{"gene":"PF3D7_1019800","run_date":"2026-09-08T19:44:17","timeline":{"discoveries":[{"year":2023,"finding":"MNMA (PF3D7_1019800) was localized to the P. falciparum apicoplast by direct experiment. Deletion of MNMA (enabled by a chemical bypass method) caused disruption of the apicoplast organelle and loss of the organellar genome, phenocopying deletion of the cysteine desulfurase SufS. Complementation with a bacterial MnmA and its cognate cysteine desulfurase strongly suggests that parasite SufS provides sulfur directly to MNMA for tRNA 2-thio modification in the apicoplast.","method":"Chemical bypass deletion (PfMevattB line), organelle maintenance assays (loss of apicoplast genome readout), complementation with heterologous bacterial MnmA + cognate cysteine desulfurase","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic deletion with defined organellar phenotype, complementation with heterologous system, multiple orthogonal methods in a single rigorous study","pmids":["37166116"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2024,"finding":"Conditional knockdown of MNMA (PF3D7_1019800) in an ART-sensitive P. falciparum background led to increased artemisinin survival (phenocopying ART resistance), demonstrating that hypomodification of s2U on tRNA is sufficient to alter the parasite ART response. The knockdown also altered sensitivity to other drugs (increased tolerance to atovaquone and WLL; increased susceptibility to azithromycin and fosmidomycin) and caused formation of defective schizonts.","method":"Conditional knockdown (cKD) of MNMA combined with LC-MS/MS tRNA modification analysis, drug survival assays, and proteomic/codon-bias analysis","journal":"Nature microbiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockdown with multiple orthogonal readouts (tRNA modification by LC-MS/MS, drug survival, proteomics, schizont morphology) in a single rigorous study","pmids":["38632343"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":"Dd2"}]},{"year":2025,"finding":"Deletion of MNMA (PF3D7_1019800) in P. falciparum produces a 'disrupted apicoplast' phenotype (loss of apicoplast genome and appearance of multiple vesicles containing nucleus-encoded apicoplast proteins), establishing it as essential for apicoplast maintenance. This phenotype is also observed upon deletion of MnmE and MnmG, which catalyze the xm5 modification on the same tRNA wobble position (xm5s2U pathway), placing MNMA in the terminal s2U step of the apicoplast xm5s2U biosynthetic pathway.","method":"Genetic deletion using chemical bypass (PfMevattB line), comparative genomics to identify pathway orthologs, apicoplast maintenance assays","journal":"bioRxiv : the preprint server for biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic deletion with defined organellar phenotype, but preprint and the MNMA-specific results here largely corroborate the published eLife 2023 findings; pathway placement via comparative genomics is supporting evidence","pmids":["39763917"],"is_preprint":true,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"MNMA (PF3D7_1019800) is a tRNA-specific 2-thiouridylase localized to the P. falciparum apicoplast, where it catalyzes the terminal s2U modification of wobble-position uridines in apicoplast tRNAs using sulfur supplied by the apicoplast cysteine desulfurase SufS; this activity is essential for apicoplast maintenance and parasite survival, and its hypomodulation underlies an epitranscriptomic mechanism contributing to artemisinin resistance."},"narrative":{"mechanistic_narrative":"MNMA (PF3D7_1019800) is a tRNA-specific 2-thiouridylase that operates in the P. falciparum apicoplast, where it is required for organelle maintenance and parasite survival [PMID:37166116]. Direct localization places MNMA in the apicoplast, and its genetic deletion (via chemical bypass) disrupts the organelle and eliminates the apicoplast genome, phenocopying loss of the apicoplast cysteine desulfurase SufS; complementation with a bacterial MnmA together with its cognate cysteine desulfurase indicates that parasite SufS supplies sulfur directly to MNMA for tRNA 2-thio modification [PMID:37166116]. MNMA catalyzes the terminal 2-thiouridine (s2U) step of the apicoplast wobble-position xm5s2U tRNA modification pathway, downstream of the xm5-generating enzymes MnmE and MnmG, whose deletion produces the same disrupted-apicoplast phenotype [PMID:39763917]. Beyond its role in organelle biology, conditional knockdown of MNMA in an artemisinin-sensitive background hypomodifies s2U and increases artemisinin survival, establishing an epitranscriptomic contribution to the parasite drug response; knockdown also shifts sensitivity to atovaquone, WLL, azithromycin, and fosmidomycin and yields defective schizonts [PMID:38632343].","teleology":[{"year":2023,"claim":"Establishing