{"gene":"SEPHS1","run_date":"2026-04-28T20:42:07","timeline":{"discoveries":[{"year":2004,"finding":"Human SEPHS1 (Sps1) uses L-selenocysteine as a selenium substrate (via a selenocysteine lyase salvage pathway) rather than selenite, in contrast to SEPHS2 which assimilates selenite directly. This was established by in vivo complementation of an E. coli selD mutant: Sps1 provided weak complementation with selenite but better complementation when L-selenocysteine was supplied, indicating substrate specificity distinct from SEPHS2.","method":"In vivo complementation assay in E. coli selD mutant with exogenous selenium sources; measurement of formate dehydrogenase H activity as readout","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 1 in vivo functional assay; single lab, single study","pmids":["15534230"],"is_preprint":false},{"year":2008,"finding":"SPS1 (SEPHS1) ortholog is present in insects that entirely lack selenoproteins and the selenocysteine biosynthesis/insertion machinery, demonstrating that SPS1 functions in a pathway unrelated to selenoprotein synthesis. This was established by comparative genomics across arthropod species.","method":"Comparative genomic/phylogenomic analysis of selenoproteomes across insects including Tribolium castaneum and Bombyx mori, which retain SPS1 but lack all other Sec machinery","journal":"Protein science : a publication of the Protein Society","confidence":"Medium","confidence_rationale":"Tier 2 — strong genomic evidence from multiple species; single method but replicated across many taxa","pmids":["18156471"],"is_preprint":false},{"year":2003,"finding":"In Drosophila, null mutation of selD (the SPS1/SEPHS1 homolog) causes impairment of selenoprotein biosynthesis, accumulation of reactive oxygen species (ROS), and triggers apoptosis through stabilization of Dmp53, transcriptional induction of reaper, activation of initiator caspase DRONC, and processing of effector caspase DRICE. Ectopic DIAP1 expression rescues viability of mutant cells.","method":"Genetic loss-of-function (null mutation selDptuf) in Drosophila imaginal discs; epistasis analysis with hid, Dmp53, rpr; caspase activity assays; rescue by DIAP1 overexpression","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with multiple orthogonal readouts (apoptosis markers, caspase processing, genetic rescue); moderate evidence from single lab","pmids":["14576353"],"is_preprint":false},{"year":2017,"finding":"SEPHS1 forms oligomers in mammalian cells and interacts with SEPHS2, SEPSECS (selenocysteine synthase), and SECp43, establishing SEPHS1 as a physical component of the selenocysteine biosynthesis/incorporation protein complex. SEPHS2–SEPSECS and SEPHS2–SEPHS1 interactions were confirmed by co-immunoprecipitation.","method":"Bioluminescence resonance energy transfer (BRET) assay in mammalian cells; co-immunoprecipitation; small-angle X-ray scattering of SECp43; phage display to map interaction sites","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (BRET + Co-IP + SAXS) from single lab; interactions confirmed by two independent assays","pmids":["28414460"],"is_preprint":false},{"year":2022,"finding":"SEPHS1 retains ATPase activity (producing ADP and inorganic phosphate) but has lost selenophosphate synthesis activity due to the absence of Sec or Cys at the catalytic position. The three-dimensional structural model of the SEPHS1 homodimer confirms it cannot form selenophosphate. Phylogenetic analysis shows the ancestral SEPHS contained both selenophosphate synthesis and another unknown activity, and that SEPHS1 specifically lost the selenophosphate synthesis function.","method":"Structural modeling of SEPHS1 homodimer; ATPase activity assay; phylogenetic analysis of SEPHS paralogs","journal":"Archives of biochemistry and biophysics","confidence":"Medium","confidence_rationale":"Tier 1-2 — structural modeling combined with enzymatic assay; single review/analysis paper","pmids":["36202216"],"is_preprint":false},{"year":2021,"finding":"SEPHS1 is a positive regulator of SMAD2/3/4 expression and TGF-β/SMAD signaling in hepatocellular carcinoma cells. SEPHS1 knockdown decreases SMAD2/3/4 protein levels and mesenchymal markers (snail, slug, N-cadherin), reduces cell migration and invasion, and suppresses TGF-β-stimulated invasion. SMAD3 knockdown abrogates the pro-invasive effect of SEPHS1 overexpression.","method":"siRNA knockdown and overexpression in HCC cell lines; Western blotting for SMAD2/3/4 and EMT markers; transwell migration/invasion assay; epistasis via SMAD3 knockdown","journal":"Experimental hematology & oncology","confidence":"Medium","confidence_rationale":"Tier 2-3 — clean KD/OE with defined cellular phenotype and pathway placement via epistasis; single lab","pmids":["33622411"],"is_preprint":false},{"year":2021,"finding":"SEPHS1 deficiency in mouse endothelial cells (2H11) causes accumulation of superoxide and lipid peroxide, reduction of nitric oxide, inhibition of cell proliferation, G2/M arrest with increased γH2AX foci, and impaired angiogenic tube formation. Superoxide accumulation results from induction of xanthine oxidase and NADPH oxidase and decreased SOD1/SOD3.","method":"CRISPR/Cas9 knockout of Sephs1 in 2H11 cells; ROS measurement (superoxide, lipid peroxide, nitric oxide); cell proliferation assay; flow cytometry cell cycle analysis; γH2AX immunofluorescence; tube formation assay","journal":"International journal of molecular sciences","confidence":"High","confidence_rationale":"Tier 2 — clean KO with multiple orthogonal cellular phenotype readouts and mechanistic pathway characterization; single lab","pmids":["34769076"],"is_preprint":false},{"year":2021,"finding":"SEPHS1 deficiency in mouse embryos disturbs redox homeostasis in a time-dependent manner during gastrulation, progressively altering signaling