SEPSECS (Q9HD40) — Gene Review Notes

Identity and nomenclature

• HGNC symbol: SEPSECS; synonym TRNP48. UniProt Q9HD40, SPCS_HUMAN, 501 aa, chromosome 4.
• RecName: O-phosphoseryl-tRNA(Sec) selenium transferase; EC 2.9.1.2 [file:human/SEPSECS/SEPSECS-uniprot.txt "RecName: Full=O-phosphoseryl-tRNA(Sec) selenium transferase; ... EC=2.9.1.2"].
• Many AltNames reflect its history as an autoantigen: Liver-pancreas antigen (LP), SLA-p35, SLA/LP autoantigen, Soluble liver antigen (SLA), Selenocysteine synthase / Sec synthase, Sep-tRNA:Sec-tRNA synthase (SepSecS), UGA suppressor tRNA-associated protein, tRNA(Ser/Sec)-associated antigenic protein [file:human/SEPSECS/SEPSECS-uniprot.txt "AltName: Full=Selenocysteine synthase; Short=Sec synthase"].

Molecular function (catalysis)

• Final (terminal) step of selenocysteine (Sec) biosynthesis, which uniquely occurs on the cognate tRNA in archaea/eukaryotes.
• CATALYTIC ACTIVITY (RHEA:25041): O-phospho-L-seryl-tRNA(Sec) + selenophosphate + H2O = L-selenocysteinyl-tRNA(Sec) + 2 phosphate, EC 2.9.1.2 [file:human/SEPSECS/SEPSECS-uniprot.txt "Reaction=O-phospho-L-seryl-tRNA(Sec) + selenophosphate + H2O = L- selenocysteinyl-tRNA(Sec) + 2 phosphate"].
• FUNCTION: "Converts O-phosphoseryl-tRNA(Sec) to selenocysteinyl- tRNA(Sec) required for selenoprotein biosynthesis." [file:human/SEPSECS/SEPSECS-uniprot.txt] (ECO:0000269|PubMed:17142313).
• PLP (pyridoxal 5'-phosphate)-dependent enzyme: COFACTOR = pyridoxal 5'-phosphate (ECO:0000269|PubMed:17142313, PubMed:19608919). PLP is covalently bound via Schiff base to Lys284 (MOD_RES 284 = N6-(pyridoxal phosphate)lysine) [file:human/SEPSECS/SEPSECS-uniprot.txt].
• Belongs to the SepSecS family, a distinct branch of fold-type I PLP enzymes PMID:19608919.

Mechanism (PMID:17142313, PMID:19608919)

• Two-step eukaryal/archaeal Sec route: Ser is charged onto tRNA(Sec) by SerRS → PSTK phosphorylates it to Sep-tRNA(Sec) → SepSecS converts Sep-tRNA(Sec) to Sec-tRNA(Sec) using selenophosphate (from SEPHS2/SelD) as the Se donor PMID:17142313.
• SepSecS acts on phosphoserine linked to tRNA(Sec), not free phosphoserine or Ser-tRNA(Sec) PMID:19608919.
• PLP-based mechanism: amino group of Sep attacks the Lys284–PLP Schiff base → external aldimine → β-elimination of phosphate → dehydroalanyl-tRNA(Sec) intermediate → nucleophilic attack of selenium from selenophosphate → Sec-tRNA(Sec) PMID:19608919.
• Reduction of the Schiff base (NaBH4 cross-linking PLP to Lys284) or removal of PLP (hydroxylamine) renders SepSecS completely inactive — confirms PLP dependence PMID:19608919.
• Human and archaeal SepSecS complement an E. coli SelA (Sec synthase) deletion in vivo; purified recombinant SepSecS converts Sep-tRNA(Sec) to Sec-tRNA(Sec) in vitro with Na-selenite + SelD (in vitro validation) PMID:17142313.
• Lys284→Ala abolishes activity (MUTAGEN); active-site/tRNA-binding residues Arg75, Gln105, Arg313 (substrate/PLP phosphate) and Arg398 (discriminator base G73), Arg271 (variable arm) are catalytically/recognition critical [file:human/SEPSECS/SEPSECS-uniprot.txt; PMID:19608919].

tRNA binding / substrate

• SepSecS binds the acceptor-, TΨC-, and variable arms of tRNA(Sec) PMID:19608919.
• Recognition via discriminator base G73 (↔ Arg398) and the unusual 13-bp acceptor-TΨC arm / long variable arm of the 90-nt tRNA(Sec); tRNA(Ser) cannot bind (shorter acceptor-TΨC arm) PMID:19608919.
• tRNA binding induces conformational changes that organize the catalytic protomer's active site — tRNA-dependent activation PMID:36929010.
• Historically identified as the antigen of the tRNP(Ser)Sec ribonucleoprotein (SLA/LP), i.e. the tRNA(Sec)-associated antigenic protein PMID:10801173.

