidine incorporation with human DHS","pmids":["15279952"],"confidence":"Medium","gaps":["Used human DHS rather than the parasite enzyme","Did not identify the modified lysine position","No cellular function established"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2004,"claim":"Transcript profiling asked whether EIF5A expression is stage-restricted, showing it is constitutively transcribed across the erythrocytic cycle.","evidence":"Quantitative real-time PCR of synchronized ring, trophozoite, and schizont stages","pmids":["15279952"],"confidence":"Low","gaps":["Transcript-level only, no protein or activity correlation","No functional consequence tested"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2007,"claim":"Demonstrating modification by the parasite's own DHS confirmed EIF5A is the direct endogenous substrate of plasmodial deoxyhypusine synthase, not merely of a heterologous enzyme.","evidence":"Recombinant P. vivax EIF5A modified in vitro by truncated P. falciparum NF54 DHS, Western blot with anti-eIF5A antiserum","pmids":["17591443"],"confidence":"Medium","gaps":["Substrate protein was P. vivax ortholog, not P. falciparum EIF5A directly","Full-length DHS not used","No in-parasite validation"],"attribution":[{"species":"Plasmodium vivax","strain":""},{"species":"Plasmodium falciparum","strain":"NF54"}]},{"year":2008,"claim":"Proteomic detection of multiple EIF5A isoforms asked whether the protein is post-translationally modified in vivo, consistent with hypusination during development.","evidence":"2D-DIGE and mass spectrometry of schizont-stage P. falciparum across a synchronized time-course","pmids":["19091060"],"confidence":"Low","gaps":["Isoform differences not molecularly assigned to hypusination","No functional readout"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2009,"claim":"Identifying DOHH activity on EIF5A resolved the second enzymatic step, placing EIF5A hydroxylation downstream of DHS and completing the hypusine pathway.","evidence":"In vitro DOHH hydroxylase assay on EIF5A deoxyhypusine substrate","pmids":["19740108"],"confidence":"Medium","gaps":["In vitro reconstitution only","No demonstration that DOHH step is rate-limiting or essential in the parasite"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2009,"claim":"Linking spermidine availability to EIF5A levels placed polyamine metabolism upstream of EIF5A maturation in the parasite.","evidence":"SAM486A (AdoMetDC inhibitor) treatment of P. falciparum cultures, 2D gels, Western blot, polyamine quantification","pmids":["19949824"],"confidence":"Low","gaps":["Indirect via upstream enzyme inhibition","Did not distinguish loss of hypusination from loss of total protein"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2012,"claim":"In vivo silencing tested whether hypusinated EIF5A is actually required for parasite growth, showing loss of the hypusinated form and reduced parasitemia.","evidence":"shRNA silencing in transgenic P. berghei schizonts, murine infection, RT-PCR, Western blot","pmids":["22694849"],"confidence":"Medium","gaps":["Knockdown, not clean loss-of-function","Mechanism connecting EIF5A to iNOS induction unclear","Specific mRNA targets not identified"],"attribution":[{"species":"Plasmodium berghei","strain":"ANKA"},{"species":"Plasmodium falciparum","strain":""}]},{"year":2016,"claim":"Reverse genetics asked whether EIF5A is dispensable, and the failure to obtain a knockout established it as essential for asexual blood-stage development.","evidence":"Targeted disruption and knock-in in P. berghei with selection and genotyping","pmids":["27516964"],"confidence":"Medium","gaps":["Essentiality inferred from failed disruption rather than conditional depletion","No stage-specific requirement mapped"],"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2019,"claim":"Conditional attenuation of the modifying enzyme addressed whether hypusinated EIF5A acts globally or specifically in translation, revealing a growth defect without impaired bulk protein synthesis.","evidence":"glmS riboswitch knockdown of PfDHS, hypusination assay, nascent protein synthesis assay, competitive growth assay in P. falciparum","pmids":["31024761"],"confidence":"Medium","gaps":["Perturbs DHS rather than EIF5A directly","Specific target mRNAs not identified","No structural or ribosome-profiling data"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2025,"claim":"Genetic disruption of spermidine biosynthesis confirmed that EIF5A hypusination is a critical downstream function of spermidine and that its loss is lethal to the parasite.","evidence":"Genetic disruption of spermidine biosynthesis, hypusination assay, viability and ROS measurement in P. falciparum","pmids":["40531988"],"confidence":"Medium","gaps":["Spermidine has functions beyond EIF5A that could contribute to lethality","Direct causal separation of hypusination loss from other spermidine effects not established"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"The specific mRNAs whose translation depends on hypusinated EIF5A, and the molecular basis of that selectivity, remain unidentified.","evidence":"No discovery