{"gene":"PF3D7_0922200","run_date":"2026-09-08T12:51:27","timeline":{"discoveries":[{"year":1999,"finding":"PF3D7_0922200 (SAMS) was cloned and shown to encode a 402 amino acid polypeptide (44844 Da) that catalyses the formation of S-adenosylmethionine from methionine and ATP (EC 2.5.1.6). The gene contains no introns and maps to chromosome 9. Molecular modelling guided by E. coli SAMS crystal structure indicates PfSAMS binds ATP/Mg2+ similarly to E. coli SAMS but cannot form tetramers and is likely a dimer instead. Expressed PfSAMS showed differential sensitivity to cycloleucine inhibition compared to human hepatic SAMS (Ki 17 mM vs. 10 mM, respectively), demonstrating enzymatic activity and structural differences from the human ortholog.","method":"Gene cloning, recombinant protein expression, in vitro enzymatic assay with cycloleucine inhibition (Ki determination), molecular modelling guided by E. coli crystal structure, phylogenetic analysis","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 1-2 / Weak — in vitro enzymatic characterization and inhibition assay with mutagenesis-level structural inference by modelling, but single lab, no crystal structure of PfSAMS itself and no mutagenesis of active-site residues reported","pmids":["10567242"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2016,"finding":"PF3D7_0922200 (SAMS, referred to as PfalMAT) enzymatic activity is subject to redox regulation: reduced thioredoxin increases its activity, while S-glutathionylation and S-nitrosylation inhibit it. Site-directed mutagenesis and homology modelling identified Cys52, Cys113, and Cys187 as residues contributing to redox regulation by influencing enzyme structure and activity, linking cellular S-adenosylmethionine synthesis to the cellular redox state.","method":"In vitro enzymatic activity assay, S-glutathionylation and S-nitrosylation treatments, recombinant thioredoxin addition, site-directed mutagenesis of cysteine residues (Cys52, Cys113, Cys187), homology modelling","journal":"Journal of biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay combined with site-directed mutagenesis of specific residues and multiple orthogonal redox modification treatments (S-glutathionylation, S-nitrosylation, reduced thioredoxin) in a single study","pmids":["27466371"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2022,"finding":"PF3D7_0922200 (SAMS) colocalizes with PfTPx-1 (thioredoxin peroxidase I) in the nucleus of P. falciparum, and overexpression of PfSAMS leads to activation of var2csa (similar to PfTPx-1 overexpression), placing SAMS in a nuclear pathway involved in var gene activation.","method":"Colocalization microscopy of SAMS and PfTPx-1 in the nucleus, overexpression experiments with var2csa activation as functional readout","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2-3 / Weak — colocalization and overexpression phenotype from a single lab; SAMS is a secondary finding in a paper primarily focused on PfTPx-1 and lncRNA, with limited mechanistic detail about SAMS itself","pmids":["35939693"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2010,"finding":"Following inhibition of PfSpdSyn (spermidine synthase) in P. falciparum 3D7, SAMS (S-adenosylmethionine synthetase) was differentially expressed at both the transcript and protein level, indicating that SAMS expression is responsive to perturbation of the polyamine biosynthetic pathway.","method":"Global transcriptomic analysis (gene expression microarray), proteomic analysis following PfSpdSyn inhibition with cyclohexylamine","journal":"BMC genomics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — differential expression at transcript/protein level shown in a perturbation study; no direct mechanistic experiment on SAMS itself, single lab, pathway placement inferred from correlation","pmids":["20385001"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":"3D7"}]}],"current_model":"PF3D7_0922200 (SAMS) is a dimeric S-adenosylmethionine synthetase that catalyses AdoMet formation from methionine and ATP; its enzymatic activity is upregulated by reduced thioredoxin and inhibited by S-glutathionylation and S-nitrosylation via key cysteine residues (Cys52, Cys113, Cys187), linking AdoMet synthesis to cellular redox state; it also localizes to the nucleus where it colocalizes with PfTPx-1 and, upon overexpression, activates var gene expression."},"narrative":{"mechanistic_narrative":"PF3D7_0922200 (SAMS) is the P. falciparum S-adenosylmethionine synthetase, catalysing AdoMet formation from methionine and ATP (EC 2.5.1.6); recombinant enzyme is active in vitro, binds ATP/Mg2+ as in the E. coli enzyme, and is inferred by modelling to function as a dimer rather than a tetramer, with a cycloleucine sensitivity distinct from the human ortholog [PMID:10567242]. Its catalytic output is coupled to cellular redox state: reduced thioredoxin stimulates activity while S-glutathionylation and S-nitrosylation inhibit it, with Cys52, Cys113 and Cys187 identified as the cysteine residues mediating this regulation [PMID:27466371]. Beyond its metabolic role, SAMS colocalizes with the thioredoxin peroxidase PfTPx-1 in the nucleus, and its overexpression activates