PEMT (phosphatidylethanolamine N-methyltransferase) is an integral, multi-pass endoplasmic-reticulum membrane enzyme that provides the alternative, liver-enriched route for de novo biosynthesis of phosphatidylcholine (PC). It catalyzes three sequential S-adenosyl-L-methionine (SAM)-dependent methylations of phosphatidylethanolamine (PE): PE is methylated to phosphatidyl-monomethyl- ethanolamine (PMME), PMME to phosphatidyl-dimethylethanolamine (PDME), and PDME to phosphatidylcholine, releasing S-adenosyl-L-homocysteine at each step (the first methylation is rate-limiting). This methylation route is the only pathway that synthesizes PC without preformed choline, complementing the choline-dependent CDP-choline (Kennedy) pathway, and accounts for roughly 30% of hepatic PC. Because it consumes SAM and yields choline moieties, PEMT is an important node in one-carbon (SAM) metabolism and choline homeostasis. The enzyme is expressed primarily in liver, resides in the ER membrane including the mitochondria-associated membrane (MAM) subdomain, with a minor mitochondrial-membrane pool, and adopts a topology with both termini in the cytosol. PEMT belongs to the class VI-like SAM-binding methyltransferase superfamily (PEMT/PEM2 family). Human PEMT variants are associated with susceptibility to non-alcoholic fatty liver disease and to choline-deficiency phenotypes.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000773 phosphatidyl-N-methylethanolamine N-methyltransferase activity | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetically-inferred molecular function capturing the second and third methylation steps (PMME->PDME->PC). PEMT genuinely performs these later methylations, but this is a sub-activity of the enzyme's overall PE->PC methyltransferase function; the more informative and complete core MF is GO:0004608. Retain as a valid non-core sub-activity. Reason: Correct sub-activity (later methylation steps) but narrower than the enzyme's full three-step PE->PC role captured by GO:0004608. Supporting Evidence: file:human/PEMT/PEMT-uniprot.txt Uses S-adenosylmethionine (S-adenosyl-L-methionine, SAM or AdoMet) as the methyl group donor for the methylation of phosphatidylethanolamine |
| GO:0005783 endoplasmic reticulum | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically-inferred site of action in the endoplasmic reticulum. This is consistent with all experimental evidence: PEMT is an ER-membrane enzyme where most activity is generated. Accept. Supporting Evidence: file:human/PEMT/PEMT-uniprot.txt Found in endoplasmic reticulum where most PEMT activity is generated |
| GO:0006656 phosphatidylcholine biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically-inferred involvement in phosphatidylcholine biosynthesis. This is the core biological process of PEMT: it catalyzes the methylation route to PC. Accept as core. Supporting Evidence: file:human/PEMT/PEMT-uniprot.txt Catalyzes the three sequential steps of the methylation pathway for the biosynthesis of phosphatidylcholine |
| GO:0000773 phosphatidyl-N-methylethanolamine N-methyltransferase activity | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Electronic (UniRule/RHEA/EC 2.1.1.71) assertion of the later methylation sub-activity, duplicating the IBA annotation to the same term. Valid but a narrower sub-activity than the full PE->PC role (GO:0004608). Reason: Correct electronic sub-activity annotation, redundant with the IBA to GO:0000773; narrower than the core GO:0004608. Supporting Evidence: file:human/PEMT/PEMT-uniprot.txt PMME to phosphatidyldimethylethanolamine (1,2-diacyl-sn-glycero-3-phospho-N,N- |
| GO:0004608 phosphatidylethanolamine N-methyltransferase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic (UniRule/RHEA:11164/EC 2.1.1.17) assertion of the core molecular function, phosphatidylethanolamine N-methyltransferase activity (the first, rate-limiting methylation and the overall PE->PC activity). This is the correct and central MF, also supported experimentally (TAS PMID:9989271). Redundant with the experimental annotation to the same term. Reason: Correct, central core MF (PE N-methyltransferase); the electronic assertion is redundant across evidence types with the experimental TAS annotation to GO:0004608, not an over-annotation — accepted. Supporting Evidence: file:human/PEMT/PEMT-uniprot.txt the methylation of phosphatidylethanolamine |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic subcellular-location mapping (UniProt SubCell SL-0095) to endoplasmic reticulum. Correct compartment, redundant with the IDA (HPA) and IBA annotations to the same term. Reason: Correct compartment (ER); the electronic assertion is redundant across evidence types with the IDA/IBA annotations to GO:0005783, not an over-annotation — accepted. Supporting Evidence: file:human/PEMT/PEMT-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Electronic (UniRule/SubCell SL-0097) assertion of the more precise compartment, endoplasmic reticulum membrane. PEMT is a multi-pass ER membrane protein, so this is correct and more informative than plain ER. Redundant with the TAS annotation to the same term. Reason: Correct precise location (ER membrane), consistent with multi-pass topology; redundant with the Reactome TAS to the same term. Supporting Evidence: file:human/PEMT/PEMT-uniprot.txt [Isoform 1]: Endoplasmic reticulum membrane |
| GO:0006656 phosphatidylcholine biosynthetic process | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic (UniRule/InterPro/UniPathway UPA00753) assertion of the core biological process, phosphatidylcholine biosynthesis. Correct, redundant with the IBA and TAS annotations to the same term. Reason: Correct core BP (PC biosynthesis); the electronic assertion is redundant across evidence types with the IBA/TAS annotations to GO:0006656, not an over-annotation — accepted. Supporting Evidence: file:human/PEMT/PEMT-uniprot.txt Phospholipid metabolism; phosphatidylcholine biosynthesis. |
