FADS1 (Fatty Acid Desaturase 1) encodes the delta-5 desaturase (D5D), a rate-limiting enzyme in the biosynthesis of long-chain polyunsaturated fatty acids (LC-PUFAs). The enzyme catalyzes the introduction of a cis double bond at the delta-5 position of C20 polyunsaturated acyl-CoA substrates, specifically converting dihomo-gamma-linolenic acid (DGLA; 20:3n-6) to arachidonic acid (AA; 20:4n-6) in the omega-6 pathway, and eicosatetraenoic acid (ETA; 20:4n-3) to eicosapentaenoic acid (EPA; 20:5n-3) in the omega-3 pathway. FADS1 is an ER membrane-localized enzyme with an N-terminal cytochrome b5-like domain and three conserved histidine-box motifs essential for catalysis. The enzyme requires cytochrome b5 and NADH-cytochrome b5 reductase as electron donors. By controlling AA and EPA synthesis, FADS1 is the rate-limiting step in the production of eicosanoid precursors and thus regulates inflammatory lipid mediator production including prostaglandins. The PUFAs synthesized by FADS1 are incorporated into membrane phospholipids and are substrates for lipid peroxidation, a key driver of ferroptosis. Common genetic variants in the FADS1/FADS2 gene cluster strongly influence circulating PUFA levels and show evidence of evolutionary selection across human populations.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0006629 lipid metabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: FADS1 is unambiguously involved in lipid metabolism as a delta-5 fatty acid desaturase that catalyzes key steps in long-chain PUFA biosynthesis. This IBA annotation from phylogenetic analysis is well-supported. Reason: FADS1 is a core enzyme in lipid metabolism, specifically in the biosynthesis of polyunsaturated fatty acids. The phylogenetic inference is sound and consistent with experimental evidence (PMID:10601301, PMID:10769175). Supporting Evidence: PMID:10601301 One of the two rate-limiting steps in the production of these polyenoic fatty acids is the desaturation of 20:3(n-6) and 20:4(n-3) by Delta-5 desaturase file:human/FADS1/FADS1-deep-research-falcon.md model: Edison Scientific Literature |
| GO:0016020 membrane | IBA GO_REF:0000033 | ACCEPT | Summary: FADS1 is a multi-pass transmembrane protein localized to the ER membrane. The IBA annotation for membrane localization is correct but could be more specific. Reason: This general membrane annotation is correct. More specific annotations (ER membrane) are also present with better evidence. Retaining as it reflects phylogenetic conservation of membrane localization. Supporting Evidence: PMID:10601301 The Delta-5 desaturase contains two membrane-spanning domains, three histidine-rich regions, and a cytochrome b(5) domain that all align perfectly with the same domains located in the Delta-6 desaturase. |
| GO:0016717 oxidoreductase activity, acting on paired donors, with oxidation of a pair of donors resulting in the reduction of molecular oxygen to two molecules of water | IBA GO_REF:0000033 | ACCEPT | Summary: FADS1 is indeed an oxidoreductase that uses paired donors (cytochrome b5) and molecular oxygen. This is the correct parent class for its enzymatic mechanism. Reason: The reaction mechanism of FADS1 involves oxidation of two ferrous cytochrome b5 molecules coupled to reduction of O2, making this annotation accurate at the mechanistic level. The more specific term GO:0062076 (acyl-CoA (8-3)- desaturase activity) is also present. Supporting Evidence: PMID:10769175 The human Delta(5)-desaturase contained a predicted N-terminal cytochrome b(5)-like domain, as well as three histidine-rich domains. |