pathways including retinoic acid signaling, coagulation, Wnt, prolactin, and insulin-like growth hormone signaling before triggering apoptosis and DNA damage at E9.5. Systemic Sephs1 knockout mice exhibit developmental retardation and die by E11.5.","method":"Systemic Sephs1 knockout mice; transcriptomic/bioinformatic pathway analysis at E6.5, E7.5, E8.5; histological and morphological analysis; DNA damage (γH2AX) and apoptosis markers at E9.5","journal":"International journal of molecular sciences","confidence":"High","confidence_rationale":"Tier 2 — in vivo knockout with bioinformatics-driven pathway identification verified by structural/morphological phenotypes; multiple time points","pmids":["34769078"],"is_preprint":false},{"year":2019,"finding":"SEPHS1 is required for acquisition of pluripotency and for survival of human embryonic stem cells (hESCs). SEPHS1 knockdown reduces reprogramming efficiency and alters expression of ROS pathway and apoptosis genes without affecting pluripotency gene expression, indicating a role in stem cell survival via selenium-mediated redox signaling.","method":"siRNA knockdown of SEPHS1 in hESCs; reprogramming efficiency assay; transcriptome analysis; clonogenicity assay; selenium treatment dose-response","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2-3 — KD with multiple phenotypic readouts (reprogramming, clonogenicity, transcriptomics); single lab","pmids":["31607477"],"is_preprint":false},{"year":2021,"finding":"SEPHS1 is dispensable for mouse ESC pluripotency maintenance and proliferation but is indispensable for cardiac differentiation. Sephs1 KO ESCs fail to produce beating embryoid bodies, express low levels of cardiac and contraction markers, and show impaired differentiation into all three germ layers.","method":"CRISPR/Cas9 Sephs1 KO in mouse ESCs; embryoid body beating assay; RNA-seq analysis; germ layer differentiation assay; gastruloid aggregation","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO with RNA-seq and functional differentiation assay; single lab","pmids":["34974300"],"is_preprint":false},{"year":2022,"finding":"SPS1 deficiency in Drosophila S2 cells activates the innate immune system by upregulating PGRP-LC (IMD pathway) and Toll expression, leading to increased antimicrobial peptide expression. Double knockdown epistasis showed that both IMD and Toll pathways cross-talk to regulate AMP expression downstream of SPS1.","method":"RNAi knockdown of Sps1 in Drosophila S2 cells; double knockdown epistasis with PGRP-LC and Toll; AMP expression quantification by RT-qPCR; overexpression experiments","journal":"Biology open","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis with overexpression validation in Drosophila cells; single lab","pmids":["35723425"],"is_preprint":false},{"year":2024,"finding":"Heterozygous missense variants in SEPHS1 exon 9 (particularly at residue Arg371) cause a neurodevelopmental disorder with developmental delay, growth/feeding problems, hypotonia, and dysmorphic features. Biochemical assays showed that Trp352 variants reduce thermal stability of the enzyme, while Arg371 variants do not affect stability but modulate protein-protein interactions. SEPHS1 variants enhance cell proliferation by modulating ROS homeostasis in neuronal SH-SY5Y cells.","method":"Human genetics (9 individuals, 8 families); structural modeling; thermal stability biochemical assays; cell proliferation assay; ROS measurement; mRNA expression of stress-related selenoproteins in SH-SY5Y cells","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 1-2 — structural modeling + biochemical thermal stability + cell biology + human genetics; multiple orthogonal methods; recurrent variant in multiple unrelated individuals","pmids":["38531365"],"is_preprint":false},{"year":2023,"finding":"SEPHS1 delays nucleus pulposus cell senescence by reducing ROS production, and its overexpression or inhibition of downstream Hippo-Yap/Taz signaling alleviates intervertebral disc degeneration in rats. Selenium-deficient diet and SEPHS1 deficiency synergistically aggravate IVDD, placing SEPHS1 upstream of the Hippo-Yap/Taz pathway in oxidative stress-driven senescence.","method":"IL-1β-induced NPC senescence model in vitro; Sephs1 overexpression; ROS measurement; rat needle puncture IVDD model in vivo; Hippo-Yap/Taz pathway inhibition; selenium-deficient diet intervention","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro and in vivo models with pathway epistasis; single lab, moderate evidence","pmids":["38105759"],"is_preprint":false}],"current_model":"SEPHS1 is a eukaryotic selenophosphate synthetase paralog that has lost selenophosphate synthesis activity but retains ATPase activity; it physically interacts with SEPHS2, SEPSECS, and SECp43 as part of the selenocysteine biosynthesis complex, functions primarily as a regulator of cellular redox homeostasis (controlling superoxide, ROS, and nitric oxide levels) by modulating xanthine oxidase, NADPH oxidase, and SOD activities, and is required for embryonic development, cardiac differentiation, and stem cell survival—with its loss causing ROS accumulation that progressively dysregulates multiple signaling pathways (retinoic acid, Wnt, TGF-β/SMAD, Hippo-Yap/Taz) and ultimately triggers apoptosis and developmental lethality."