where MNMA acts and how it obtains its sulfur substrate resolved whether this thiouridylase functions in the apicoplast and depends on the organellar cysteine desulfurase.","evidence":"Direct apicoplast localization plus chemical-bypass deletion with organelle-maintenance readouts and heterologous complementation using bacterial MnmA and its cognate cysteine desulfurase in P. falciparum","pmids":["37166116"],"confidence":"High","gaps":["Physical/enzymatic interaction between MNMA and SufS not directly reconstituted in vitro","The specific apicoplast tRNA substrates modified by MNMA are not enumerated by this study"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2024,"claim":"Determining whether loss of s2U modification alters the drug response tested if MNMA activity is an epitranscriptomic modulator of artemisinin susceptibility rather than purely a housekeeping factor.","evidence":"Conditional knockdown of MNMA in an ART-sensitive P. falciparum Dd2 background with LC-MS/MS tRNA modification analysis, drug survival assays, proteomics/codon-bias analysis, and schizont morphology","pmids":["38632343"],"confidence":"High","gaps":["Mechanism linking s2U hypomodification to altered translation of specific proteins not fully resolved","How MNMA hypomodification is triggered in naturally ART-resistant parasites not established"],"attribution":[{"species":"Plasmodium falciparum","strain":"Dd2"}]},{"year":2025,"claim":"Placing MNMA within the xm5s2U biosynthetic pathway clarified that it performs the terminal 2-thio step downstream of the xm5-generating enzymes, unifying the organellar essentiality of the pathway.","evidence":"Chemical-bypass genetic deletion of MNMA, MnmE, and MnmG with apicoplast maintenance assays and comparative genomics in P. falciparum (preprint)","pmids":["39763917"],"confidence":"Medium","gaps":["Preprint; MNMA-specific results largely corroborate the 2023 eLife study","Pathway ordering rests on comparative genomics rather than direct biochemical sequencing of intermediates","Direct demonstration that MNMA acts strictly after MnmE/MnmG on the same tRNA not shown"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"The precise molecular coupling of SufS-derived sulfur to MNMA catalysis, the full set of apicoplast tRNA substrates, and the translational consequences that link s2U loss to drug-response phenotypes remain to be defined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No in vitro reconstitution of MNMA thiouridylase activity","No structural model of MNMA or of an MNMA–SufS complex","Codon-level mechanism connecting hypomodification to differential protein expression not established"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":["SUFS (APICOPLAST CYSTEINE DESULFURASE; SULFUR DONOR INFERRED FROM COMPLEMENTATION AND PHENOCOPY) [#0]","MNME / MNMG (UPSTREAM XM5 MODIFICATION ENZYMES IN THE SAME APICOPLAST XM5S2U PATHWAY) [#2]"],"other_free_text":["MNMA deletion causes loss of the apicoplast genome and organelle disruption, phenocopying SufS, MnmE, and MnmG loss [#0, #2]","Conditional knockdown hypomodifies s2U and increases artemisinin survival, altering sensitivity to atovaquone, WLL, azithromycin, and fosmidomycin and producing defective schizonts [#1]","Essential for apicoplast maintenance and parasite survival [#0, #2]"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"37166116","id":"PMC_37166116","title":"The Plasmodium falciparum apicoplast cysteine desulfurase provides sulfur for both iron-sulfur cluster assembly and tRNA modification.","date":"2023","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/37166116","citation_count":13,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["MNMA"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"39763917","id":"PMC_39763917","title":"tRNA modifying enzymes MnmE and MnmG are essential for Plasmodium falciparum apicoplast maintenance.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/39763917","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["MNMA"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"38632343","id":"","title":"tRNA modification reprogramming contributes to artemisinin resistance in Plasmodium falciparum.","date":"2024","source":"Nature microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/38632343","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["MNMA"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"38734409","id":"","title":"Charting new territory: The Plasmodium falciparum tRNA modification landscape.","date":"2024","source":"Biomedical journal","url":"https://pubmed.ncbi.nlm.nih.gov/38734409","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["MNMA"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"40113990","id":"","title":"tRNA lysidinylation is essential