var2csa expression, placing it in a nuclear pathway linked to var gene activation [PMID:35939693]. No crystal structure of PfSAMS itself, and no direct genetic essentiality or knockout phenotype, has been characterized in the available corpus.","teleology":[{"year":1999,"claim":"Establishing that the P. falciparum gene encodes a functional AdoMet synthetase answered whether the parasite possesses its own catalytically active, structurally distinct enzyme for AdoMet supply.","evidence":"Gene cloning, recombinant expression and in vitro enzymatic/cycloleucine inhibition assay with E. coli-guided molecular modelling","pmids":["10567242"],"confidence":"Medium","gaps":["No experimental crystal structure of PfSAMS; oligomeric state inferred by modelling only","No mutagenesis of active-site residues to confirm catalytic mechanism","Dimer prediction not biochemically validated"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2010,"claim":"Perturbation of polyamine biosynthesis revealed that SAMS expression is not constitutive but responds to metabolic flux, hinting at pathway-level co-regulation.","evidence":"Transcriptomic and proteomic profiling after PfSpdSyn inhibition with cyclohexylamine in strain 3D7","pmids":["20385001"],"confidence":"Low","gaps":["Correlative expression change only, no direct mechanistic test on SAMS","Does not establish whether SAMS drives or merely responds to polyamine pathway state","Regulatory mechanism of the expression change unknown"],"attribution":[{"species":"Plasmodium falciparum","strain":"3D7"}]},{"year":2016,"claim":"Identifying redox-sensitive cysteines answered how AdoMet synthesis is coupled to the parasite's redox environment, defining a post-translational control layer on the enzyme.","evidence":"In vitro activity assays with reduced thioredoxin, S-glutathionylation and S-nitrosylation treatments plus site-directed mutagenesis of Cys52/Cys113/Cys187 and homology modelling","pmids":["27466371"],"confidence":"High","gaps":["Redox regulation shown in vitro; physiological relevance in living parasites not demonstrated","Structural basis of cysteine-dependent modulation rests on homology modelling","Interplay of the three cysteines not fully dissected"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2022,"claim":"Localizing SAMS to the nucleus with PfTPx-1 and linking its overexpression to var2csa activation extended the enzyme beyond metabolism into a candidate role in antigenic variation.","evidence":"Colocalization microscopy with PfTPx-1 and overexpression experiments using var2csa activation as readout","pmids":["35939693"],"confidence":"Medium","gaps":["SAMS is a secondary finding; direct mechanism connecting its activity to var activation not established","Colocalization does not demonstrate a physical or functional complex","Whether AdoMet-dependent methylation underlies the var effect is untested"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"How SAMS-derived AdoMet mechanistically couples redox regulation to nuclear var gene activation, and whether the gene is essential, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No genetic knockout/essentiality data in the corpus","No experimental structure of PfSAMS","Causal link between AdoMet output and var activation undefined"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":["PFTPX-1 (THIOREDOXIN PEROXIDASE I) — NUCLEAR COLOCALIZATION [#2]","THIOREDOXIN (REDUCED) — ACTIVATOR OF ENZYMATIC ACTIVITY [#1]"],"other_free_text":["Predicted homodimer (not tetramer) by molecular modelling; no experimental structure [#0]","Redox regulation via Cys52, Cys113, Cys187; inhibited by S-glutathionylation and S-nitrosylation [#1]","Distinct cycloleucine sensitivity from human ortholog (Ki 17 mM vs 10 mM) [#0]","Expression responsive to polyamine pathway perturbation (PfSpdSyn inhibition) [#3]","Overexpression activates var2csa [#2]"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"20385001","id":"PMC_20385001","title":"Plasmodium falciparum spermidine synthase inhibition results in unique perturbation-specific effects observed on transcript, protein and metabolite levels.","date":"2010","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/20385001","citation_count":20,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["S-adenosylmethionine synthetase"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"10567242","id":"PMC_10567242","title":"Molecular characterization of Plasmodium falciparum S-adenosylmethionine synthetase.","date":"1999","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/10567242","citation_count":17,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["S-adenosylmethionine synthetase","SAMS"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"35939693","id":"PMC_35939693","title":"A nuclear redox sensor modulates gene activation and var switching in Plasmodium falciparum.","date":"2022","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/35939693","citation_count":15,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["S-adenosylmethionine synthetase"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"27466371","id":"PMC_27466371","title":"Characterization and redox regulation of Plasmodium