| GO:0005739 mitochondrion | IEA GO_REF:0000044 | ACCEPT | Summary: Some evidence supports mitochondrial localization of FADS1, particularly for the alternative isoform 2. Reason: UniProt subcellular location indicates mitochondrial localization for isoform 1, supported by experimental evidence in PMID:22619218 (Park et al. 2012). The primary localization is ER membrane, but mitochondrial presence is documented. Supporting Evidence: PMID:22619218 FADS1, but not FADS1AT1, localizes to endoplasmic reticulum and mitochondria. |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: FADS1 is a multi-pass transmembrane protein primarily localized to the ER membrane where it performs fatty acid desaturation. Reason: ER membrane is the primary and canonical localization for FADS1. This is supported by UniProt subcellular location mapping and extensive literature evidence. The enzyme functions as part of the ER-based PUFA biosynthetic machinery. Supporting Evidence: PMID:10601301 The Delta-5 desaturase contains two membrane-spanning domains, three histidine-rich regions, and a cytochrome b(5) domain that all align perfectly with the same domains located in the Delta-6 desaturase. |
| GO:0006629 lipid metabolic process | IEA GO_REF:0000120 | ACCEPT | Summary: Redundant with the IBA annotation for lipid metabolic process. Both are correct annotations. Reason: This IEA annotation from combined automated methods correctly identifies FADS1's role in lipid metabolism. Duplicates with different evidence codes are acceptable. |
| GO:0006631 fatty acid metabolic process | IEA GO_REF:0000043 | ACCEPT | Summary: FADS1 is specifically involved in fatty acid metabolism as a fatty acid desaturase. Reason: This is a core function of FADS1. The enzyme desaturates fatty acyl-CoA substrates, making fatty acid metabolic process an accurate annotation. Supporting Evidence: PMID:10601301 Expression of the open reading frame in Chinese hamster ovary cells instilled the ability to convert 20:3(n-6) to 20:4(n-6). |
| GO:0006633 fatty acid biosynthetic process | IEA GO_REF:0000043 | ACCEPT | Summary: FADS1 participates in the biosynthesis of long-chain polyunsaturated fatty acids by introducing double bonds into fatty acid precursors. Reason: FADS1 is directly involved in fatty acid biosynthesis - specifically the biosynthesis of highly unsaturated fatty acids (HUFAs) from dietary PUFA precursors. Supporting Evidence: PMID:10769175 Expression of this ORF in mouse fibroblast cells demonstrated that the encoded protein was a Delta(5)-desaturase, as determined by the conversion of dihomo-gamma-linolenic acid (C(20:3,n-6)) into arachidonic acid (C(20:4,n-6)). |
| GO:0016491 oxidoreductase activity | IEA GO_REF:0000120 | ACCEPT | Summary: FADS1 is an oxidoreductase enzyme. This is a parent term of the more specific desaturase activities. Reason: Correct but general. FADS1 is classified under EC 1.14.19.44, placing it in the oxidoreductase class. More specific terms (GO:0062076, GO:0016717) are also present. |
| GO:0062076 acyl-CoA (8-3)-desaturase activity | IEA GO_REF:0000120 | ACCEPT | Summary: This is the specific molecular function term for FADS1's enzymatic activity, describing the delta-5 desaturase reaction on acyl-CoA substrates. Reason: This is the most specific and accurate molecular function term for FADS1. The nomenclature (8-3) refers to the position of the new double bond relative to an existing double bond. Experimental evidence (IDA) also supports this annotation. Supporting Evidence: PMID:10769175 Expression of this ORF in mouse fibroblast cells demonstrated that the encoded protein was a Delta(5)-desaturase, as determined by the conversion of dihomo-gamma-linolenic acid (C(20:3,n-6)) into arachidonic acid (C(20:4,n-6)). |
| GO:0036109 alpha-linolenic acid metabolic process | TAS Reactome:R-HSA-2046106 | ACCEPT | Summary: FADS1 participates in alpha-linolenic acid (ALA, 18:3n-3) metabolism by performing the delta-5 desaturation step in the omega-3 pathway. Reason: FADS1 catalyzes a key step in ALA metabolism, converting eicosatetraenoic acid (ETA, 20:4n-3) to EPA (20:5n-3) in the omega-3 PUFA biosynthetic pathway. Reactome annotation is accurate. Supporting Evidence: PMID:10769175 Expression of this ORF in mouse fibroblast cells demonstrated that the encoded protein was a Delta(5)-desaturase, as determined by the conversion of dihomo-gamma-linolenic acid (C(20:3,n-6)) into arachidonic acid (C(20:4,n-6)). |
