SEPHS2 (selenophosphate synthetase 2, selenide/water dikinase 2, EC 2.7.9.3) is the catalytically active human enzyme that synthesizes the activated selenium donor for selenocysteine biosynthesis. It catalyzes the ATP- and Mg2+-dependent conversion of hydrogenselenide (selenide) plus water to monoselenophosphate, releasing AMP and phosphate. The monoselenophosphate product is the immediate selenium donor used by selenocysteine synthase (SEPSECS) to convert O-phosphoseryl-tRNA(Sec) to selenocysteyl-tRNA(Sec), thereby supplying selenocysteine for the whole selenoproteome. SEPHS2 is itself a selenoprotein: it carries a catalytic selenocysteine (encoded by an in-frame UGA read through via the Sec-insertion machinery), so its own synthesis depends on the pathway it supplies, an autoregulatory arrangement. The enzyme is a homodimer with an ATP-binding site shared between the dimeric partners, adopts a PurM-like fold, and acts in the cytosol. It associates with other components of the selenocysteine biosynthesis/incorporation machinery, including its paralog SEPHS1, the selenocysteine synthase SEPSECS, and TRNAU1AP/SECp43.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) annotation placing SEPHS2 activity in the cytoplasm. Consistent with the direct IDA localization (PMID:28414460), the Reactome cytosol assignment, and the soluble, non-membrane PurM-like enzyme. Accept. Supporting Evidence: file:human/SEPHS2/SEPHS2-uniprot.txt Cytoplasm {ECO:0000269|PubMed:28414460} |
| GO:0016260 L-selenocysteine biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) annotation to L-selenocysteine biosynthetic process. This is the correct core biological process: SEPHS2 makes the selenophosphate donor consumed in selenocysteine synthesis. Concordant with the IMP (PMID:15534230), Reactome TAS, and NAS support. Accept as a core process annotation. Supporting Evidence: PMID:8986768 the selenium donor compound required for synthesis of selenocysteine |
| GO:0004756 selenide, water dikinase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) annotation to the core catalytic molecular function. This is the defining activity of SEPHS2 (EC 2.7.9.3), directly supported by human enzymology (PMID:15534230), UniProt FUNCTION/CATALYTIC ACTIVITY, and Reactome. Accept as the core molecular function. Supporting Evidence: file:human/SEPHS2/SEPHS2-uniprot.txt Selenophosphate synthase that generates the selenium donor |
| GO:0004756 selenide, water dikinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Automated (IEA) assertion of the core catalytic function, backed by Rhea RHEA:18737 / EC 2.7.9.3 and ortholog transfer. Redundant with the IBA/ISS/TAS/NAS instances of the same well-supported activity. Accept. |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro (IEA) ATP binding annotation. ATP is a genuine co-substrate of the selenide, water dikinase reaction and UniProt annotates multiple ATP-binding residues (shared between the dimeric partners). This is a real, mechanistically relevant molecular function directly supporting catalysis. Accept. Supporting Evidence: file:human/SEPHS2/SEPHS2-uniprot.txt selenophosphate from selenide and ATP |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Automated (IEA) cytoplasm annotation derived from the UniProt subcellular location mapping. Redundant with, and corroborated by, the experimental IDA cytoplasm annotation (PMID:28414460). Accept. Supporting Evidence: file:human/SEPHS2/SEPHS2-uniprot.txt Cytoplasm {ECO:0000269|PubMed:28414460} |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: Bare 'protein binding' from a high-throughput AP-MS interactome screen (BioPlex 3.0), with WITH/FROM SEPHS1 (P49903). The interaction is real and corroborated by the SEPHS1-SEPHS2 oligomerization/co-IP data (PMID:28414460) and UniProt INTERACTION, but the term conveys no specific molecular function. Per policy, IPI protein binding is not removed; mark as over-annotated and retain as an interaction detail rather than a core function. Supporting Evidence: PMID:33961781 BioPlex suggests function, localization, and complex membership for thousands of proteins |
| GO:0016260 L-selenocysteine biosynthetic process | IEA GO_REF:0000120 | ACCEPT | Summary: Automated (IEA) annotation to L-selenocysteine biosynthetic process (ARBA + ortholog transfer). Redundant with the experimentally supported IMP and the IBA/TAS/NAS instances of this core process. Accept. |
| GO:0016260 L-selenocysteine biosynthetic process | TAS Reactome:R-HSA-2408557 | ACCEPT | Summary: Reactome (TAS) placement of SEPHS2 in the 'Selenocysteine synthesis' pathway, corresponding to the core biological process. Concordant with experimental evidence. Accept. |
| GO:0004756 selenide, water dikinase activity | TAS Reactome:R-HSA-8959510 | ACCEPT | Summary: Reactome (TAS) annotation of the core catalytic function, representing the reaction in which SEPHS2 converts selenide (H2Se) to selenophosphate. Concordant with UniProt and the human enzymology. Accept. Supporting Evidence: file:human/SEPHS2/SEPHS2-uniprot.txt selenophosphate from selenide and ATP |
| GO:0004756 selenide, water dikinase activity | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity (ISS) transfer of the core catalytic function from the mouse ortholog (P97364). Consistent with the direct human characterization. Accept. |
| GO:0005737 cytoplasm | IDA PMID:28414460 Analysis of Novel Interactions between Components of the Sel... | ACCEPT | Summary: Direct experimental (IDA) evidence that SEPHS2 localizes to the cytoplasm (PMID:28414460). This is the strongest localization annotation and matches the soluble, non-membrane nature of the enzyme. Accept. Supporting Evidence: file:human/SEPHS2/SEPHS2-uniprot.txt Cytoplasm {ECO:0000269|PubMed:28414460} |
| GO:0016260 L-selenocysteine biosynthetic process | IMP PMID:15534230 Selenophosphate synthetase genes from lung adenocarcinoma ce... | ACCEPT | Summary: Experimental (IMP) support: human Sps2 (as the Cys form) complemented an E. coli selD mutant, restoring selenoprotein (formate dehydrogenase H) activity, demonstrating its role in supplying selenophosphate for selenocysteine synthesis. The strongest evidence for this core biological process. Accept. Supporting Evidence: PMID:15534230 A labile selenium donor compound monoselenophosphate is synthesized from selenide and ATP by selenophosphate synthetase |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8959510 | ACCEPT | Summary: Reactome (TAS) cytosol localization for the SEPHS2 reaction. Consistent with the IDA cytoplasm annotation and the soluble enzyme; cytosol is a more precise cellular location. Accept. Supporting Evidence: file:human/SEPHS2/SEPHS2-uniprot.txt Cytoplasm {ECO:0000269|PubMed:28414460} |
| GO:0004756 selenide, water dikinase activity | NAS PMID:8986768 Identification of a novel selD homolog from eukaryotes, bact... | ACCEPT | Summary: Non-traceable author statement (NAS) from the original Sps2 cloning paper attributing selenophosphate synthetase (selenide, water dikinase) activity to SEPHS2. Now backed by direct experimental characterization (PMID:15534230). Accept. Supporting Evidence: PMID:8986768 the selenium donor compound required for synthesis of selenocysteine |
| GO:0016260 L-selenocysteine biosynthetic process | NAS PMID:8986768 Identification of a novel selD homolog from eukaryotes, bact... | ACCEPT | Summary: NAS annotation to L-selenocysteine biosynthetic process from the original Sps2 paper, which established that the selenophosphate product is required for selenocysteine synthesis and that SPS2 is itself a selenoenzyme (autoregulatory). Concordant with the IMP. Accept. Supporting Evidence: PMID:8986768 SPS2 is a selenoenzyme |
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