FAR2 (fatty acyl-CoA reductase 2) is a peroxisomal, NADPH-dependent, alcohol-forming fatty acyl-CoA reductase (EC 1.2.1.84) and a paralog of FAR1. It reduces a fatty acyl-CoA to the corresponding primary fatty alcohol with release of CoA. FAR2 has a more saturation-restricted substrate preference than FAR1, favoring saturated C16/C18 acyl-CoA (with lower activity on shorter chains), and can also generate very-long-chain and ultra-long-chain fatty alcohols, including branched-chain species. The fatty alcohols it produces are substrates for wax monoester synthesis and for ether lipid (plasmalogen) biosynthesis. FAR2 is a single-pass, tail-anchored peroxisomal membrane protein with a large cytoplasmic N-terminal catalytic region and a short C-terminal tail in the peroxisomal lumen. Its mRNA has a restricted tissue distribution, being most abundant in the eyelid, where wax-laden Meibomian glands produce meibum lipids, and is also present in brain, a tissue rich in ether lipids.
Definition: The chemical reactions and pathways resulting in the formation of fatty alcohol. (Existing term GO:1903175; proposed here as a more direct product-level process annotation for FAR2, which is not currently in GOA.)
Justification: FAR2 directly produces primary fatty alcohols from fatty acyl-CoA. GOA currently annotates the substrate side (GO:0035336 long-chain fatty-acyl-CoA metabolic process) and downstream products (GO:0010025 wax biosynthetic process) but not the fatty alcohol biosynthetic process itself (GO:1903175), which is the most direct product-level process term for this enzyme.
Supporting Evidence:
Definition: The chemical reactions and pathways resulting in the formation of ether lipids. (Existing term GO:0008611; proposed here to capture FAR2's documented role in supplying fatty alcohols for ether lipid/plasmalogen synthesis, not currently in GOA.)
Justification: UniProt states FAR2 is involved in the production of ether lipids/plasmalogens, whose synthesis requires fatty alcohols as substrates. An ether lipid biosynthetic process annotation (GO:0008611) would capture this documented role, which is not currently represented in GOA.
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005778 peroxisomal membrane | IBA GO_REF:0000033 | ACCEPT | Summary: FAR2 is a peroxisomal membrane protein; the phylogenetic (IBA) inference to peroxisomal membrane is consistent with direct experimental evidence and UniProt annotation, and represents a core localization for this gene. Reason: FAR2 is experimentally localized to the peroxisome (PMID:15220348) and annotated by UniProt as a single-pass peroxisomal membrane protein. The IBA transfer across the fatty acyl-CoA reductase family is well founded. Supporting Evidence: file:human/FAR2/FAR2-uniprot.txt Peroxisome membrane {ECO:0000269|PubMed:15220348, |
| GO:0080019 alcohol-forming very long-chain fatty acyl-CoA reductase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Core molecular function. FAR2 is an alcohol-forming fatty acyl-CoA reductase that can also produce very-long-chain fatty alcohols; the phylogenetic inference across the FAR family is supported by direct experimental evidence. Reason: UniProt records that FAR2 can produce very long-chain and ultra long-chain fatty alcohols; this term captures the family-conserved catalytic activity. Supporting Evidence: file:human/FAR2/FAR2-uniprot.txt Can produce very long-chain and ultra long-chain |
| GO:0035336 long-chain fatty-acyl-CoA metabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: FAR2 acts on long-chain fatty acyl-CoA substrates (C16/C18), so involvement in long-chain fatty-acyl-CoA metabolism is a reasonable process-level annotation consistent with its enzymatic role. Reason: Long-chain fatty acyl-CoAs (e.g. palmitoyl-CoA, stearoyl-CoA) are the preferred substrates that FAR2 consumes; the IBA process annotation follows directly from the catalytic activity. Supporting Evidence: PMID:15220348 FAR2 preferred saturated fatty acids of 16 or 18 carbons |