},"narrative":{"teleology":[{"year":2003,"claim":"The first functional link between SEPHS1/SPS1 and redox biology was established when Drosophila selD null mutants were shown to accumulate ROS and activate a p53–caspase apoptotic cascade, revealing that SPS1 loss is cell-lethal through oxidative stress rather than simply through selenoprotein depletion.","evidence":"Genetic null mutation in Drosophila imaginal discs with epistasis analysis of Dmp53, reaper, DRONC, DRICE, and rescue by DIAP1","pmids":["14576353"],"confidence":"High","gaps":["Mechanism by which SPS1 loss elevates ROS was unknown","Whether this apoptotic pathway operates in mammals was untested","Whether SPS1 function is separable from selenoprotein biosynthesis was unclear"]},{"year":2004,"claim":"Establishing that SEPHS1 and SEPHS2 differ in selenium substrate preference resolved a long-standing ambiguity about paralog redundancy: SEPHS1 preferentially uses L-selenocysteine (salvage pathway) rather than selenite, suggesting distinct metabolic roles for the two paralogs.","evidence":"In vivo complementation of E. coli selD mutant with different selenium sources; formate dehydrogenase H activity readout","pmids":["15534230"],"confidence":"Medium","gaps":["Whether SEPHS1 synthesizes selenophosphate at all under physiological conditions was debated","The biological significance of substrate specificity in mammalian cells was not addressed","Complementation was weak, leaving open whether it reflects a secondary activity"]},{"year":2008,"claim":"Comparative genomics across arthropods demonstrated that SPS1 orthologs persist in species that completely lack selenoproteins and Sec incorporation machinery, definitively establishing that SPS1 functions in a pathway independent of selenoprotein biosynthesis.","evidence":"Phylogenomic analysis of selenoproteomes across insects including Tribolium castaneum and Bombyx mori","pmids":["18156471"],"confidence":"Medium","gaps":["The selenoprotein-independent function of SPS1 was not identified","Whether the selenoprotein-independent role is conserved in vertebrates was unknown"]},{"year":2017,"claim":"Despite functioning independently of selenophosphate synthesis, SEPHS1 was shown to physically associate with SEPHS2, SEPSECS, and SECp43 within the selenocysteine biosynthesis complex, establishing it as a structural component that may regulate complex assembly or activity.","evidence":"BRET assay and co-immunoprecipitation in mammalian cells; SAXS of SECp43; phage display interaction mapping","pmids":["28414460"],"confidence":"High","gaps":["Functional consequence of SEPHS1's presence in the complex was not determined","Whether SEPHS1 regulates SEPHS2 enzymatic activity within the complex was untested","Stoichiometry and dynamics of the complex in vivo were not resolved"]},{"year":2019,"claim":"SEPHS1 was linked to stem cell biology when its knockdown reduced reprogramming efficiency and survival of human ESCs through altered ROS and apoptosis gene expression, establishing a requirement for SEPHS1 in maintaining redox balance during pluripotency acquisition.","evidence":"siRNA knockdown in hESCs with reprogramming efficiency, clonogenicity, and transcriptome readouts","pmids":["31607477"],"confidence":"Medium","gaps":["Whether SEPHS1's role in reprogramming is direct or secondary to ROS accumulation was unclear","Rescue by antioxidant supplementation was not tested"]},{"year":2021,"claim":"The molecular mechanism of ROS accumulation upon SEPHS1 loss was resolved: SEPHS1 deficiency induces xanthine oxidase and NADPH oxidase while decreasing SOD1/SOD3, causing superoxide and lipid peroxide accumulation and nitric oxide depletion, with downstream consequences including DNA damage, G2/M arrest, and impaired angiogenesis.","evidence":"CRISPR knockout in mouse endothelial cells with measurement of superoxide, lipid peroxide, NO, γH2AX, cell cycle, and tube formation","pmids":["34769076"],"confidence":"High","gaps":["How SEPHS1 regulates xanthine oxidase and NADPH oxidase expression or activity is unknown","Whether ATPase activity of SEPHS1 is required for redox regulation was not tested"]},{"year":2021,"claim":"In vivo knockout established that SEPHS1 is essential for mouse embryonic development: Sephs1-null embryos die by E11.5 with progressive dysregulation of retinoic acid, Wnt, and other signaling pathways preceding DNA damage and apoptosis during gastrulation, demonstrating that redox control by SEPHS1 is upstream of multiple developmental signaling cascades.","evidence":"Systemic Sephs1 KO mice; transcriptomic time-course at E6.5–E8.5; histology and γH2AX/apoptosis markers at E9.5","pmids":["34769078"],"confidence":"High","gaps":["Which tissue(s) are primarily responsible for lethality was not determined by conditional KO","Whether antioxidant supplementation can rescue developmental lethality was not tested"]},{"year":2021,"claim":"SEPHS1 was placed upstream of TGF-β/SMAD signaling and EMT: its knockdown decreases SMAD2/3/4 levels and mesenchymal markers in hepatocellular carcinoma cells, and SMAD3 epistasis confirms SEPHS1 acts through this pathway to promote invasion, extending its signaling role beyond development.","evidence":"siRNA knockdown and overexpression in HCC cell lines; Western blot for SMAD2/3/4 and EMT markers; transwell assay; SMAD3 epistasis","pmids":["33622411"],"confidence":"Medium","gaps":["Whether SEPHS1's effect on SMAD levels is transcriptional or post-translational was not resolved","Whether this is mediated through ROS or a parallel mechanism was not established"]},{"year":2021,"claim":"SEPHS1 KO in mouse ESCs demonstrated it is dispensable for pluripotency maintenance but indispensable for cardiac differentiation and tri-lineage germ layer commitment, refining the understanding that SEPHS1's critical role is in differentiation rather than self-renewal.","evidence":"CRISPR KO in mouse ESCs; embryoid body beating assay; RNA-seq; germ layer and gastruloid assays","pmids":["34974300"],"confidence":"Medium","gaps":["Which specific differentiation signals require SEPHS1 was not identified","Whether redox imbalance is the sole cause of differentiation failure was not tested"]},{"year":2022,"claim":"Structural and enzymatic characterization confirmed that SEPHS1 retains ATPase activity but cannot synthesize selenophosphate