FAR1 (fatty acyl-CoA reductase 1) is an NADPH-dependent, peroxisomal-membrane oxidoreductase that catalyzes the two-step reduction of long-chain fatty acyl-CoA (preferring saturated and unsaturated C16 and C18 species such as palmitoyl-, stearoyl- and oleoyl-CoA) to the corresponding primary fatty alcohol, with release of CoA (EC 1.2.1.84). It is a C-terminally tail-anchored, single-pass peroxisomal membrane protein whose targeting is mediated by the PEX19 receptor, with a large cytoplasmic catalytic domain. The fatty alcohols it produces are the committed precursors for ether-lipid (plasmalogen) biosynthesis, where alkyl-dihydroxyacetone-phosphate synthase (AGPS) uses them to form the characteristic ether bond; FAR1 is the rate-limiting enzyme of this pathway and is feedback-regulated by cellular plasmalogen levels through modulation of its protein stability. Its fatty alcohol product also feeds wax monoester synthesis. Loss-of-function of FAR1 causes an autosomal-recessive peroxisomal disorder (severe intellectual disability, epilepsy, cataracts), and gain-of-function variants that escape plasmalogen feedback cause an autosomal-dominant cataract/spastic-paraparesis syndrome.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005778 peroxisomal membrane | IBA GO_REF:0000033 | ACCEPT | Summary: FAR1 is a single-pass peroxisomal membrane protein; the phylogenetic (IBA) assignment of peroxisomal membrane as its active-in location is correct and represents a core aspect of the gene. Directly supported by experimental data (tail-anchored peroxisomal membrane protein). Supporting Evidence: PMID:24108123 Far1 is shown to be a peroxisomal tail-anchored protein |
| GO:0080019 alcohol-forming very long-chain fatty acyl-CoA reductase activity | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: The alcohol-forming acyl-CoA reductase activity type is correct, but the chain-length specialization is wrong for human FAR1: this term is for VERY long-chain (>22C) substrates, whereas FAR1 preferentially reduces C16/C18 (long-chain, 13-22C) fatty acyl-CoA. The very-long-chain term is a family-level (phylogenetic) over-annotation; the correct, experimentally supported term is GO:0102965 (alcohol-forming long-chain fatty acyl-CoA reductase activity). Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH WRONG ORTHOLOG OR PARALOG Sources checked: PANTHER:PTN000110226 · fatty acyl-CoA reductase family node (includes plant/insect FARs acting on very-long-chain substrates) SUPPORTS SOURCE BUT NOT TARGET Proposed replacements: alcohol-forming long-chain fatty acyl-CoA reductase activity Supporting Evidence: file:human/FAR1/FAR1-uniprot.txt Catalyzes the reduction of saturated and unsaturated C16 or |
| GO:0035336 long-chain fatty-acyl-CoA metabolic process | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: FAR1 consumes long-chain (C16/C18) fatty acyl-CoA as its substrate, so participation in long-chain fatty-acyl-CoA metabolic process is correct. This is a somewhat generic process descriptor; the core biological role is better captured by ether lipid biosynthesis, but the annotation is valid. Supporting Evidence: PMID:15220348 FAR1 preferred saturated |
| GO:0005777 peroxisome | IEA GO_REF:0000117 | ACCEPT | Summary: Peroxisome localization is the correct, experimentally established location of FAR1. This electronic annotation is redundant with, and supported by, the IDA/HPA peroxisome annotations; accept as a core cellular component. Supporting Evidence: PMID:15220348 were localized in the peroxisome |
| GO:0005778 peroxisomal membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Peroxisomal membrane is the correct location of this single-pass tail-anchored membrane protein. This Subcellular-Location-mapping IEA is redundant with the IDA/HDA evidence; accept as a core cellular component. Supporting Evidence: file:human/FAR1/FAR1-uniprot.txt Single-pass membrane protein |
| GO:0008610 lipid biosynthetic process | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: A very high-level parent term. FAR1 does participate in lipid biosynthesis, but this generic ARBA-derived annotation is uninformative and redundant with the specific ether-lipid / wax / glycerophospholipid biosynthetic process annotations. |
| GO:0016620 oxidoreductase activity, acting on the aldehyde or oxo group of donors, NAD or NADP as acceptor | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: This term describes oxidation of an aldehyde/oxo donor with NAD(P) as acceptor. The physiological FAR1 reaction reduces fatty acyl-CoA (with NADPH as donor) to a fatty alcohol; the aldehyde is a transient intermediate and the acceptor/donor direction of this generic term does not accurately capture the enzyme's function. Better captured by the specific alcohol-forming acyl-CoA reductase term (GO:0102965). Generic ARBA over-annotation. Proposed replacements: alcohol-forming long-chain fatty acyl-CoA reductase activity |