| GO:0005777 peroxisome | IEA GO_REF:0000117 | ACCEPT | Summary: Peroxisome localization is correct for FAR2 and is supported experimentally; this ARBA electronic annotation is a correct parent of the more specific peroxisomal membrane localization. Reason: FAR2 was localized to the peroxisome by confocal microscopy and is a peroxisomal membrane protein; the compartment-level term is correct. Supporting Evidence: PMID:15220348 FAR1 and FAR2 were localized in the peroxisome |
| GO:0005778 peroxisomal membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Correct core localization derived from the UniProt Subcellular Location "Peroxisome membrane" mapping. Redundant with the experimental IDA but correct; retained as ACCEPT. Reason: UniProt curates FAR2 as a single-pass peroxisomal membrane protein; the SubCell mapping to peroxisomal membrane is accurate. Supporting Evidence: file:human/FAR2/FAR2-uniprot.txt Peroxisome membrane {ECO:0000269|PubMed:15220348, |
| GO:0010025 wax biosynthetic process | IEA GO_REF:0000117 | ACCEPT | Summary: FAR2 supplies fatty alcohols for wax monoester synthesis; involvement in wax biosynthesis is a correct core process annotation for this gene. Reason: The fatty alcohols produced by FAR2 are required substrates for wax monoester biosynthesis; FAR2 is expressed at high levels in the eyelid, which contains wax-laden Meibomian glands. Supporting Evidence: PMID:15220348 conversion of fatty acids to fatty alcohols is required for the synthesis of wax monoesters and ether lipids |
| GO:0080019 alcohol-forming very long-chain fatty acyl-CoA reductase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Redundant electronic annotation of the core alcohol-forming reductase activity (very-long-chain form). Correct and supported; retained as ACCEPT rather than flagged as over-annotation because it is FAR2's own core MF. Reason: Matches the IBA and IDA annotations of the same term; UniProt records very-long-chain and ultra-long-chain fatty alcohol production by FAR2. Supporting Evidence: file:human/FAR2/FAR2-uniprot.txt Can produce very long-chain and ultra long-chain |
| GO:0102965 alcohol-forming long-chain fatty acyl-CoA reductase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Core molecular function corresponding to EC 1.2.1.84 acting on long-chain (C16/C18) fatty acyl-CoA. This is FAR2's best-characterized reaction (palmitoyl-CoA to hexadecanol) and is strongly supported. Reason: FAR2 reduces long-chain fatty acyl-CoA (e.g. palmitoyl-CoA) to the corresponding primary fatty alcohol using NADPH; UniProt assigns EC 1.2.1.84 and a long-chain fatty acyl-CoA reductase reaction (RHEA:52716). Supporting Evidence: file:human/FAR2/FAR2-uniprot.txt a long-chain primary fatty alcohol + 2 NADP(+) + CoA |
| GO:0010025 wax biosynthetic process | TAS Reactome:R-HSA-9640463 | ACCEPT | Summary: Reactome traceable annotation placing FAR2 in wax biosynthesis, where it reduces fatty acids to fatty alcohols in the peroxisome for downstream wax ester formation. Correct core process. Reason: Reactome's Wax biosynthesis pathway explicitly assigns FAR1/FAR2 the fatty-acid-to-fatty-alcohol reduction step upstream of AWAT wax ester synthesis. Supporting Evidence: Reactome:R-HSA-9640463 FAR1 and FAR2 catalyze the reduction of fatty acids to fatty alcohols in the peroxisome |
| GO:0016491 oxidoreductase activity | TAS Reactome:R-HSA-390438 | MARK AS OVER ANNOTATED | Summary: Correct but overly general. FAR2 is an oxidoreductase, but the specific alcohol-forming fatty acyl-CoA reductase terms (GO:0080019, GO:0102965) capture its function precisely. Flagged as over-annotation, not removed. Reason: GO:0016491 is a high-level parent of the specific reductase activities already annotated; it adds no functional specificity beyond the child terms. Supporting Evidence: file:human/FAR2/FAR2-uniprot.txt a long-chain primary fatty alcohol + 2 NADP(+) + CoA |