| GO:0043651 linoleic acid metabolic process | TAS Reactome:R-HSA-2046105 | ACCEPT | Summary: FADS1 participates in linoleic acid (LA, 18:2n-6) metabolism by performing the delta-5 desaturation step in the omega-6 pathway. Reason: FADS1 catalyzes the rate-limiting delta-5 desaturation converting DGLA (20:3n-6) to arachidonic acid (20:4n-6) in the omega-6 PUFA biosynthetic pathway downstream of linoleic acid. Supporting Evidence: PMID:10601301 Expression of the open reading frame in Chinese hamster ovary cells instilled the ability to convert 20:3(n-6) to 20:4(n-6). |
| GO:0006636 unsaturated fatty acid biosynthetic process | IEA GO_REF:0000041 | ACCEPT | Summary: FADS1 is directly involved in unsaturated fatty acid biosynthesis by introducing cis double bonds into fatty acid substrates. Reason: This is a core function of FADS1. The enzyme specifically introduces double bonds to create polyunsaturated fatty acids. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-1989757 | ACCEPT | Summary: ER membrane localization for FADS1 expression and function. Reason: Reactome pathway information correctly places FADS1 at the ER membrane, consistent with its function as a microsomal desaturase. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-2046089 | ACCEPT | Summary: ER membrane localization for the omega-3 desaturation reaction. Reason: Duplicate ER membrane annotation from different Reactome reactions is acceptable as it provides pathway context. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-2046092 | ACCEPT | Summary: ER membrane localization for the omega-6 desaturation reaction. Reason: Duplicate ER membrane annotation from different Reactome reactions is acceptable as it provides pathway context. |
| GO:0005739 mitochondrion | ISS GO_REF:0000024 | ACCEPT | Summary: Mitochondrial localization supported by sequence similarity to characterized orthologs. Reason: ISS annotation based on sequence similarity is consistent with experimental evidence for mitochondrial localization (PMID:22619218). Both ER and mitochondrial localizations are documented. |
| GO:0005789 endoplasmic reticulum membrane | ISS GO_REF:0000024 | ACCEPT | Summary: ER membrane localization supported by sequence similarity to characterized orthologs. Reason: ISS annotation correctly identifies primary localization of FADS1. |
| GO:0062076 acyl-CoA (8-3)-desaturase activity | IDA PMID:10769175 cDNA cloning and characterization of human Delta5-desaturase... | ACCEPT | Summary: Direct experimental demonstration of delta-5 desaturase activity by expression in mammalian cells. Reason: This IDA annotation is based on direct experimental evidence from Leonard et al. 2000, who expressed FADS1 in mouse fibroblast cells and demonstrated conversion of DGLA to AA. Supporting Evidence: PMID:10769175 Expression of this ORF in mouse fibroblast cells demonstrated that the encoded protein was a Delta(5)-desaturase, as determined by the conversion of dihomo-gamma-linolenic acid (C(20:3,n-6)) into arachidonic acid (C(20:4,n-6)). |
| GO:0045485 omega-6 fatty acid desaturase activity | TAS Reactome:R-HSA-2046089 | ACCEPT | Summary: FADS1 acts on omega-6 fatty acid substrates (DGLA) to produce arachidonic acid. Reason: FADS1 desaturates both omega-6 (DGLA to AA) and omega-3 (ETA to EPA) substrates. The omega-6 desaturase activity is well documented. Supporting Evidence: PMID:10601301 Expression of the open reading frame in Chinese hamster ovary cells instilled the ability to convert 20:3(n-6) to 20:4(n-6). |
| GO:0045485 omega-6 fatty acid desaturase activity | TAS Reactome:R-HSA-2046092 | ACCEPT | Summary: Duplicate annotation for omega-6 fatty acid desaturase activity from different Reactome reaction. Reason: Consistent with FADS1 function in omega-6 PUFA biosynthesis. |