in the corpus defines EIF5A target transcripts or its ribosome-level mechanism","pmids":[],"confidence":"Low","gaps":["No target mRNA set defined","No structural model of EIF5A-ribosome interaction","No mapping of the modified lysine in the parasite protein"],"attribution":[]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":["DEOXYHYPUSINE SYNTHASE (DHS) — MODIFIES EIF5A IN THE FIRST HYPUSINATION STEP [#0, #1, #7]","DEOXYHYPUSINE HYDROXYLASE (DOHH) — HYDROXYLATES EIF5A DEOXYHYPUSINE IN THE SECOND STEP [#2]"],"other_free_text":["EIF5A is the acceptor substrate for hypusine biosynthesis, receiving an aminobutyl group from spermidine via DHS and hydroxylation via DOHH [#0, #1, #2].","Hypusination of EIF5A depends on intracellular spermidine availability [#4, #8].","Hypusinated EIF5A is required for asexual blood-stage proliferation; the gene is refractory to knockout [#5, #6].","Loss of EIF5A hypusination causes a growth defect without impairing global protein synthesis, indicating a role in translation of specific mRNAs [#7].","EIF5A mRNA is constitutively transcribed across erythrocytic stages in P. falciparum and detected in P. vivax trophozoite and ring stages [#9, #10]."]}},"prefetch_data":{},"corpus_meta":[{"pmid":"19091060","id":"PMC_19091060","title":"Quantitative protein expression profiling reveals extensive post-transcriptional regulation and post-translational modifications in schizont-stage malaria parasites.","date":"2008","source":"Genome biology","url":"https://pubmed.ncbi.nlm.nih.gov/19091060","citation_count":99,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EIF5A"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"30333232","id":"PMC_30333232","title":"Polyamines in protozoan pathogens.","date":"2018","source":"The Journal of biological 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Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/35458660","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["EIF5A"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":17671,"output_tokens":2906,"usd":0.048301,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8545,"output_tokens":3810,"usd":0.068987,"stage2_stop_reason":"end_turn"},"total_usd":0.117288,"stage1_batch_id":"msgbatch_011BPjN2BL33F8cJXD1r7V7T","stage2_batch_id":"msgbatch_01Qwg6vP7qxkpL6Gsc7tajsb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"A cDNA encoding P. falciparum EIF5A was cloned and expressed as a His-tagged fusion protein in E. coli; radioactive incorporation studies with [1,8-3H] spermidine demonstrated that the recombinant protein can serve as a substrate for human deoxyhypusine synthase (DHS), establishing its role as the acceptor protein in hypusine biosynthesis.\",\n      \"method\": \"cDNA cloning, recombinant protein expression, in vitro radioactive spermidine incorporation assay with human DHS\",\n      \"journal\": \"Molecular and biochemical parasitology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — direct in vitro enzymatic substrate assay, single lab, single method\",\n      \"pmids\": [\"15279952\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Recombinant EIF5A from P. vivax (97% amino acid identity to P. falciparum EIF5A) was expressed and purified, and shown to be modified in vitro by a truncated recombinant DHS from P. falciparum NF54, confirming EIF5A as the direct substrate of plasmodial DHS in the first step of hypusine biosynthesis.\",\n      \"method\": \"Recombinant protein expression, Nickel affinity chromatography purification, in vitro DHS modification assay, Western blot with anti-eIF5A antiserum\",\n      \"journal\": \"Bioorganic & medicinal chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — reconstituted in vitro enzymatic modification, single lab, single study\",\n      \"pmids\": [\"17591443\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium vivax\", \"strain\": \"\"}, {\"species\": \"Plasmodium falciparum\", \"strain\": \"NF54\"}]\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Recombinant DOHH from P. falciparum was shown by in vitro enzymatic assay to hydroxylate deoxyhypusine in EIF5A, completing the two-step hypusine modification of EIF5A (DHS acting first, DOHH acting second).\",\n      \"method\": \"In vitro DOHH hydroxylase activity assay with EIF5A substrate; enzymatic studies documented via MINT interaction database\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — direct in vitro enzymatic assay establishing pathway position of EIF5A modification, single lab\",\n      \"pmids\": [\"19740108\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Mass spectrometry identification of protein spots from 2D-DIGE analysis of schizont-stage P. falciparum revealed that EIF5A is represented by more than one isoform with different expression patterns, indicating it undergoes post-translational modifications during intra-erythrocytic development.