| GO:0005778 peroxisomal membrane | TAS Reactome:R-HSA-390438 | ACCEPT | Summary: Reactome traceable annotation of peroxisomal membrane localization, consistent with the experimental IDA and UniProt curation. Correct core localization. Reason: FAR2 is a single-pass peroxisomal membrane protein; the Reactome localization matches the experimental and UniProt evidence. Supporting Evidence: file:human/FAR2/FAR2-uniprot.txt Peroxisome membrane {ECO:0000269|PubMed:15220348, |
| GO:0005778 peroxisomal membrane | IDA PMID:24108123 Topogenesis and homeostasis of fatty acyl-CoA reductase 1. | ACCEPT | Summary: Direct experimental localization to the peroxisomal membrane. Although this paper's title foregrounds FAR1 topogenesis, the full text assays both FAR1 and FAR2, and FAR2 is confirmed as a peroxisomal membrane protein. Core localization; retained. Reason: Experimental (IDA) annotation from a paper (full text available) that characterizes FAR1 and FAR2 as peroxisomal membrane (tail-anchored) proteins; consistent with UniProt topology (single-pass, C-terminal anchor). Supporting Evidence: PMID:24108123 Far1, but not Far2, was preferentially degraded in response to the cellular level of plasmalogens file:human/FAR2/FAR2-uniprot.txt Peroxisome membrane {ECO:0000269|PubMed:15220348, |
| GO:0035336 long-chain fatty-acyl-CoA metabolic process | IDA PMID:15220348 Mammalian wax biosynthesis. I. Identification of two fatty a... | ACCEPT | Summary: Direct experimental evidence that FAR2 metabolizes long-chain (C16/C18) fatty acyl-CoA substrates. Correct process annotation reflecting its enzymatic role. Retained. Reason: FAR2 was shown to reduce fatty acyl-CoA esters, preferring saturated C16/C18 substrates; consuming long-chain fatty acyl-CoA is the process it participates in. Supporting Evidence: PMID:15220348 FAR2 preferred saturated fatty acids of 16 or 18 carbons |
| GO:0080019 alcohol-forming very long-chain fatty acyl-CoA reductase activity | IDA PMID:15220348 Mammalian wax biosynthesis. I. Identification of two fatty a... | ACCEPT | Summary: Direct experimental evidence that FAR2 is an alcohol-forming fatty acyl-CoA reductase (reduces fatty acyl-CoA to fatty alcohol, NADPH-dependent). Core molecular function; retained. Reason: Expression studies showed FAR2 cDNA encodes an isozyme that reduces fatty acids to fatty alcohols using fatty acyl-CoA as substrate; the alcohol-forming reductase activity is the defining function. Supporting Evidence: PMID:15220348 FAR1 and FAR2 cDNAs encoded isozymes that reduced fatty acids to fatty alcohols |
| GO:0005777 peroxisome | ISS GO_REF:0000024 | ACCEPT | Summary: Peroxisome localization inferred by sequence similarity to the mouse ortholog (Q7TNT2). Consistent with the experimental evidence in human; correct compartment-level annotation. Reason: ISS transfer from the mouse ortholog agrees with the direct human evidence that FAR2 is peroxisomal. Supporting Evidence: PMID:15220348 FAR1 and FAR2 were localized in the peroxisome |
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Download this section (compressed HTML)Q: What is the relative in vivo contribution of FAR2 versus FAR1 to Meibomian gland (meibum) fatty alcohol pools, and does FAR2 loss produce a distinct Meibomian/ocular-surface phenotype?
Q: Does human FAR2 physiologically produce very-long-chain and ultra-long-chain fatty alcohols in tissues, or is this activity mainly observed under overexpression conditions?
Experiment: Quantify chain-length and saturation preferences of purified human FAR2 across a panel of acyl-CoA substrates (C16-C30, saturated/unsaturated, branched) with NADPH, to firmly establish the in vitro substrate spectrum underlying the long-chain vs very-long-chain reductase annotations.
Experiment: Tissue-specific FAR2 knockout (e.g. Meibomian gland) with lipidomic profiling of fatty alcohols, wax monoesters, and ether lipids/plasmalogens to define the non-redundant biological role of FAR2 relative to FAR1.
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