due to the absence of Sec/Cys at its catalytic position, resolving the long-standing question of whether SEPHS1 is a catalytically dead paralog or has a modified enzymatic function.","evidence":"SEPHS1 homodimer structural modeling; ATPase activity assay; phylogenetic analysis of SEPHS paralogs","pmids":["36202216"],"confidence":"Medium","gaps":["The biological substrate or product of SEPHS1's ATPase activity is unknown","Whether ATPase activity is required for SEPHS1's redox regulatory function has not been tested by catalytic-dead mutants"]},{"year":2022,"claim":"SPS1 deficiency in Drosophila was shown to activate innate immune signaling through both IMD and Toll pathways, broadening SEPHS1's functional repertoire beyond redox regulation to immune defense.","evidence":"RNAi knockdown and double-knockdown epistasis in Drosophila S2 cells; RT-qPCR for antimicrobial peptides","pmids":["35723425"],"confidence":"Medium","gaps":["Whether immune activation is a direct function of SPS1 or secondary to ROS accumulation was not distinguished","Relevance to mammalian innate immunity was not examined"]},{"year":2023,"claim":"SEPHS1 was positioned upstream of Hippo-Yap/Taz signaling in oxidative stress-driven cellular senescence, with its overexpression or Hippo pathway inhibition alleviating intervertebral disc degeneration in vivo, adding another downstream signaling cascade regulated by SEPHS1-dependent redox control.","evidence":"IL-1β-induced NPC senescence model; Sephs1 overexpression; rat IVDD model; Hippo-Yap/Taz pathway inhibition; selenium-deficient diet","pmids":["38105759"],"confidence":"Medium","gaps":["Mechanism linking SEPHS1 to Hippo pathway regulation is unknown","Whether Hippo pathway dysregulation contributes to embryonic lethality in Sephs1 KO mice was not tested"]},{"year":2024,"claim":"Human genetic evidence established that heterozygous missense variants in SEPHS1 cause a neurodevelopmental disorder, linking its redox-regulatory function to brain development and providing the first Mendelian disease association.","evidence":"Cohort of 9 individuals from 8 families with exon 9 variants; thermal stability assays; ROS and proliferation assays in SH-SY5Y neuronal cells","pmids":["38531365"],"confidence":"High","gaps":["Whether variants act as loss-of-function, gain-of-function, or dominant-negative is not fully resolved","Animal models recapitulating the neurodevelopmental phenotype have not been generated","The specific neuronal cell types and developmental windows affected are unknown"]},{"year":null,"claim":"The direct molecular mechanism by which SEPHS1's ATPase activity controls ROS-generating and ROS-scavenging enzymes remains unknown, as does the identity of any physiological substrate beyond ATP.","evidence":"","pmids":[],"confidence":"High","gaps":["No substrate or product of SEPHS1 ATPase beyond ADP/Pi has been identified","Catalytic-dead mutant analysis to separate ATPase from scaffolding functions has not been performed","Tissue-specific conditional knockouts to define critical cell types for developmental lethality are lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[4]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[6,7]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[6,7,12]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[2,7]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[7,9]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,12]}],"complexes":["selenocysteine biosynthesis complex"],"partners":["SEPHS2","SEPSECS","SECP43"],"other_free_text":[]},"mechanistic_narrative":"SEPHS1 is a selenophosphate synthetase paralog that has lost selenophosphate synthesis activity but retains ATPase activity, functioning primarily as a guardian of cellular redox homeostasis essential for embryonic development and cell differentiation [PMID:36202216, PMID:34769078]. SEPHS1 physically associates with SEPHS2, SEPSECS, and SECp43 within the selenocysteine biosynthesis complex, though its own catalytic role is independent of selenophosphate production [PMID:28414460, PMID:18156471]. Loss of SEPHS1 causes superoxide and lipid peroxide accumulation through induction of xanthine oxidase and NADPH oxidase coupled with decreased SOD activity, progressively dysregulating retinoic acid, Wnt, TGF-β/SMAD, and Hippo-Yap/Taz signaling pathways, ultimately triggering DNA damage and apoptosis [PMID:34769076, PMID:34769078, PMID:38105759, PMID:33622411]. Heterozygous missense variants in SEPHS1 cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, and dysmorphic features [PMID:38531365]."},"prefetch_data":{"uniprot":{"accession":"P49903","full_name":"Zincore component SEPHS1","aliases":["Selenide, water dikinase 1","Selenium donor protein 1","Selenophosphate synthase 1"],"length_aa":392,"mass_kda":42.9,"function":"Core component of the zincore complex, a heterotetramer that acts as a molecular 'grip' to stabilize transcription factors at DNA-binding sites across the genome, thereby controlling gene expression (PubMed:40608935). The zincore complex binds specifically to zinc finger transcription factors, such as ZFP91, ZNF652, ZNF526 and PRDM15, and stabilizes them onto their cognate DNA motif (PubMed:40608935). Within the complex, SEPHS1, recognizes and binds the backbone of zinc fingers of transcription factors in a sequence-independent manner via its arginine clamp, enhancing their DNA-binding stability (PubMed:40608935). Plays an essential role in redox homeostasis (PubMed:31607477). May also be involved in selenocysteine biosynthesis by catalyzing formation of selenophosphate from selenide and ATP (PubMed:7665581). Its role in selenocysteine biosynthesis is however unclear and several studies suggest that it does not act as a selenophosphate synthase in vivo or plays an non-essential role (PubMed:15534230). 