\",\n      \"method\": \"2D differential gel electrophoresis (2D-DIGE), mass spectrometry protein identification, synchronized culture time-course\",\n      \"journal\": \"Genome biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — proteomic identification of multiple isoforms consistent with PTM, single lab, no direct characterization of specific modification\",\n      \"pmids\": [\"19091060\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Treatment of P. falciparum in vitro cultures with 10 µM SAM486A (an AdoMETDC inhibitor that depletes spermidine) suppressed EIF5A protein levels as detected by 2D gel electrophoresis and Western blot, establishing that intracellular spermidine availability is required upstream of EIF5A hypusination in the parasite.\",\n      \"method\": \"In vitro P. falciparum culture drug treatment, 2D gel electrophoresis, Western blot, intracellular polyamine quantification\",\n      \"journal\": \"Amino acids\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — indirect pathway evidence via upstream enzyme inhibition and Western blot, single lab\",\n      \"pmids\": [\"19949824\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In vivo silencing of P. berghei EIF5A via expressed shRNA in transgenic schizonts resulted in absence of hypusinated EIF5A (confirmed by Western blot) and reduced parasitemia, demonstrating that hypusinated EIF5A is required for proliferation of the malaria parasite during blood-stage infection; the hypusine pathway was also linked to host iNOS induction.\",\n      \"method\": \"shRNA-mediated gene silencing in transgenic Plasmodium schizonts, murine infection model, RT-PCR, Western blot\",\n      \"journal\": \"BMC microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vivo knockdown with defined proliferation phenotype and Western blot confirmation, single lab\",\n      \"pmids\": [\"22694849\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"ANKA\"}, {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Targeted gene disruption of EIF5A in P. berghei was not achievable (full knockout not obtained); instead, only episome-carrying parasites were recovered, and knock-in of the endogenous EIF5A gene yielded viable recombinant parasites, indicating EIF5A is essential for asexual blood-stage development.\",\n      \"method\": \"Targeted gene disruption and knock-in strategy in Plasmodium berghei, selection and genotyping of transgenic parasites\",\n      \"journal\": \"FEBS open bio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — failed knockout implying essentiality, single lab, standard reverse genetics approach\",\n      \"pmids\": [\"27516964\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Attenuation of PfDHS (the enzyme that catalyzes the first step of EIF5A hypusination) by glmS riboswitch in transgenic P. falciparum led to a significant reduction of hypusinated EIF5A protein (assessed by hypusination assay) without affecting global protein synthesis, and caused a significant parasite growth defect, supporting that hypusinated EIF5A has a specific rather than global role in translation.\",\n      \"method\": \"glmS riboswitch conditional knockdown, Western blot, hypusination assay, nascent protein synthesis assay, competitive growth assay in P. falciparum\",\n      \"journal\": \"PeerJ\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal assays (hypusination, global translation, growth) in conditional knockdown system, single lab\",\n      \"pmids\": [\"31024761\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In P. falciparum, spermidine is indispensable for hypusination of EIF5A and thereby for regulating protein translation; depletion of spermidine (via disruption of spermidine biosynthesis) leads to parasite death, demonstrating that EIF5A hypusination is a critical downstream function of spermidine in intraerythrocytic development.\",\n      \"method\": \"Genetic disruption of spermidine biosynthesis, hypusination assay, parasite viability assay, reactive oxygen species measurement\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genetic disruption with functional readout of EIF5A hypusination, single study\",\n      \"pmids\": [\"40531988\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"EIF5A transcription in P. vivax was detected in both trophozoite and ring developmental stages, indicating the gene is expressed throughout the erythrocytic cycle.\",\n      \"method\": \"Transcription analysis of staged parasite cultures (developmental stage assessment)\",\n      \"journal\": \"Bioorganic & medicinal chemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, transcription stage-profiling only, no functional consequence established\",\n      \"pmids\": [\"17591443\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium vivax\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Quantitative real-time PCR of synchronized erythrocytic stages of P. falciparum showed no significant induction or downregulation of EIF5A mRNA across ring, trophozoite, and schizont stages, indicating the gene is constitutively transcribed without major stage-specific variation.