for the minimal translation system in the Plasmodium falciparum apicoplast.","date":"2025","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/40113990","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["MNMA"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6868,"output_tokens":1143,"usd":0.018874,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5979,"output_tokens":2224,"usd":0.042748,"stage2_stop_reason":"end_turn"},"total_usd":0.061622,"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\": 2023,\n      \"finding\": \"MNMA (PF3D7_1019800) was localized to the P. falciparum apicoplast by direct experiment. Deletion of MNMA (enabled by a chemical bypass method) caused disruption of the apicoplast organelle and loss of the organellar genome, phenocopying deletion of the cysteine desulfurase SufS. Complementation with a bacterial MnmA and its cognate cysteine desulfurase strongly suggests that parasite SufS provides sulfur directly to MNMA for tRNA 2-thio modification in the apicoplast.\",\n      \"method\": \"Chemical bypass deletion (PfMevattB line), organelle maintenance assays (loss of apicoplast genome readout), complementation with heterologous bacterial MnmA + cognate cysteine desulfurase\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic deletion with defined organellar phenotype, complementation with heterologous system, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"37166116\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Conditional knockdown of MNMA (PF3D7_1019800) in an ART-sensitive P. falciparum background led to increased artemisinin survival (phenocopying ART resistance), demonstrating that hypomodification of s2U on tRNA is sufficient to alter the parasite ART response. The knockdown also altered sensitivity to other drugs (increased tolerance to atovaquone and WLL; increased susceptibility to azithromycin and fosmidomycin) and caused formation of defective schizonts.\",\n      \"method\": \"Conditional knockdown (cKD) of MNMA combined with LC-MS/MS tRNA modification analysis, drug survival assays, and proteomic/codon-bias analysis\",\n      \"journal\": \"Nature microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockdown with multiple orthogonal readouts (tRNA modification by LC-MS/MS, drug survival, proteomics, schizont morphology) in a single rigorous study\",\n      \"pmids\": [\"38632343\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"Dd2\"}]\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Deletion of MNMA (PF3D7_1019800) in P. falciparum produces a 'disrupted apicoplast' phenotype (loss of apicoplast genome and appearance of multiple vesicles containing nucleus-encoded apicoplast proteins), establishing it as essential for apicoplast maintenance. This phenotype is also observed upon deletion of MnmE and MnmG, which catalyze the xm5 modification on the same tRNA wobble position (xm5s2U pathway), placing MNMA in the terminal s2U step of the apicoplast xm5s2U biosynthetic pathway.\",\n      \"method\": \"Genetic deletion using chemical bypass (PfMevattB line), comparative genomics to identify pathway orthologs, apicoplast maintenance assays\",\n      \"journal\": \"bioRxiv : the preprint server for biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic deletion with defined organellar phenotype, but preprint and the MNMA-specific results here largely corroborate the published eLife 2023 findings; pathway placement via comparative genomics is supporting evidence\",\n      \"pmids\": [\"39763917\"],\n      \"is_preprint\": true,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"MNMA (PF3D7_1019800) is a tRNA-specific 2-thiouridylase localized to the P. falciparum apicoplast, where it catalyzes the terminal s2U modification of wobble-position uridines in apicoplast tRNAs using sulfur supplied by the apicoplast cysteine desulfurase SufS; this activity is essential for apicoplast maintenance and parasite survival, and its hypomodulation underlies an epitranscriptomic mechanism contributing to artemisinin resistance.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MNMA (PF3D7_1019800) is a tRNA-specific 2-thiouridylase that operates in the P. falciparum apicoplast, where it is required for organelle maintenance and parasite survival [#0]. Direct localization places MNMA in the apicoplast, and its genetic deletion (via chemical bypass) disrupts the organelle and eliminates the apicoplast genome, phenocopying loss of the apicoplast cysteine desulfurase SufS; complementation with a bacterial MnmA together with its cognate cysteine desulfurase indicates that parasite SufS supplies sulfur directly to MNMA for tRNA 2-thio modification [#0]. MNMA catalyzes the terminal 2-thiouridine (s2U) step of the apicoplast wobble-position xm5s2U tRNA modification pathway, downstream of the xm5-generating enzymes MnmE and MnmG, whose deletion produces the same disrupted-apicoplast phenotype [#2]. Beyond its role in organelle biology, conditional knockdown of MNMA in an artemisinin-sensitive background hypomodifies s2U and increases artemisinin survival, establishing an epitranscriptomic contribution to the parasite drug response; knockdown also shifts sensitivity to atovaquone, WLL, azithromycin, and fosmidomycin and yields defective schizonts [#1].