| GO:0006636 unsaturated fatty acid biosynthetic process | IDA PMID:10601301 Cloning, expression, and fatty acid regulation of the human ... | ACCEPT | Summary: Direct experimental evidence for involvement in unsaturated fatty acid biosynthesis from the original cloning paper. Reason: Cho et al. 1999 demonstrated that FADS1 expression enables conversion of 20:3(n-6) to 20:4(n-6), directly establishing its role in unsaturated fatty acid biosynthesis. Supporting Evidence: PMID:10601301 Expression of the open reading frame in Chinese hamster ovary cells instilled the ability to convert 20:3(n-6) to 20:4(n-6). |
| GO:0016213 acyl-CoA 6-desaturase activity | IDA PMID:10601301 Cloning, expression, and fatty acid regulation of the human ... | REMOVE | Summary: This annotation appears to be an error. FADS1 has delta-5 desaturase activity, not delta-6. FADS2 has delta-6 desaturase activity. Reason: This annotation is incorrect. PMID:10601301 clearly characterizes FADS1 as a delta-5 desaturase, not a delta-6 desaturase. The delta-6 desaturase activity (GO:0016213) belongs to FADS2. The paper explicitly states this is a Delta-5 desaturase and compares it to the distinct Delta-6 desaturase. Supporting Evidence: PMID:10601301 This report describes the cloning and expression of the human Delta-5 desaturase, and it compares the structural characteristics and nutritional regulation of the Delta-5 and Delta-6 desaturases. |
| GO:0042759 long-chain fatty acid biosynthetic process | IDA PMID:10601301 Cloning, expression, and fatty acid regulation of the human ... | ACCEPT | Summary: FADS1 participates in long-chain fatty acid biosynthesis by desaturating C20 fatty acid substrates. Reason: The substrates and products of FADS1 (DGLA, AA, ETA, EPA) are all long-chain fatty acids (C20), making this annotation accurate. Supporting Evidence: PMID:10601301 Expression of the open reading frame in Chinese hamster ovary cells instilled the ability to convert 20:3(n-6) to 20:4(n-6). |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | ACCEPT | Summary: High-throughput data confirms membrane localization of FADS1 in NK cells. Reason: This HDA annotation from proteomics of NK cell membranes provides additional support for membrane localization, consistent with FADS1's known topology as a multi-pass transmembrane protein. Supporting Evidence: PMID:19946888 Defining the membrane proteome of NK cells. |
| GO:0000248 C-5 sterol desaturase activity | TAS PMID:10601301 Cloning, expression, and fatty acid regulation of the human ... | REMOVE | Summary: This annotation appears incorrect. FADS1 is a fatty acid desaturase, not a sterol desaturase. The C-5 position refers to sterols, not to the delta-5 position in fatty acids. Reason: This is a misannotation. FADS1 is a delta-5 fatty acid desaturase that acts on acyl-CoA substrates, not a C-5 sterol desaturase. The GO term GO:0000248 describes sterol desaturation (ergosterol pathway), not fatty acid desaturation. PMID:10601301 characterizes FADS1 as acting on fatty acids (20:3(n-6) to 20:4(n-6)), not sterols. Supporting Evidence: PMID:10601301 Expression of the open reading frame in Chinese hamster ovary cells instilled the ability to convert 20:3(n-6) to 20:4(n-6). |
| GO:0006355 regulation of DNA-templated transcription | NAS PMID:10601301 Cloning, expression, and fatty acid regulation of the human ... | REMOVE | Summary: This annotation suggests FADS1 regulates transcription. The NAS evidence likely refers to the fact that PUFA products regulate transcription factors like PPARs, not that FADS1 itself is a transcriptional regulator. Reason: This is an over-annotation. FADS1 is an enzyme that produces PUFAs, which can then act as ligands for nuclear receptors like PPARs. However, FADS1 itself does not directly regulate transcription. The paper discusses that PUFAs are "regulators of nuclear transcription factors" but this function is attributed to the PUFA products, not to FADS1 as an enzyme. Supporting Evidence: PMID:10601301 Arachidonic (20:4(n-6)), eicosapentaenoic (20:5(n-3)), and docosahexaenoic (22:6(n-3)) acids are major components of brain and retina phospholipids, substrates for eicosanoid production, and regulators of nuclear transcription factors. |