| GO:0080019 alcohol-forming very long-chain fatty acyl-CoA reductase activity | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: Same issue as the IBA assignment of this term: the InterPro family maps to alcohol-forming acyl-CoA reductase activity, but human FAR1 prefers C16/C18 (long-chain) rather than very-long-chain (>22C) substrates. The correct term is GO:0102965. Proposed replacements: alcohol-forming long-chain fatty acyl-CoA reductase activity Supporting Evidence: file:human/FAR1/FAR1-uniprot.txt Catalyzes the reduction of saturated and unsaturated C16 or |
| GO:0102965 alcohol-forming long-chain fatty acyl-CoA reductase activity | IEA GO_REF:0000120 | ACCEPT | Summary: This is the correct core molecular function of FAR1: alcohol-forming long-chain (C16/C18) fatty acyl-CoA reductase activity (EC 1.2.1.84). This electronic (RHEA/EC-based) annotation agrees with the experimental IDA annotations; accept as the core function. Supporting Evidence: file:human/FAR1/FAR1-uniprot.txt Reaction=a long-chain fatty acyl-CoA + 2 NADPH + 2 H(+) = a long-chain |
| GO:1901568 fatty acid derivative metabolic process | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: Generic high-level process term. FAR1's product (fatty alcohol) is a fatty acid derivative, so the annotation is not wrong, but it is uninformative and redundant with the specific biosynthetic-process annotations. Generic ARBA over-annotation. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Bare 'protein binding' from a large-scale yeast two-hybrid interactome (IntAct records with KLF11, a BAG6 isoform, and a COL26A1 isoform). These high-throughput interactions have no established biological role for FAR1 and the term is uninformative. Removal does not mean the interactions are false, only that no informative molecular function follows from them. The functionally meaningful interaction (PEX19, for peroxisomal targeting) is a distinct, literature-curated interaction (PMID:24108123). |
| GO:0010025 wax biosynthetic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: FAR1's fatty-alcohol product is a precursor for wax monoester synthesis; wax biosynthetic process is a valid downstream role, largely inferred from the mouse ortholog and Reactome. It is not the primary (ether-lipid) role in human, so keep as non-core. Supporting Evidence: file:human/FAR1/FAR1-uniprot.txt also required for wax monoesters |
| GO:0010025 wax biosynthetic process | TAS Reactome:R-HSA-9640463 | KEEP AS NON CORE | Summary: Same wax biosynthetic role, asserted by Reactome. Valid downstream use of the fatty-alcohol product; keep as non-core (the principal human role is ether-lipid/plasmalogen biosynthesis). Supporting Evidence: Reactome:R-HSA-9640463 FAR1 and FAR2 catalyze the reduction of fatty acids to fatty alcohols |
| GO:0005777 peroxisome | IDA GO_REF:0000052 | ACCEPT | Summary: Immunofluorescence (HPA) localization to the peroxisome; consistent with confocal microscopy in the original characterization and with the membrane-topology study. Core cellular component. Supporting Evidence: PMID:15220348 were localized in the peroxisome |
| GO:0102965 alcohol-forming long-chain fatty acyl-CoA reductase activity | IDA PMID:15220348 Mammalian wax biosynthesis. I. Identification of two fatty a... | ACCEPT | Summary: Direct experimental demonstration that FAR1 reduces C16/C18 fatty acyl-CoA to fatty alcohols in an NADPH-dependent manner. This is the core molecular function of the gene. Supporting Evidence: PMID:15220348 FAR1 preferred saturated |
| GO:0102965 alcohol-forming long-chain fatty acyl-CoA reductase activity | IDA PMID:20071337 Posttranslational regulation of fatty acyl-CoA reductase 1, ... | ACCEPT | Summary: Direct evidence supporting the alcohol-forming long-chain fatty acyl-CoA reductase activity of FAR1 (fatty-alcohol supply for ether-bond formation). Core molecular function. Supporting Evidence: PMID:20071337 supplies the fatty alcohols used in the |
| GO:0102965 alcohol-forming long-chain fatty acyl-CoA reductase activity | IDA PMID:24108123 Topogenesis and homeostasis of fatty acyl-CoA reductase 1. | ACCEPT | Summary: Direct evidence for FAR1's alcohol-forming fatty acyl-CoA reductase activity (Far1 expression increases plasmalogen synthesis; rate-limiting enzyme). Core molecular function. Supporting Evidence: PMID:24108123 Far1 is a rate-limiting enzyme for plasmalogen synthesis |
