UniProt: Q99611 (SPS2_HUMAN). Gene: SEPHS2 (synonym SPS2). 448 aa. HGNC:19686.
SEPHS2 = Selenide, water dikinase 2 (EC 2.7.9.3), also "Selenium donor protein 2" /
"Selenophosphate synthase 2". It is the catalytically active human selenophosphate
synthetase.
The reaction product, monoselenophosphate, is the activated selenium donor used
downstream by SEPSECS to convert O-phosphoseryl-tRNA(Sec) to selenocysteyl-tRNA(Sec),
supplying Sec for all selenoproteins.
PMID:15534230 (Tamura et al. 2004, abstract only): "A labile selenium donor compound
monoselenophosphate is synthesized from selenide and ATP by selenophosphate synthetase
(SPS)." Sps2 was cloned from human lung adenocarcinoma cells; the in-frame TGA was
mutated to TGT (Cys) for expression; Sps2Cys effectively complemented an E. coli selD
mutant, restoring formate dehydrogenase H activity, whereas Sps1 only weakly
complemented. Conclusion: "the Sps2 enzyme can function with a selenite assimilation
system" (Sps1 recycles L-selenocysteine). This is the IMP support for involvement in
L-selenocysteine biosynthetic process (GO:0016260) and the EC=2.7.9.3 basis.
PMID:8986768 (Guimarães et al. 1996, full text): original cloning of human/mouse Sps2
(selD homolog). "Escherichia coli selenophosphate synthetase (SPS, the selD gene
product) catalyzes the production of monoselenophosphate, the selenium donor compound
required for synthesis of selenocysteine (Sec) and seleno-tRNAs." Sps2 has an in-frame
TGA at the putative active site. Using a FLAG-tagged mouse SPS2 they documented
"readthrough of the in-frame TGA codon and the incorporation of 75Se into SPS2",
concluding "SPS2 is a selenoenzyme" and proposing an autoregulatory loop ("the
incorporation of Sec into SPS2"). NAS support for MF and BP.
UniProt FT NON_STD 60 = Selenocysteine; ACT_SITE 60; KW "Selenocysteine", "Selenium".
The catalytic residue is a Sec (U) at position 60. Thus SEPHS2's own synthesis depends
on the selenocysteine biosynthesis pathway it feeds — an autoregulatory feature
PMID:8986768.
MUTAGEN U60->C "Does not affect the selenophosphate synthase activity"
(ECO:0000269|PubMed:15534230), so the Cys mutant is catalytically competent — this is why
the recombinant Sps2Cys form was used for the E. coli complementation assay.
Human paralog SEPHS1 (SPS1, P49903) does NOT contain Sec (has Thr/Arg at the homologous
position) and is proposed to act in a selenium salvage/recycling role rather than de novo
selenophosphate synthesis; its exact enzymatic function is debated. SEPHS2 is the
Sec-containing, catalytically active enzyme for de novo selenophosphate synthesis.
UniProt SUBUNIT: "Homodimer (By similarity). Component of a complex composed of SEPHS1,
SEPHS2, SEPSECS and TRNAU1AP" (PubMed:16508009, PubMed:28414460).
[file:human/SEPHS2/SEPHS2-uniprot.txt]
PMID:28414460 (Oudouhou et al. 2017, abstract only): BRET in mammalian cells showed
"selenophosphate synthetases SEPHS1 and SEPHS2 form oligomers in eukaryotic cells";
"SEPHS2 interacts with SEPSECS and SEPHS1; these interactions were confirmed by
co-immunoprecipitation." Also reports SEPHS2 SUBCELLULAR LOCATION (cytoplasm) — the
source of the IDA cytoplasm annotation.
PMID:33961781 (Huttlin et al. 2021, BioPlex 3.0): the source of the IPI "protein
binding" (GO:0005515) annotation. GOA WITH/FROM = UniProtKB:P49903 (SEPHS1), consistent
with the SEPHS1–SEPHS2 interaction. This is a high-throughput AP-MS screen; "BioPlex
suggests function, localization, and complex membership for thousands of proteins". The
IPI captures a real, corroborated interaction (SEPHS1) but "protein binding" is
uninformative as a molecular function; kept as non-core (interaction detail).
SIMILARITY: "Belongs to the selenophosphate synthase 1 family. Class I subfamily."
PurM-like fold (Pfam AIRS / AIRS_C; CDD SelD; TIGR selD; PANTHER PTHR10256:SF1 "SELENIDE,
WATER DIKINASE 2"). ATP- and Mg2+-binding residues annotated by similarity to P49903;
ATP is "ligand shared between dimeric partners" (consistent with the functional
homodimer). [file:human/SEPHS2/SEPHS2-uniprot.txt]
Core:
- MF GO:0004756 selenide, water dikinase activity (enables) — ACCEPT (IBA/ISS); the two
literature-supported instances (Reactome TAS R-HSA-8959510; NAS PMID:8986768) ACCEPT;
the redundant IEA also ACCEPT.
- BP GO:0016260 L-selenocysteine biosynthetic process (involved_in) — ACCEPT (IMP
PMID:15534230 is the strongest); IBA/IEA/TAS/NAS instances ACCEPT.
- CC cytoplasm/cytosol — ACCEPT (IDA PMID:28414460 strongest; IBA is_active_in and
IEA/TAS ACCEPT).
- MF GO:0005524 ATP binding (IEA, InterPro) — ACCEPT; ATP is a genuine substrate/ligand
(FT BINDING; Rhea reaction), directly part of catalysis.
Non-core:
- MF GO:0005515 protein binding (IPI PMID:33961781, with SEPHS1) — MARK_AS_OVER_ANNOTATED
(uninformative bare protein binding; per policy never REMOVE an IPI). Real interaction,
but no specific MF conveyed.
No REMOVE actions: all annotations are biologically consistent with SEPHS2 as the
Sec-containing selenophosphate synthetase.