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This was established by in vivo complementation of an E. coli selD mutant: Sps1 provided weak complementation with selenite but better complementation when L-selenocysteine was supplied, indicating substrate specificity distinct from SEPHS2.\",\n      \"method\": \"In vivo complementation assay in E. coli selD mutant with exogenous selenium sources; measurement of formate dehydrogenase H activity as readout\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 in vivo functional assay; single lab, single study\",\n      \"pmids\": [\"15534230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SPS1 (SEPHS1) ortholog is present in insects that entirely lack selenoproteins and the selenocysteine biosynthesis/insertion machinery, demonstrating that SPS1 functions in a pathway unrelated to selenoprotein synthesis. This was established by comparative genomics across arthropod species.\",\n      \"method\": \"Comparative genomic/phylogenomic analysis of selenoproteomes across insects including Tribolium castaneum and Bombyx mori, which retain SPS1 but lack all other Sec machinery\",\n      \"journal\": \"Protein science : a publication of the Protein Society\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — strong genomic evidence from multiple species; single method but replicated across many taxa\",\n      \"pmids\": [\"18156471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"In Drosophila, null mutation of selD (the SPS1/SEPHS1 homolog) causes impairment of selenoprotein biosynthesis, accumulation of reactive oxygen species (ROS), and triggers apoptosis through stabilization of Dmp53, transcriptional induction of reaper, activation of initiator caspase DRONC, and processing of effector caspase DRICE. Ectopic DIAP1 expression rescues viability of mutant cells.\",\n      \"method\": \"Genetic loss-of-function (null mutation selDptuf) in Drosophila imaginal discs; epistasis analysis with hid, Dmp53, rpr; caspase activity assays; rescue by DIAP1 overexpression\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with multiple orthogonal readouts (apoptosis markers, caspase processing, genetic rescue); moderate evidence from single lab\",\n      \"pmids\": [\"14576353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SEPHS1 forms oligomers in mammalian cells and interacts with SEPHS2, SEPSECS (selenocysteine synthase), and SECp43, establishing SEPHS1 as a physical component of the selenocysteine biosynthesis/incorporation protein complex. SEPHS2–SEPSECS and SEPHS2–SEPHS1 interactions were confirmed by co-immunoprecipitation.\",\n      \"method\": \"Bioluminescence resonance energy transfer (BRET) assay in mammalian cells; co-immunoprecipitation; small-angle X-ray scattering of SECp43; phage display to map interaction sites\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (BRET + Co-IP + SAXS) from single lab; interactions confirmed by two independent assays\",\n      \"pmids\": [\"28414460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SEPHS1 retains ATPase activity (producing ADP and inorganic phosphate) but has lost selenophosphate synthesis activity due to the absence of Sec or Cys at the catalytic position. The three-dimensional structural model of the SEPHS1 homodimer confirms it cannot form selenophosphate. Phylogenetic analysis shows the ancestral SEPHS contained both selenophosphate synthesis and another unknown activity, and that SEPHS1 specifically lost the selenophosphate synthesis function.\",\n      \"method\": \"Structural modeling of SEPHS1 homodimer; ATPase activity assay; phylogenetic analysis of SEPHS paralogs\",\n      \"journal\": \"Archives of biochemistry and biophysics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — structural modeling combined with enzymatic assay; single review/analysis paper\",\n      \"pmids\": [\"36202216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SEPHS1 is a positive regulator of SMAD2/3/4 expression and TGF-β/SMAD signaling in hepatocellular carcinoma cells. SEPHS1 knockdown decreases SMAD2/3/4 protein levels and mesenchymal markers (snail, slug, N-cadherin), reduces cell migration and invasion, and suppresses TGF-β-stimulated invasion. SMAD3 knockdown abrogates the pro-invasive effect of SEPHS1 overexpression.\",\n      \"method\": \"siRNA knockdown and overexpression in HCC cell lines; Western blotting for SMAD2/3/4 and EMT markers; transwell migration/invasion assay; epistasis via SMAD3 knockdown\",\n      \"journal\": \"Experimental hematology & oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — clean KD/OE with defined cellular phenotype and pathway placement via epistasis; single lab\",\n      \"pmids\": [\"33622411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SEPHS1 deficiency in mouse endothelial cells (2H11) causes accumulation of superoxide and lipid peroxide, reduction of nitric oxide, inhibition of cell proliferation, G2/M arrest with increased γH2AX foci, and impaired angiogenic tube formation. Superoxide accumulation results from induction of xanthine oxidase and NADPH oxidase and decreased SOD1/SOD3.\",\n      \"method\": \"CRISPR/Cas9 knockout of Sephs1 in 2H11 cells; ROS measurement (superoxide, lipid peroxide, nitric oxide); cell proliferation assay; flow cytometry cell cycle analysis; γH2AX immunofluorescence; tube formation assay\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with multiple orthogonal cellular phenotype readouts and mechanistic pathway characterization; single lab\",\n      \"pmids\": [\"34769076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SEPHS1 deficiency in mouse embryos disturbs redox homeostasis in a time-dependent manner during gastrulation, progressively altering signaling pathways including retinoic acid signaling, coagulation, Wnt, prolactin, and insulin-like growth hormone signaling before triggering apoptosis and DNA damage at E9.5. Systemic Sephs1 knockout mice exhibit developmental retardation and die by E11.5.