falciparum methionine adenosyltransferase.","date":"2016","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27466371","citation_count":9,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["curated_ref"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":5298,"output_tokens":1508,"usd":0.019257,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6464,"output_tokens":2232,"usd":0.04406,"stage2_stop_reason":"end_turn"},"total_usd":0.063317,"stage1_batch_id":"msgbatch_01DisAaTypwmC8QwdMBuePHo","stage2_batch_id":"msgbatch_0184zxZTqxiEfdYYfPMfkqjb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"PF3D7_0922200 (SAMS) was cloned and shown to encode a 402 amino acid polypeptide (44844 Da) that catalyses the formation of S-adenosylmethionine from methionine and ATP (EC 2.5.1.6). The gene contains no introns and maps to chromosome 9. Molecular modelling guided by E. coli SAMS crystal structure indicates PfSAMS binds ATP/Mg2+ similarly to E. coli SAMS but cannot form tetramers and is likely a dimer instead. Expressed PfSAMS showed differential sensitivity to cycloleucine inhibition compared to human hepatic SAMS (Ki 17 mM vs. 10 mM, respectively), demonstrating enzymatic activity and structural differences from the human ortholog.\",\n      \"method\": \"Gene cloning, recombinant protein expression, in vitro enzymatic assay with cycloleucine inhibition (Ki determination), molecular modelling guided by E. coli crystal structure, phylogenetic analysis\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Weak — in vitro enzymatic characterization and inhibition assay with mutagenesis-level structural inference by modelling, but single lab, no crystal structure of PfSAMS itself and no mutagenesis of active-site residues reported\",\n      \"pmids\": [\"10567242\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PF3D7_0922200 (SAMS, referred to as PfalMAT) enzymatic activity is subject to redox regulation: reduced thioredoxin increases its activity, while S-glutathionylation and S-nitrosylation inhibit it. Site-directed mutagenesis and homology modelling identified Cys52, Cys113, and Cys187 as residues contributing to redox regulation by influencing enzyme structure and activity, linking cellular S-adenosylmethionine synthesis to the cellular redox state.\",\n      \"method\": \"In vitro enzymatic activity assay, S-glutathionylation and S-nitrosylation treatments, recombinant thioredoxin addition, site-directed mutagenesis of cysteine residues (Cys52, Cys113, Cys187), homology modelling\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay combined with site-directed mutagenesis of specific residues and multiple orthogonal redox modification treatments (S-glutathionylation, S-nitrosylation, reduced thioredoxin) in a single study\",\n      \"pmids\": [\"27466371\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PF3D7_0922200 (SAMS) colocalizes with PfTPx-1 (thioredoxin peroxidase I) in the nucleus of P. falciparum, and overexpression of PfSAMS leads to activation of var2csa (similar to PfTPx-1 overexpression), placing SAMS in a nuclear pathway involved in var gene activation.\",\n      \"method\": \"Colocalization microscopy of SAMS and PfTPx-1 in the nucleus, overexpression experiments with var2csa activation as functional readout\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Weak — colocalization and overexpression phenotype from a single lab; SAMS is a secondary finding in a paper primarily focused on PfTPx-1 and lncRNA, with limited mechanistic detail about SAMS itself\",\n      \"pmids\": [\"35939693\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Following inhibition of PfSpdSyn (spermidine synthase) in P. falciparum 3D7, SAMS (S-adenosylmethionine synthetase) was differentially expressed at both the transcript and protein level, indicating that SAMS expression is responsive to perturbation of the polyamine biosynthetic pathway.\",\n      \"method\": \"Global transcriptomic analysis (gene expression microarray), proteomic analysis following PfSpdSyn inhibition with cyclohexylamine\",\n      \"journal\": \"BMC genomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — differential expression at transcript/protein level shown in a perturbation study; no direct mechanistic experiment on SAMS itself, single lab, pathway placement inferred from correlation\",\n      \"pmids\": [\"20385001\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"}]\n    }\n  ],\n  \"current_model\": \"PF3D7_0922200 (SAMS) is a dimeric S-adenosylmethionine synthetase that catalyses AdoMet formation from methionine and ATP; its enzymatic activity is upregulated by reduced thioredoxin and inhibited by S-glutathionylation and S-nitrosylation via key cysteine residues (Cys52, Cys113, Cys187), linking AdoMet synthesis to cellular redox state; it also localizes to the nucleus where it colocalizes with PfTPx-1 and, upon overexpression, activates var gene expression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PF3D7_0922200 (SAMS) is the P. falciparum S-adenosylmethionine synthetase, catalysing AdoMet formation from methionine and ATP (EC 2.5.1.6); recombinant enzyme is active in vitro, binds ATP/Mg2+ as in the E. coli enzyme, and