\",\n      \"method\": \"Quantitative real-time PCR on synchronized P. falciparum cultures\",\n      \"journal\": \"Molecular and biochemical parasitology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method, transcription-level only with no functional consequence\",\n      \"pmids\": [\"15279952\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"P. falciparum EIF5A (PF3D7_1204300) is a 161-amino-acid protein that undergoes an essential two-step post-translational modification: deoxyhypusine synthase (DHS) first transfers an aminobutyl moiety from spermidine to a specific lysine residue of the EIF5A precursor, and deoxyhypusine hydroxylase (DOHH) then hydroxylates this intermediate to generate the unique amino acid hypusine; this hypusination depends on intracellular spermidine availability, is required for parasite proliferation during blood-stage infection (knockdown abolishes the hypusinated form and arrests growth), and appears to regulate translation of specific mRNAs rather than global protein synthesis, while the gene itself is essential—full genetic knockout has not been achieved.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"EIF5A (PF3D7_1204300) is a translation factor whose activity in Plasmodium depends on an essential two-step post-translational modification, hypusination, that is required for asexual blood-stage proliferation [#5, #7]. Recombinant P. falciparum EIF5A serves as the direct acceptor substrate for deoxyhypusine synthase (DHS), which transfers an aminobutyl moiety from spermidine to the EIF5A precursor [#0, #1], after which P. falciparum DOHH hydroxylates the deoxyhypusine intermediate to complete formation of the mature hypusine residue [#2]. This modification depends on intracellular spermidine: pharmacological depletion of spermidine suppresses EIF5A protein levels [#4], and genetic disruption of spermidine biosynthesis abolishes hypusination and kills the parasite [#8]. Hypusinated EIF5A is functionally required for parasite proliferation—in vivo silencing in P. berghei eliminates the hypusinated form and reduces parasitemia [#5], and the gene is refractory to knockout, consistent with essentiality for asexual blood-stage development [#6]. Attenuation of the upstream modifying enzyme DHS reduces hypusinated EIF5A and causes a growth defect without affecting global protein synthesis, indicating that hypusinated EIF5A regulates translation of specific mRNAs rather than bulk protein production [#7]. Beyond its role as the hypusinated substrate in this pathway, the specific mRNA targets and translational mechanism of EIF5A have not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Establishing that P. falciparum encodes a bona fide hypusination substrate answered whether the parasite possesses the eIF5A/hypusine axis at all.\",\n      \"evidence\": \"cDNA cloning, recombinant His-tagged expression, and in vitro [3H]spermidine incorporation with human DHS\",\n      \"pmids\": [\"15279952\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Used human DHS rather than the parasite enzyme\", \"Did not identify the modified lysine position\", \"No cellular function established\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Transcript profiling asked whether EIF5A expression is stage-restricted, showing it is constitutively transcribed across the erythrocytic cycle.\",\n      \"evidence\": \"Quantitative real-time PCR of synchronized ring, trophozoite, and schizont stages\",\n      \"pmids\": [\"15279952\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Transcript-level only, no protein or activity correlation\", \"No functional consequence tested\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrating modification by the parasite's own DHS confirmed EIF5A is the direct endogenous substrate of plasmodial deoxyhypusine synthase, not merely of a heterologous enzyme.\",\n      \"evidence\": \"Recombinant P. vivax EIF5A modified in vitro by truncated P. falciparum NF54 DHS, Western blot with anti-eIF5A antiserum\",\n      \"pmids\": [\"17591443\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Substrate protein was P. vivax ortholog, not P. falciparum EIF5A directly\", \"Full-length DHS not used\", \"No in-parasite validation\"],\n      \"attribution\": [{\"species\": \"Plasmodium vivax\", \"strain\": \"\"}, {\"species\": \"Plasmodium falciparum\", \"strain\": \"NF54\"}]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Proteomic detection of multiple EIF5A isoforms asked whether the protein is post-translationally modified in vivo, consistent with hypusination during development.\",\n      \"evidence\": \"2D-DIGE and mass spectrometry of schizont-stage P. falciparum across a synchronized time-course\",\n      \"pmids\": [\"19091060\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Isoform differences not molecularly assigned to hypusination\", \"No functional readout\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identifying DOHH activity on EIF5A resolved the second enzymatic step, placing EIF5A hydroxylation downstream of DHS and completing the hypusine pathway.\",\n      \"evidence\": \"In vitro DOHH hydroxylase assay on EIF5A deoxyhypusine substrate\",\n      \"pmids\": [\"19740108\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vitro reconstitution only\", \"No demonstration that DOHH step is rate-limiting or essential in the parasite\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Linking spermidine availability to EIF5A levels placed polyamine metabolism upstream of EIF5A maturation in the parasite.