\",\n      \"method\": \"Systemic Sephs1 knockout mice; transcriptomic/bioinformatic pathway analysis at E6.5, E7.5, E8.5; histological and morphological analysis; DNA damage (γH2AX) and apoptosis markers at E9.5\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo knockout with bioinformatics-driven pathway identification verified by structural/morphological phenotypes; multiple time points\",\n      \"pmids\": [\"34769078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SEPHS1 is required for acquisition of pluripotency and for survival of human embryonic stem cells (hESCs). SEPHS1 knockdown reduces reprogramming efficiency and alters expression of ROS pathway and apoptosis genes without affecting pluripotency gene expression, indicating a role in stem cell survival via selenium-mediated redox signaling.\",\n      \"method\": \"siRNA knockdown of SEPHS1 in hESCs; reprogramming efficiency assay; transcriptome analysis; clonogenicity assay; selenium treatment dose-response\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — KD with multiple phenotypic readouts (reprogramming, clonogenicity, transcriptomics); single lab\",\n      \"pmids\": [\"31607477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SEPHS1 is dispensable for mouse ESC pluripotency maintenance and proliferation but is indispensable for cardiac differentiation. Sephs1 KO ESCs fail to produce beating embryoid bodies, express low levels of cardiac and contraction markers, and show impaired differentiation into all three germ layers.\",\n      \"method\": \"CRISPR/Cas9 Sephs1 KO in mouse ESCs; embryoid body beating assay; RNA-seq analysis; germ layer differentiation assay; gastruloid aggregation\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with RNA-seq and functional differentiation assay; single lab\",\n      \"pmids\": [\"34974300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SPS1 deficiency in Drosophila S2 cells activates the innate immune system by upregulating PGRP-LC (IMD pathway) and Toll expression, leading to increased antimicrobial peptide expression. Double knockdown epistasis showed that both IMD and Toll pathways cross-talk to regulate AMP expression downstream of SPS1.\",\n      \"method\": \"RNAi knockdown of Sps1 in Drosophila S2 cells; double knockdown epistasis with PGRP-LC and Toll; AMP expression quantification by RT-qPCR; overexpression experiments\",\n      \"journal\": \"Biology open\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with overexpression validation in Drosophila cells; single lab\",\n      \"pmids\": [\"35723425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Heterozygous missense variants in SEPHS1 exon 9 (particularly at residue Arg371) cause a neurodevelopmental disorder with developmental delay, growth/feeding problems, hypotonia, and dysmorphic features. Biochemical assays showed that Trp352 variants reduce thermal stability of the enzyme, while Arg371 variants do not affect stability but modulate protein-protein interactions. SEPHS1 variants enhance cell proliferation by modulating ROS homeostasis in neuronal SH-SY5Y cells.\",\n      \"method\": \"Human genetics (9 individuals, 8 families); structural modeling; thermal stability biochemical assays; cell proliferation assay; ROS measurement; mRNA expression of stress-related selenoproteins in SH-SY5Y cells\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — structural modeling + biochemical thermal stability + cell biology + human genetics; multiple orthogonal methods; recurrent variant in multiple unrelated individuals\",\n      \"pmids\": [\"38531365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SEPHS1 delays nucleus pulposus cell senescence by reducing ROS production, and its overexpression or inhibition of downstream Hippo-Yap/Taz signaling alleviates intervertebral disc degeneration in rats. Selenium-deficient diet and SEPHS1 deficiency synergistically aggravate IVDD, placing SEPHS1 upstream of the Hippo-Yap/Taz pathway in oxidative stress-driven senescence.\",\n      \"method\": \"IL-1β-induced NPC senescence model in vitro; Sephs1 overexpression; ROS measurement; rat needle puncture IVDD model in vivo; Hippo-Yap/Taz pathway inhibition; selenium-deficient diet intervention\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo models with pathway epistasis; single lab, moderate evidence\",\n      \"pmids\": [\"38105759\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SEPHS1 is a eukaryotic selenophosphate synthetase paralog that has lost selenophosphate synthesis activity but retains ATPase activity; it physically interacts with SEPHS2, SEPSECS, and SECp43 as part of the selenocysteine biosynthesis complex, functions primarily as a regulator of cellular redox homeostasis (controlling superoxide, ROS, and nitric oxide levels) by modulating xanthine oxidase, NADPH oxidase, and SOD activities, and is required for embryonic development, cardiac differentiation, and stem cell survival—with its loss causing ROS accumulation that progressively dysregulates multiple signaling pathways (retinoic acid, Wnt, TGF-β/SMAD, Hippo-Yap/Taz) and ultimately triggers apoptosis and developmental lethality.