is inferred by modelling to function as a dimer rather than a tetramer, with a cycloleucine sensitivity distinct from the human ortholog [#0]. Its catalytic output is coupled to cellular redox state: reduced thioredoxin stimulates activity while S-glutathionylation and S-nitrosylation inhibit it, with Cys52, Cys113 and Cys187 identified as the cysteine residues mediating this regulation [#1]. Beyond its metabolic role, SAMS colocalizes with the thioredoxin peroxidase PfTPx-1 in the nucleus, and its overexpression activates var2csa expression, placing it in a nuclear pathway linked to var gene activation [#2]. No crystal structure of PfSAMS itself, and no direct genetic essentiality or knockout phenotype, has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Establishing that the P. falciparum gene encodes a functional AdoMet synthetase answered whether the parasite possesses its own catalytically active, structurally distinct enzyme for AdoMet supply.\",\n      \"evidence\": \"Gene cloning, recombinant expression and in vitro enzymatic/cycloleucine inhibition assay with E. coli-guided molecular modelling\",\n      \"pmids\": [\"10567242\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No experimental crystal structure of PfSAMS; oligomeric state inferred by modelling only\", \"No mutagenesis of active-site residues to confirm catalytic mechanism\", \"Dimer prediction not biochemically validated\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Perturbation of polyamine biosynthesis revealed that SAMS expression is not constitutive but responds to metabolic flux, hinting at pathway-level co-regulation.\",\n      \"evidence\": \"Transcriptomic and proteomic profiling after PfSpdSyn inhibition with cyclohexylamine in strain 3D7\",\n      \"pmids\": [\"20385001\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Correlative expression change only, no direct mechanistic test on SAMS\", \"Does not establish whether SAMS drives or merely responds to polyamine pathway state\", \"Regulatory mechanism of the expression change unknown\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"}]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identifying redox-sensitive cysteines answered how AdoMet synthesis is coupled to the parasite's redox environment, defining a post-translational control layer on the enzyme.\",\n      \"evidence\": \"In vitro activity assays with reduced thioredoxin, S-glutathionylation and S-nitrosylation treatments plus site-directed mutagenesis of Cys52/Cys113/Cys187 and homology modelling\",\n      \"pmids\": [\"27466371\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Redox regulation shown in vitro; physiological relevance in living parasites not demonstrated\", \"Structural basis of cysteine-dependent modulation rests on homology modelling\", \"Interplay of the three cysteines not fully dissected\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Localizing SAMS to the nucleus with PfTPx-1 and linking its overexpression to var2csa activation extended the enzyme beyond metabolism into a candidate role in antigenic variation.\",\n      \"evidence\": \"Colocalization microscopy with PfTPx-1 and overexpression experiments using var2csa activation as readout\",\n      \"pmids\": [\"35939693\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SAMS is a secondary finding; direct mechanism connecting its activity to var activation not established\", \"Colocalization does not demonstrate a physical or functional complex\", \"Whether AdoMet-dependent methylation underlies the var effect is untested\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SAMS-derived AdoMet mechanistically couples redox regulation to nuclear var gene activation, and whether the gene is essential, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No genetic knockout/essentiality data in the corpus\", \"No experimental structure of PfSAMS\", \"Causal link between AdoMet output and var activation undefined\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0004478\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0006556\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"PfTPx-1 (thioredoxin peroxidase I) — nuclear colocalization [#2]\",\n      \"thioredoxin (reduced) — activator of enzymatic activity [#1]\"\n    ],\n    \"other_free_text\": [\n      \"Predicted homodimer (not tetramer) by molecular modelling; no experimental structure [#0]\",\n      \"Redox regulation via Cys52, Cys113, Cys187; inhibited by S-glutathionylation and S-nitrosylation [#1]\",\n      \"Distinct cycloleucine sensitivity from human ortholog (Ki 17 mM vs 10 mM) [#0]\",\n      \"Expression responsive to polyamine pathway perturbation (PfSpdSyn inhibition) [#3]\",\n      \"Overexpression activates var2csa [#2]\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_0922200","name":null,"product":"S-adenosylmethionine synthetase","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_0823100","name":null,"product":"S-adenosylmethionine synthetase, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_0720200","name":null,"product":"S-adenosylmethionine synthetase, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"SAMS","evaluation":null}