SELENOI (EPT1) — gene review notes

UniProt: Q9C0D9 (EPT1_HUMAN). HGNC:29361. Human, NCBITaxon:9606. 397 aa.
Gene symbol SELENOI (synonyms EPT1, SELI, KIAA1724). All identifiers and quotes
below from file:human/SELENOI/SELENOI-uniprot.txt unless a PMID is given.

Core identity

SELENOI is ethanolaminephosphotransferase 1 (EPT1 / hEPT1), a selenoprotein
(Selenoprotein I) and a multi-pass ER-membrane enzyme of the CDP-alcohol
phosphatidyltransferase class-I family. It catalyzes the final (third) step of
the CDP-ethanolamine branch of the Kennedy pathway for phosphatidylethanolamine
(PE) biosynthesis.

• RecName in UniProt: "Ethanolaminephosphotransferase 1"; Short "hEPT1"; EC 2.7.8.1
  [file:human/SELENOI/SELENOI-uniprot.txt "RecName: Full=Ethanolaminephosphotransferase 1"].
• Selenoprotein: contains a selenocysteine at residue 387 (NON_STD 387 /note="Selenocysteine"),
  established by PMID:12775843 ("Characterization of mammalian selenoproteomes");
  AltName "Selenoprotein I" [file:human/SELENOI/SELENOI-uniprot.txt "AltName: Full=Selenoprotein I"].
• Multi-pass ER membrane protein: 10 TRANSMEM helices annotated; SUBCELLULAR LOCATION
  "Endoplasmic reticulum membrane ... Multi-pass membrane protein"
  [file:human/SELENOI/SELENOI-uniprot.txt "SUBCELLULAR LOCATION: Endoplasmic reticulum membrane"].
• Family: "Belongs to the CDP-alcohol phosphatidyltransferase class-I family"
  [file:human/SELENOI/SELENOI-uniprot.txt "Belongs to the CDP-alcohol phosphatidyltransferase class-I"].

Catalytic activity

Two reactions in UniProt CATALYTIC ACTIVITY:
1. Diacyl (canonical PE): CDP-ethanolamine + 1,2-diacyl-sn-glycerol (DAG) =
1,2-diacyl-sn-glycero-3-phosphoethanolamine (PE) + CMP + H+ (RHEA:32943; EC 2.7.8.1),
evidenced experimentally by PubMed:17132865, 28052917, 29500230.
2. Ether-linked (plasmanyl-PE): 1-O-alkyl-2-acyl-sn-glycerol + CDP-ethanolamine =
1-O-alkyl-2-acyl-sn-glycero-3-phosphoethanolamine + CMP + H+ (RHEA:36187),
ECO:0000305 from PubMed:29500230.

Cofactor: Mg(2+) or Mn(2+) (ECO:0000269|PubMed:17132865). Kinetics: KM 1.8 uM for
CDP-ethanolamine (PubMed:17132865). Explains the metal ion binding (GO:0046872,
UniProtKB-KW) IEA annotation, though this is over-annotation of the divalent-cation
requirement rather than a distinct informative MF.

PATHWAY: "Phospholipid metabolism; phosphatidylethanolamine biosynthesis;
phosphatidylethanolamine from ethanolamine: step 3/3"
[file:human/SELENOI/SELENOI-uniprot.txt "phosphatidylethanolamine from ethanolamine: step 3/3"].

Experimental evidence for GO annotations

• PMID:17132865 (Horibata & Hirabayashi 2007, J Lipid Res) — abstract-only cache
  (full_text_available: false). Identified/characterized hEPT1: bacterial (E. coli)
  expression showed the product "specifically used CDP-ethanolamine as the phosphobase
  donor to produce PE with the activation by both Mn(2+) and Mg(2+)"
  PMID:17132865.
  Supports GO:0004307 (IDA, HGNC) and GO:0006646 (IDA). CDP-alcohol phosphatidyltransferase
  signature noted PMID:17132865.
  Tissue specificity: ubiquitous; highest in brain cerebellum.

• PMID:28052917 (Ahmed et al. 2017, Brain) — FULL TEXT available. First human disease
  (complex HSP / SPG81) from EPT1 mutation; p.Arg112Pro in the CDP-alcohol phosphotransferase
  motif. WT and mutant human EPT1 expressed in an S. cerevisiae strain "devoid of endogenous
  ethanolaminephosphotransferase activity"; 14C-ethanolamine incorporation into PE by the
  mutant was "only 3% that of wild-type EPT1" — a loss-of-function
  PMID:28052917. Supports IMP GO:0004307 & GO:0006646.
  ER-membrane / integral-membrane: the enzyme was "associated with the membrane fraction as
  would be expected for an integral membrane protein"
  PMID:28052917.
  NOTE: the "is_active_in ER membrane" IDA (ECO:0000314, PubMed:28052917) rests on membrane-
  fraction association in the heterologous yeast system, not on direct human-cell imaging;
  the ER localization is nonetheless firmly established across sources (UniProt SUBCELLULAR
  LOCATION, Reactome). Kept as core location.
  Function: "catalyses the final step in the synthesis of PE via the Kennedy pathway"
  PMID:28052917.