\",\n  \"teleology\": [\n    {\n      \"year\": 2023,\n      \"claim\": \"Establishing where MNMA acts and how it obtains its sulfur substrate resolved whether this thiouridylase functions in the apicoplast and depends on the organellar cysteine desulfurase.\",\n      \"evidence\": \"Direct apicoplast localization plus chemical-bypass deletion with organelle-maintenance readouts and heterologous complementation using bacterial MnmA and its cognate cysteine desulfurase in P. falciparum\",\n      \"pmids\": [\"37166116\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Physical/enzymatic interaction between MNMA and SufS not directly reconstituted in vitro\",\n        \"The specific apicoplast tRNA substrates modified by MNMA are not enumerated by this study\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Determining whether loss of s2U modification alters the drug response tested if MNMA activity is an epitranscriptomic modulator of artemisinin susceptibility rather than purely a housekeeping factor.\",\n      \"evidence\": \"Conditional knockdown of MNMA in an ART-sensitive P. falciparum Dd2 background with LC-MS/MS tRNA modification analysis, drug survival assays, proteomics/codon-bias analysis, and schizont morphology\",\n      \"pmids\": [\"38632343\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism linking s2U hypomodification to altered translation of specific proteins not fully resolved\",\n        \"How MNMA hypomodification is triggered in naturally ART-resistant parasites not established\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"Dd2\"}]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placing MNMA within the xm5s2U biosynthetic pathway clarified that it performs the terminal 2-thio step downstream of the xm5-generating enzymes, unifying the organellar essentiality of the pathway.\",\n      \"evidence\": \"Chemical-bypass genetic deletion of MNMA, MnmE, and MnmG with apicoplast maintenance assays and comparative genomics in P. falciparum (preprint)\",\n      \"pmids\": [\"39763917\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Preprint; MNMA-specific results largely corroborate the 2023 eLife study\",\n        \"Pathway ordering rests on comparative genomics rather than direct biochemical sequencing of intermediates\",\n        \"Direct demonstration that MNMA acts strictly after MnmE/MnmG on the same tRNA not shown\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The precise molecular coupling of SufS-derived sulfur to MNMA catalysis, the full set of apicoplast tRNA substrates, and the translational consequences that link s2U loss to drug-response phenotypes remain to be defined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No in vitro reconstitution of MNMA thiouridylase activity\",\n        \"No structural model of MNMA or of an MNMA–SufS complex\",\n        \"Codon-level mechanism connecting hypomodification to differential protein expression not established\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016783\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0002143\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0020011\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0002098\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"SufS (apicoplast cysteine desulfurase; sulfur donor inferred from complementation and phenocopy) [#0]\",\n      \"MnmE / MnmG (upstream xm5 modification enzymes in the same apicoplast xm5s2U pathway) [#2]\"\n    ],\n    \"other_free_text\": [\n      \"MNMA deletion causes loss of the apicoplast genome and organelle disruption, phenocopying SufS, MnmE, and MnmG loss [#0, #2]\",\n      \"Conditional knockdown hypomodifies s2U and increases artemisinin survival, altering sensitivity to atovaquone, WLL, azithromycin, and fosmidomycin and producing defective schizonts [#1]\",\n      \"Essential for apicoplast maintenance and parasite survival [#0, #2]\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1019800","name":null,"product":"tRNA-specific 2-thiouridylase MnmA","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_0504000","name":null,"product":"tRNA methyltransferase, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_0604000","name":null,"product":"tRNA methyltransferase, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"MNMA","evaluation":null}