Quaternary structure / complex

• Homotetramer = catalytic dimer + non-catalytic dimer; the non-catalytic dimer is a binding platform orienting tRNA(Sec) for catalysis; each tetramer binds two tRNA(Sec) via their CCA ends pointing to the catalytic dimer's active sites [file:human/SEPSECS/SEPSECS-uniprot.txt "Homotetramer formed by a catalytic dimer and a non-catalytic dimer serving as a binding platform"; PMID:19608919 "Two SepSecS monomers form a homodimer ... The two homodimers associate into a tetramer"].
• Also reported as component of a wider complex with SEPHS1, SEPHS2, SEPSECS and TRNAU1AP (SECp43) (supramolecular Sec machinery) [file:human/SEPSECS/SEPSECS-uniprot.txt "Component of a complex composed of SEPHS1, SEPHS2, SEPSECS and TRNAU1AP"; PMID:28414460 "selenocysteine synthase (SEPSECS), SECp43, and selenophosphate synthetases SEPHS1 and SEPHS2 form oligomers in eukaryotic cells"].
• ComplexPortal CPX-26538 "SepSecS-tRNASec complex" (referenced by GOA ComplexPortal annotations to GO:0005829 cytosol and GO:1990234 transferase complex, PMID:36929010).

Subcellular location

• Cytoplasm / cytosol [file:human/SEPSECS/SEPSECS-uniprot.txt "SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:28414460}"]. No credible evidence for a nuclear function; the nucleus annotations are ISS/IEA transfers from mouse ortholog Q6P6M7 and are treated as over-annotations.

Biological process

• Selenocysteinyl-tRNA(Sec) biosynthesis (UniPathway UPA00906, UER00898): "Aminoacyl-tRNA biosynthesis; selenocysteinyl-tRNA(Sec) biosynthesis; selenocysteinyl-tRNA(Sec) from L-seryl-tRNA(Sec) (archaeal/eukaryal route): step 2/2." [file:human/SEPSECS/SEPSECS-uniprot.txt].
• Feeds selenoprotein synthesis: charged Sec-tRNA(Sec) is delivered by EEFSEC to recode UGA codons during translation PMID:19608919.
• GO:0001514 "selenocysteine incorporation" is the downstream translational process the whole Sec pathway serves; SEPSECS is upstream (tRNA charging) rather than itself the ribosomal incorporation step, but is legitimately annotated involved_in this process.

Disease

• Pontocerebellar hypoplasia type 2D (PCH2D) [MIM:613811] / progressive cerebello-cerebral atrophy — autosomal recessive; postnatal progressive cerebral+cerebellar atrophy, microcephaly, profound intellectual disability, spasticity, seizures [file:human/SEPSECS/SEPSECS-uniprot.txt "Pontocerebellar hypoplasia 2D (PCH2D)"; PMID:20920667].
• Pathogenic missense variants: A239T and Y334C both abrogate enzyme activity (VARIANT, characterized) [file:human/SEPSECS/SEPSECS-uniprot.txt "A -> T (in PCH2D; abrogates enzyme activity)"]; also T325S PMID:26115735. Establishes that loss of SepSecS catalytic activity (loss of selenoprotein biosynthesis) is the disease mechanism.

Term-by-term reasoning (see YAML)

Core molecular function = GO:0098621 O-phosphoseryl-tRNA(Sec) selenium transferase activity (IDA, PMID:17142313) + GO:0030170 pyridoxal phosphate binding (cofactor). Core BP = GO:0001717 conversion of seryl-tRNAsec to selenocys-tRNAsec (IDA) and the broader GO:0016260 L-selenocysteine biosynthetic process. tRNA binding (GO:0000049) is a genuine, well-supported MF (structural + TAS). Cytoplasm/cytosol (GO:0005737/GO:0005829) accepted. Nucleus (GO:0005634, ISS/IEA from mouse) = over-annotation. Generic GO:0016740 transferase activity (IEA) is a redundant parent of GO:0098621. GO:0005515 protein binding (IPI, HIV gag) kept as non-core (uninformative; not a native functional partner). GO:1990234 transferase complex (part_of, ComplexPortal) accepted as non-core CC (the SepSecS tetramer / Sec machinery complex).

Note: GO:0097056 "selenocysteinyl-tRNA(Sec) biosynthetic process" is now obsolete, replaced by GO:0001717 — do not introduce it.

2026-10-09 review completion (claude-code)

Re-reviewed the INITIALIZED review against the disease literature (see history/genes/human/SEPSECS/). Status set COMPLETE; changes are summarized in the history record.