• PMID:29500230 (Horibata et al. 2018, J Lipid Res) — abstract-only cache. Patient with
  severe complicated HSP; EPT1 exon-skipping mutation. EPT "transfers phosphoethanolamine
  from cytidine diphosphate-ethanolamine to lipid acceptors to produce ethanolamine
  glycerophospholipids, such as diacyl-linked phosphatidylethanolamine (PE) and ether-linked
  plasmalogen [plasmenyl-PE]"
  PMID:29500230.
  In patient fibroblasts and EPT1-KO HeLa cells: reduced PE species and "most plasmenyl-PE
  species were significantly decreased" PMID:29500230.
  Concludes "the indispensable role of EPT1 in the myelination process and neurodevelopment,
  and in the maintenance of normal homeostasis of ether-linked phospholipids in humans"
  PMID:29500230.
  Supports IMP GO:0004307 & GO:0006646; underpins ISS/Ensembl myelination (GO:0042552) and
  ether-lipid (GO:0008611) annotations.

Disease

Spastic paraplegia 81, autosomal recessive (SPG81; MIM:618768) — a complicated HSP with
white-matter abnormalities / hypomyelination, delayed motor development, spasticity, impaired
intellectual development, bifid uvula, microcephaly, seizures, ocular anomalies
[file:human/SELENOI/SELENOI-uniprot.txt "Spastic paraplegia 81, autosomal recessive (SPG81)"].
Refs: PubMed:28052917, 29500230, 36942482. This is a phenotypic/disease association, not a GO
process the gene product directly executes; myelination (GO:0042552) is the closest BP but is
downstream/consequential and only IEA/ISS-supported → KEEP_AS_NON_CORE.

GO annotation review summary (24 GOA rows)

Core MF: GO:0004307 ethanolaminephosphotransferase activity (IDA PMID:17132865, IMP
PMID:28052917, IMP PMID:29500230; also IBA/ISS/IEA). ACCEPT the experimental ones as core.

Core BP: GO:0006646 phosphatidylethanolamine biosynthetic process (IDA/IMP experimental).
ACCEPT as core (this is the specific "PE from CDP-ethanolamine, step 3/3" pathway; no
more-specific GO child exists — verified against go.db).

Core CC: GO:0005789 endoplasmic reticulum membrane (IDA PMID:28052917; IBA; IEA; TAS
Reactome). ACCEPT as core location.

• GO:0005794 Golgi apparatus (IBA) — pan-family phylogenetic call; SELENOI itself is
  established as ER, not Golgi. UniProt/Reactome place it at the ER. IBA over-propagation →
  MARK_AS_OVER_ANNOTATED (not REMOVE: IBA, and some CEPT-family members do localize to
  Golgi/nuclear envelope).
• GO:0008611 ether lipid biosynthetic process (ISS + Ensembl IEA) — supported: plasmanyl/
  plasmenyl-PE synthesis (PMID:29500230). Real but secondary → KEEP_AS_NON_CORE.
• GO:0042552 myelination (ISS + Ensembl IEA) — downstream phenotype/consequence, not a direct
  MF/BP the enzyme executes → KEEP_AS_NON_CORE.
• GO:0008610 lipid biosynthetic process (IEA, ARBA) — correct but too general vs GO:0006646/
  GO:0008654 → MARK_AS_OVER_ANNOTATED.
• GO:0008654 phospholipid biosynthetic process (IEA, InterPro) — correct but a generalization
  of the specific PE process → MARK_AS_OVER_ANNOTATED.
• GO:0016020 membrane (IEA, InterPro) — correct but generic; ER membrane is the specific,
  experimentally-supported CC → MARK_AS_OVER_ANNOTATED.
• GO:0016780 phosphotransferase activity, for other substituted phosphate groups (IEA,
  InterPro) — parent/general form of GO:0004307 → MODIFY to GO:0004307.
• GO:0046872 metal ion binding (UniProtKB-KW; in UniProt DR, not in the 24-row seeded GOA
  TSV as a distinct reviewed row) — reflects the Mg2+/Mn2+ cofactor requirement; not a
  distinct informative MF. (Not present as a seeded existing_annotation row.)

core_functions chosen (author-supplied, strictly validated)

• MF: GO:0004307 ethanolaminephosphotransferase activity
  (+ directionally, catalysis of PE and plasmanyl-PE from CDP-ethanolamine)
• located in: GO:0005789 endoplasmic reticulum membrane
• part of BP: GO:0006646 phosphatidylethanolamine biosynthetic process (CDP-ethanolamine /
  Kennedy pathway, final step)