| GO:0006636 unsaturated fatty acid biosynthetic process | TAS PMID:10601301 Cloning, expression, and fatty acid regulation of the human ... | ACCEPT | Summary: TAS annotation for unsaturated fatty acid biosynthesis from the original characterization paper. Reason: Accurate annotation based on the functional characterization of FADS1. Supporting Evidence: PMID:10601301 Cloning, expression, and fatty acid regulation of the human delta-5 desaturase. |
| GO:0007267 cell-cell signaling | NAS PMID:10601301 Cloning, expression, and fatty acid regulation of the human ... | MARK AS OVER ANNOTATED | Summary: This annotation suggests FADS1 is involved in cell-cell signaling. This likely refers to the fact that its products (AA, EPA) are precursors to eicosanoids which mediate signaling. Reason: While FADS1 products (arachidonic acid, EPA) are precursors to eicosanoid signaling molecules, FADS1 itself is an enzymatic step removed from the signaling process. This is an indirect/over-annotation. The direct function is fatty acid desaturation; eicosanoid signaling is a downstream consequence. Supporting Evidence: PMID:10601301 Cloning, expression, and fatty acid regulation of the human delta-5 desaturase. |
| GO:0008654 phospholipid biosynthetic process | TAS PMID:10601301 Cloning, expression, and fatty acid regulation of the human ... | KEEP AS NON CORE | Summary: FADS1 products (AA, EPA) are incorporated into membrane phospholipids, but FADS1 itself does not directly synthesize phospholipids. Reason: This annotation has some validity as FADS1 provides arachidonic acid that is incorporated into phospholipids, particularly phosphatidylinositol. UniProt notes that FADS1 "Contributes to membrane phospholipid biosynthesis by providing AA as a major acyl chain esterified into phospholipids." However, it is not the core function of the enzyme. Supporting Evidence: PMID:10601301 Cloning, expression, and fatty acid regulation of the human delta-5 desaturase. |
| GO:0009267 cellular response to starvation | IDA PMID:10601301 Cloning, expression, and fatty acid regulation of the human ... | REMOVE | Summary: The paper discusses nutritional regulation of FADS1 expression, showing that dietary fat regulates mRNA levels. This is about regulation OF FADS1, not regulation BY FADS1. Reason: This annotation misinterprets the experimental findings. PMID:10601301 shows that FADS1 expression is regulated by dietary fat (higher in rats fed fat-free diet), but this demonstrates regulation of FADS1 by nutritional status, not that FADS1 mediates the cellular response to starvation. The correct interpretation is that FADS1 is a target of nutritional regulation, not an effector of starvation response. Supporting Evidence: PMID:10601301 When rats were fed a diet containing 10% safflower oil or menhaden fish oil, the level of hepatic mRNA for Delta-5 and Delta-6 desaturase was only 25% of that found in the liver of rats fed a fat-free diet or a diet containing triolein |
| GO:0016020 membrane | NAS PMID:10601301 Cloning, expression, and fatty acid regulation of the human ... | ACCEPT | Summary: General membrane localization from the original characterization. Reason: Accurate annotation based on the structural characterization showing membrane-spanning domains. Supporting Evidence: PMID:10601301 The Delta-5 desaturase contains two membrane-spanning domains, three histidine-rich regions, and a cytochrome b(5) domain that all align perfectly with the same domains located in the Delta-6 desaturase. |