| GO:0016491 oxidoreductase activity | TAS Reactome:R-HSA-390425 | KEEP AS NON CORE | Summary: FAR1 is an oxidoreductase; this Reactome-asserted parent term is correct but very generic. The specific molecular function (GO:0102965) is preferred; keep this general term as non-core. Supporting Evidence: Reactome:R-HSA-390425 FAR1 catalyzes the reaction of palmitoyl-CoA (PalmCoA) and 2 NADPH |
| GO:0005778 peroxisomal membrane | TAS Reactome:R-HSA-390425 | ACCEPT | Summary: Peroxisomal membrane localization asserted by Reactome; correct and consistent with the experimental topology data. Core cellular component. Supporting Evidence: PMID:24108123 Far1 is shown to be a peroxisomal tail-anchored protein |
| GO:0010025 wax biosynthetic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Wax biosynthetic role inferred by sequence similarity from the mouse ortholog (Q922J9). Valid downstream use of the fatty-alcohol product; keep as non-core (ether-lipid biosynthesis is the primary human role). Supporting Evidence: file:human/FAR1/FAR1-uniprot.txt also required for wax monoesters |
| GO:0005778 peroxisomal membrane | IDA PMID:24108123 Topogenesis and homeostasis of fatty acyl-CoA reductase 1. | ACCEPT | Summary: Direct experimental evidence that FAR1 is a peroxisomal tail-anchored, single-pass membrane protein targeted via PEX19. Core cellular component. Supporting Evidence: PMID:24108123 Far1 is shown to be a peroxisomal tail-anchored protein |
| GO:0008611 ether lipid biosynthetic process | IDA PMID:24108123 Topogenesis and homeostasis of fatty acyl-CoA reductase 1. | ACCEPT | Summary: Direct evidence that FAR1 is required for and rate-limiting in ether lipid/plasmalogen biosynthesis (Far1 supplies the fatty alcohols for ether-bond formation; its expression increases plasmalogen synthesis). This is the core biological process of the gene. Supporting Evidence: PMID:24108123 Peroxisomal fatty acyl-CoA reductase 1 (Far1) is essential for supplying fatty alcohols required for ether bond formation in ether glycerophospholipid synthesis |
| GO:0008611 ether lipid biosynthetic process | IMP PMID:20071337 Posttranslational regulation of fatty acyl-CoA reductase 1, ... | ACCEPT | Summary: Manipulation of Far1 (levels/activity modulated by plasmalogen feedback) controls ether glycerophospholipid synthesis, supporting involvement in ether lipid biosynthesis. Core biological process. Supporting Evidence: PMID:20071337 supplies the fatty alcohols used in the |
| GO:0035336 long-chain fatty-acyl-CoA metabolic process | IDA PMID:15220348 Mammalian wax biosynthesis. I. Identification of two fatty a... | KEEP AS NON CORE | Summary: FAR1 acts on long-chain (C16/C18) fatty acyl-CoA substrates, consistent with participation in long-chain fatty-acyl-CoA metabolic process. Correct but generic process descriptor; keep as non-core relative to ether-lipid biosynthesis. Supporting Evidence: PMID:15220348 FAR1 preferred saturated |
| GO:0046474 glycerophospholipid biosynthetic process | IDA PMID:20071337 Posttranslational regulation of fatty acyl-CoA reductase 1, ... | KEEP AS NON CORE | Summary: Ether glycerophospholipids (plasmalogens) are glycerophospholipids, so this annotation is correct; it is a more general parent of the ether-lipid-specific process. Keep as non-core; the specific term GO:0008611 better captures the role. Supporting Evidence: PMID:20071337 supplies the fatty alcohols used in the |
| GO:0005777 peroxisome | IDA PMID:20071337 Posttranslational regulation of fatty acyl-CoA reductase 1, ... | ACCEPT | Summary: Direct experimental localization of Far1 to the peroxisome. Core cellular component. Supporting Evidence: PMID:15220348 were localized in the peroxisome |
| GO:0005778 peroxisomal membrane | HDA PMID:21525035 PEX14 is required for microtubule-based peroxisome motility ... | ACCEPT | Summary: FAR1 was identified in native peroxisomal membrane protein complexes isolated from human cells by proteomics, corroborating its peroxisomal membrane localization. Core cellular component. Supporting Evidence: PMID:21525035 isolating native peroxisomal membrane |
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Download this section (compressed HTML)Q: What senses cellular plasmalogen levels to trigger FAR1 degradation, and how do the de novo Arg480 variants (autosomal-dominant spastic paraparesis with cataracts) escape this feedback while leaving catalysis intact?
Q: Does FAR2 compensate for FAR1 loss in any tissue, explaining the residual plasmalogen synthesis seen in some FAR1-deficient patients?
Experiment: Map the plasmalogen-dependent degron of FAR1 by testing degradation of Arg480 and C-terminal-region variants in plasmalogen-replete versus plasmalogen-deficient cells, with proteasome and ERAD/peroxisomal-membrane quality-control inhibitors.
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