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SEPHS1 is a selenophosphate synthetase paralog that has lost selenophosphate synthesis activity but retains ATPase activity, functioning primarily as a guardian of cellular redox homeostasis essential for embryonic development and cell differentiation [PMID:36202216, PMID:34769078]. SEPHS1 physically associates with SEPHS2, SEPSECS, and SECp43 within the selenocysteine biosynthesis complex, though its own catalytic role is independent of selenophosphate production [PMID:28414460, PMID:18156471]. Loss of SEPHS1 causes superoxide and lipid peroxide accumulation through induction of xanthine oxidase and NADPH oxidase coupled with decreased SOD activity, progressively dysregulating retinoic acid, Wnt, TGF-β/SMAD, and Hippo-Yap/Taz signaling pathways, ultimately triggering DNA damage and apoptosis [PMID:34769076, PMID:34769078, PMID:38105759, PMID:33622411]. Heterozygous missense variants in SEPHS1 cause a neurodevelopmental disorder characterized by developmental delay, hypotonia, and dysmorphic features [PMID:38531365].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"The first functional link between SEPHS1/SPS1 and redox biology was established when Drosophila selD null mutants were shown to accumulate ROS and activate a p53–caspase apoptotic cascade, revealing that SPS1 loss is cell-lethal through oxidative stress rather than simply through selenoprotein depletion.\",\n      \"evidence\": \"Genetic null mutation in Drosophila imaginal discs with epistasis analysis of Dmp53, reaper, DRONC, DRICE, and rescue by DIAP1\",\n      \"pmids\": [\"14576353\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which SPS1 loss elevates ROS was unknown\",\n        \"Whether this apoptotic pathway operates in mammals was untested\",\n        \"Whether SPS1 function is separable from selenoprotein biosynthesis was unclear\"\n      ]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Establishing that SEPHS1 and SEPHS2 differ in selenium substrate preference resolved a long-standing ambiguity about paralog redundancy: SEPHS1 preferentially uses L-selenocysteine (salvage pathway) rather than selenite, suggesting distinct metabolic roles for the two paralogs.\",\n      \"evidence\": \"In vivo complementation of E. coli selD mutant with different selenium sources; formate dehydrogenase H activity readout\",\n      \"pmids\": [\"15534230\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether SEPHS1 synthesizes selenophosphate at all under physiological conditions was debated\",\n        \"The biological significance of substrate specificity in mammalian cells was not addressed\",\n        \"Complementation was weak, leaving open whether it reflects a secondary activity\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Comparative genomics across arthropods demonstrated that SPS1 orthologs persist in species that completely lack selenoproteins and Sec incorporation machinery, definitively establishing that SPS1 functions in a pathway independent of selenoprotein biosynthesis.\",\n      \"evidence\": \"Phylogenomic analysis of selenoproteomes across insects including Tribolium castaneum and Bombyx mori\",\n      \"pmids\": [\"18156471\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The selenoprotein-independent function of SPS1 was not identified\",\n        \"Whether the selenoprotein-independent role is conserved in vertebrates was unknown\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Despite functioning independently of selenophosphate synthesis, SEPHS1 was shown to physically associate with SEPHS2, SEPSECS, and SECp43 within the selenocysteine biosynthesis complex, establishing it as a structural component that may regulate complex assembly or activity.\",\n      \"evidence\": \"BRET assay and co-immunoprecipitation in mammalian cells; SAXS of SECp43; phage display interaction mapping\",\n      \"pmids\": [\"28414460\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Functional consequence of SEPHS1's presence in the complex was not determined\",\n        \"Whether SEPHS1 regulates SEPHS2 enzymatic activity within the complex was untested\",\n        \"Stoichiometry and dynamics of the complex in vivo were not resolved\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"SEPHS1 was linked to stem cell biology when its knockdown reduced reprogramming efficiency and survival of human ESCs through altered ROS and apoptosis gene expression, establishing a requirement for SEPHS1 in maintaining redox balance during pluripotency acquisition.\",\n      \"evidence\": \"siRNA knockdown in hESCs with reprogramming efficiency, clonogenicity, and transcriptome readouts\",\n      \"pmids\": [\"31607477\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether SEPHS1's role in reprogramming is direct or secondary to ROS accumulation was unclear\",\n        \"Rescue by antioxidant supplementation was not tested\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The molecular mechanism of ROS accumulation upon SEPHS1 loss was resolved: SEPHS1 deficiency induces xanthine oxidase and NADPH oxidase while decreasing SOD1/SOD3, causing superoxide and lipid peroxide accumulation and nitric oxide depletion, with downstream consequences including DNA damage, G2/M arrest, and impaired angiogenesis.\",\n      \"evidence\": \"CRISPR knockout in mouse endothelial cells with measurement of superoxide, lipid peroxide, NO, γH2AX, cell cycle, and tube formation\",\n      \"pmids\": [\"34769076\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How SEPHS1 regulates xanthine oxidase and NADPH oxidase expression or activity is unknown\",\n        \"Whether ATPase activity of SEPHS1 is required for redox regulation was not tested\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"In vivo knockout established that SEPHS1 is essential for mouse embryonic development: Sephs1-null embryos die by E11.5 with progressive dysregulation of retinoic acid, Wnt, and other signaling pathways preceding DNA damage and apoptosis during gastrulation, demonstrating that redox control by SEPHS1 is upstream of multiple developmental signaling cascades.