\",\n      \"evidence\": \"SAM486A (AdoMetDC inhibitor) treatment of P. falciparum cultures, 2D gels, Western blot, polyamine quantification\",\n      \"pmids\": [\"19949824\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Indirect via upstream enzyme inhibition\", \"Did not distinguish loss of hypusination from loss of total protein\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"In vivo silencing tested whether hypusinated EIF5A is actually required for parasite growth, showing loss of the hypusinated form and reduced parasitemia.\",\n      \"evidence\": \"shRNA silencing in transgenic P. berghei schizonts, murine infection, RT-PCR, Western blot\",\n      \"pmids\": [\"22694849\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Knockdown, not clean loss-of-function\", \"Mechanism connecting EIF5A to iNOS induction unclear\", \"Specific mRNA targets not identified\"],\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"ANKA\"}, {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Reverse genetics asked whether EIF5A is dispensable, and the failure to obtain a knockout established it as essential for asexual blood-stage development.\",\n      \"evidence\": \"Targeted disruption and knock-in in P. berghei with selection and genotyping\",\n      \"pmids\": [\"27516964\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Essentiality inferred from failed disruption rather than conditional depletion\", \"No stage-specific requirement mapped\"],\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Conditional attenuation of the modifying enzyme addressed whether hypusinated EIF5A acts globally or specifically in translation, revealing a growth defect without impaired bulk protein synthesis.\",\n      \"evidence\": \"glmS riboswitch knockdown of PfDHS, hypusination assay, nascent protein synthesis assay, competitive growth assay in P. falciparum\",\n      \"pmids\": [\"31024761\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Perturbs DHS rather than EIF5A directly\", \"Specific target mRNAs not identified\", \"No structural or ribosome-profiling data\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Genetic disruption of spermidine biosynthesis confirmed that EIF5A hypusination is a critical downstream function of spermidine and that its loss is lethal to the parasite.\",\n      \"evidence\": \"Genetic disruption of spermidine biosynthesis, hypusination assay, viability and ROS measurement in P. falciparum\",\n      \"pmids\": [\"40531988\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Spermidine has functions beyond EIF5A that could contribute to lethality\", \"Direct causal separation of hypusination loss from other spermidine effects not established\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The specific mRNAs whose translation depends on hypusinated EIF5A, and the molecular basis of that selectivity, remain unidentified.\",\n      \"evidence\": \"No discovery in the corpus defines EIF5A target transcripts or its ribosome-level mechanism\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No target mRNA set defined\", \"No structural model of EIF5A-ribosome interaction\", \"No mapping of the modified lysine in the parasite protein\"],\n      \"attribution\": []\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003746\", \"supporting_discovery_ids\": [5, 7]},\n      {\"term_id\": \"GO:0034038\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"GO:0006417\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0008216\", \"supporting_discovery_ids\": [4, 8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"Deoxyhypusine synthase (DHS) — modifies EIF5A in the first hypusination step [#0, #1, #7]\",\n      \"Deoxyhypusine hydroxylase (DOHH) — hydroxylates EIF5A deoxyhypusine in the second step [#2]\"\n    ],\n    \"other_free_text\": [\n      \"EIF5A is the acceptor substrate for hypusine biosynthesis, receiving an aminobutyl group from spermidine via DHS and hydroxylation via DOHH [#0, #1, #2].\",\n      \"Hypusination of EIF5A depends on intracellular spermidine availability [#4, #8].\",\n      \"Hypusinated EIF5A is required for asexual blood-stage proliferation; the gene is refractory to knockout [#5, #6].\",\n      \"Loss of EIF5A hypusination causes a growth defect without impairing global protein synthesis, indicating a role in translation of specific mRNAs [#7].\",\n      \"EIF5A mRNA is constitutively transcribed across erythrocytic stages in P. falciparum and detected in P. vivax trophozoite and ring stages [#9, #10].\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1204300","name":null,"product":"eukaryotic translation initiation factor 5A","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_0603200","name":null,"product":"eukaryotic translation initiation factor 5A, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1304000","name":null,"product":"eukaryotic translation initiation factor 5A, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"EIF5A","evaluation":null}