| GO:0016020 membrane | TAS PMID:10601301 Cloning, expression, and fatty acid regulation of the human ... | ACCEPT | Summary: TAS annotation for membrane localization from the original paper. Reason: Accurate annotation based on structural characterization. Supporting Evidence: PMID:10601301 Cloning, expression, and fatty acid regulation of the human delta-5 desaturase. |
| GO:0016491 oxidoreductase activity | IDA PMID:10601301 Cloning, expression, and fatty acid regulation of the human ... | ACCEPT | Summary: Direct experimental demonstration of oxidoreductase (desaturase) activity. Reason: The functional expression experiments demonstrated enzymatic activity, confirming FADS1 as an oxidoreductase. Supporting Evidence: PMID:10601301 Cloning, expression, and fatty acid regulation of the human delta-5 desaturase. |
| GO:0043231 intracellular membrane-bounded organelle | NAS PMID:10601301 Cloning, expression, and fatty acid regulation of the human ... | ACCEPT | Summary: General term for localization to membrane-bounded organelles (ER, mitochondria). Reason: This is a parent term of the more specific ER membrane annotation. Accurate but not highly informative. Supporting Evidence: PMID:10601301 Cloning, expression, and fatty acid regulation of the human delta-5 desaturase. |
| GO:0045595 regulation of cell differentiation | NAS PMID:10601301 Cloning, expression, and fatty acid regulation of the human ... | MARK AS OVER ANNOTATED | Summary: This annotation suggests FADS1 regulates cell differentiation. The cited paper does not provide evidence for this function. Reason: While FADS1 expression changes during differentiation (as noted in UniProt: "Strongly down-regulated upon differentiation in a neuroblastoma cell line"), this does not mean FADS1 regulates differentiation. The annotation appears to confuse correlation with causation. PMID:10601301 does not discuss cell differentiation. Supporting Evidence: PMID:10601301 Cloning, expression, and fatty acid regulation of the human delta-5 desaturase. |
| GO:0046456 icosanoid biosynthetic process | TAS PMID:10601301 Cloning, expression, and fatty acid regulation of the human ... | ACCEPT | Summary: FADS1 synthesizes arachidonic acid and EPA, which are the precursors for icosanoid (eicosanoid) biosynthesis. Reason: This is a valid annotation. FADS1 is the rate-limiting step for production of arachidonic acid, which is the direct precursor for prostaglandins, leukotrienes, and other eicosanoids. UniProt explicitly states FADS1 "controls the metabolism of inflammatory lipids like prostaglandin E2." Supporting Evidence: PMID:10601301 Arachidonic (20:4(n-6)), eicosapentaenoic (20:5(n-3)), and docosahexaenoic (22:6(n-3)) acids are major components of brain and retina phospholipids, substrates for eicosanoid production, and regulators of nuclear transcription factors. |
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Download this section (compressed HTML)Q: What is the relative contribution of FADS1 vs FADS2 to membrane PUFA composition and ferroptosis sensitivity?
Q: Is FADS1 activity or expression altered in ferroptosis-resistant cancer cells?
Q: What is the functional significance of FADS1 mitochondrial localization?
Experiment: CRISPR knockout of FADS1 in cancer cell lines followed by lipidomics and ferroptosis sensitivity assays to determine direct contribution to ferroptosis susceptibility.
Hypothesis: FADS1 knockout will reduce membrane PUFA content and confer resistance to ferroptosis inducers such as erastin and RSL3.
Experiment: Comparison of FADS1 expression and activity in ferroptosis-sensitive vs resistant cell lines.
Hypothesis: Ferroptosis-resistant cells will show reduced FADS1 expression or activity, correlating with lower membrane PUFA content.
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