| GO:0008757 S-adenosylmethionine-dependent methyltransferase activity | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: InterPro2GO electronic annotation to the generic parent term S-adenosylmethionine-dependent methyltransferase activity. This is a true but uninformative ancestor of the specific PEMT activity (GO:0004608 / GO:0000773), which is captured more precisely elsewhere. Reason: Correct but overly general parent MF; the specific PEMT methyltransferase activities (GO:0004608, GO:0000773) are annotated and more informative. Supporting Evidence: file:human/PEMT/PEMT-uniprot.txt Uses S-adenosylmethionine (S-adenosyl-L-methionine, SAM or AdoMet) as the methyl group donor |
| GO:0031966 mitochondrial membrane | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Electronic (UniRule/SubCell SL-0171) assertion of mitochondrial-membrane localization. PEMT is enriched at mitochondria-associated membranes (MAM) of the ER and UniProt records a mitochondrion-membrane location for isoform 1, so a minor mitochondrial pool is plausible. This is not the primary/core site of action (the ER is), so retain as non-core. Reason: Minor/secondary localization consistent with MAM enrichment and the isoform-1 mitochondrion-membrane note; ER is the core catalytic compartment. Supporting Evidence: file:human/PEMT/PEMT-uniprot.txt Mitochondrion membrane |
| GO:0120162 positive regulation of cold-induced thermogenesis | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic orthology transfer (Ensembl Compara) from mouse Pemt to human of a cold-induced-thermogenesis phenotype. This is a downstream, whole-organism physiological consequence of altered PC/choline and hepatic glucose metabolism in Pemt-null mice (PMID:26113536), not a direct molecular or cellular function of the PEMT enzyme. It also duplicates the ISS annotation to the same term. Reason: Indirect physiological phenotype transferred by orthology; not a direct PEMT function, and redundant with the ISS annotation to GO:0120162. |
| GO:0006656 phosphatidylcholine biosynthetic process | TAS Reactome:R-HSA-1483191 | ACCEPT | Summary: Reactome traceable-author statement placing PEMT in phosphatidylcholine biosynthesis (Synthesis of PC pathway). This is the core biological process of PEMT and is well supported. Accept. Supporting Evidence: reactome/R-HSA-1483191.md PC is formed when phosphatidylethanolamine (PE) is methylated by phosphatidylethanolamine N-methyltransferase (PEMT) |
| GO:0004608 phosphatidylethanolamine N-methyltransferase activity | TAS Reactome:R-HSA-1483174 | ACCEPT | Summary: Reactome traceable-author statement for the core molecular function, phosphatidylethanolamine N-methyltransferase activity (PE methylated to PC by PEMT). This is the central catalytic function of the enzyme. Accept as core. Supporting Evidence: reactome/R-HSA-1483174.md phosphatidylethanolamine N-methyltransferase (PEMT) methylates phosphatidylethanolamine (PE) and produces phosphatidylcholine (PC) |
| GO:0005783 endoplasmic reticulum | IDA GO_REF:0000052 | ACCEPT | Summary: Direct assay (HPA immunofluorescence) localizing PEMT to the endoplasmic reticulum. This is the strongest evidence for the primary compartment and is fully consistent with the literature (ER is where most PEMT activity is generated). Accept as the core localization. Supporting Evidence: file:human/PEMT/PEMT-uniprot.txt Found in endoplasmic reticulum where most PEMT activity is generated |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-1483174 | ACCEPT | Summary: Reactome traceable-author statement localizing the PEMT reaction to the endoplasmic reticulum membrane. This is the precise compartment for this multi-pass membrane enzyme and is more informative than plain ER. Accept. Supporting Evidence: reactome/R-HSA-1483174.md At the endoplasmic reticulum (ER) membrane, phosphatidylethanolamine N-methyltransferase (PEMT) methylates phosphatidylethanolamine (PE) |
| GO:0120162 positive regulation of cold-induced thermogenesis | ISS PMID:26113536 Insufficient glucose supply is linked to hypothermia upon co... | KEEP AS NON CORE | Summary: Sequence/orthology-based (ISS from mouse Pemt) annotation of cold-induced thermogenesis. The supporting mouse study shows that HF-fed Pemt-null mice develop cold-induced hypothermia linked to hepatic hypoglycemia, reversed by choline; this is an indirect, whole-organism metabolic consequence of loss of PC/choline biosynthesis, not a direct molecular function of PEMT. Retain as a non-core, physiologically indirect process rather than removing the (non-experimental) ISS. Reason: Downstream physiological phenotype (PC/choline-dependent hepatic glucose supply and thermoregulation), indirect relative to PEMT's catalytic function. Supporting Evidence: PMID:26113536 HF-fed Pemt(-/-) mice developed hypothermia within 3 h of cold exposure |
| GO:0004608 phosphatidylethanolamine N-methyltransferase activity | TAS PMID:9989271 Identification of three novel cDNAs for human phosphatidylet... | ACCEPT | Summary: Traceable-author statement (Walkey et al. 1999) for the core molecular function. The paper cloned and expressed human PEMT cDNAs and showed a 27- to 115-fold elevation of PEMT activity on expression, establishing that this human gene product catalyzes the PE->PC methyltransferase reaction. This is the central, defining molecular function of PEMT. Accept as core. Supporting Evidence: PMID:9989271 Phosphatidylethanolamine is converted to phosphatidylcholine in mammalian liver by the enzyme phosphatidylethanolamine N-methyltransferase (PEMT) |
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