\",\n      \"evidence\": \"Systemic Sephs1 KO mice; transcriptomic time-course at E6.5–E8.5; histology and γH2AX/apoptosis markers at E9.5\",\n      \"pmids\": [\"34769078\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Which tissue(s) are primarily responsible for lethality was not determined by conditional KO\",\n        \"Whether antioxidant supplementation can rescue developmental lethality was not tested\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"SEPHS1 was placed upstream of TGF-β/SMAD signaling and EMT: its knockdown decreases SMAD2/3/4 levels and mesenchymal markers in hepatocellular carcinoma cells, and SMAD3 epistasis confirms SEPHS1 acts through this pathway to promote invasion, extending its signaling role beyond development.\",\n      \"evidence\": \"siRNA knockdown and overexpression in HCC cell lines; Western blot for SMAD2/3/4 and EMT markers; transwell assay; SMAD3 epistasis\",\n      \"pmids\": [\"33622411\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether SEPHS1's effect on SMAD levels is transcriptional or post-translational was not resolved\",\n        \"Whether this is mediated through ROS or a parallel mechanism was not established\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"SEPHS1 KO in mouse ESCs demonstrated it is dispensable for pluripotency maintenance but indispensable for cardiac differentiation and tri-lineage germ layer commitment, refining the understanding that SEPHS1's critical role is in differentiation rather than self-renewal.\",\n      \"evidence\": \"CRISPR KO in mouse ESCs; embryoid body beating assay; RNA-seq; germ layer and gastruloid assays\",\n      \"pmids\": [\"34974300\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Which specific differentiation signals require SEPHS1 was not identified\",\n        \"Whether redox imbalance is the sole cause of differentiation failure was not tested\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Structural and enzymatic characterization confirmed that SEPHS1 retains ATPase activity but cannot synthesize selenophosphate due to the absence of Sec/Cys at its catalytic position, resolving the long-standing question of whether SEPHS1 is a catalytically dead paralog or has a modified enzymatic function.\",\n      \"evidence\": \"SEPHS1 homodimer structural modeling; ATPase activity assay; phylogenetic analysis of SEPHS paralogs\",\n      \"pmids\": [\"36202216\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The biological substrate or product of SEPHS1's ATPase activity is unknown\",\n        \"Whether ATPase activity is required for SEPHS1's redox regulatory function has not been tested by catalytic-dead mutants\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"SPS1 deficiency in Drosophila was shown to activate innate immune signaling through both IMD and Toll pathways, broadening SEPHS1's functional repertoire beyond redox regulation to immune defense.\",\n      \"evidence\": \"RNAi knockdown and double-knockdown epistasis in Drosophila S2 cells; RT-qPCR for antimicrobial peptides\",\n      \"pmids\": [\"35723425\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether immune activation is a direct function of SPS1 or secondary to ROS accumulation was not distinguished\",\n        \"Relevance to mammalian innate immunity was not examined\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"SEPHS1 was positioned upstream of Hippo-Yap/Taz signaling in oxidative stress-driven cellular senescence, with its overexpression or Hippo pathway inhibition alleviating intervertebral disc degeneration in vivo, adding another downstream signaling cascade regulated by SEPHS1-dependent redox control.\",\n      \"evidence\": \"IL-1β-induced NPC senescence model; Sephs1 overexpression; rat IVDD model; Hippo-Yap/Taz pathway inhibition; selenium-deficient diet\",\n      \"pmids\": [\"38105759\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism linking SEPHS1 to Hippo pathway regulation is unknown\",\n        \"Whether Hippo pathway dysregulation contributes to embryonic lethality in Sephs1 KO mice was not tested\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Human genetic evidence established that heterozygous missense variants in SEPHS1 cause a neurodevelopmental disorder, linking its redox-regulatory function to brain development and providing the first Mendelian disease association.\",\n      \"evidence\": \"Cohort of 9 individuals from 8 families with exon 9 variants; thermal stability assays; ROS and proliferation assays in SH-SY5Y neuronal cells\",\n      \"pmids\": [\"38531365\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether variants act as loss-of-function, gain-of-function, or dominant-negative is not fully resolved\",\n        \"Animal models recapitulating the neurodevelopmental phenotype have not been generated\",\n        \"The specific neuronal cell types and developmental windows affected are unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct molecular mechanism by which SEPHS1's ATPase activity controls ROS-generating and ROS-scavenging enzymes remains unknown, as does the identity of any physiological substrate beyond ATP.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No substrate or product of SEPHS1 ATPase beyond ADP/Pi has been identified\",\n        \"Catalytic-dead mutant analysis to separate ATPase from scaffolding functions has not been performed\",\n        \"Tissue-specific conditional knockouts to define critical cell types for developmental lethality are lacking\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [6, 7, 12]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [2, 7]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [7, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 12]}\n    ],\n    \"complexes\": [\n      \"selenocysteine biosynthesis complex\"\n    ],\n    \"partners\": [\n      \"SEPHS2\",\n      \"SEPSECS\",\n      \"SECp43\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}