Existing Annotations Review

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.

Core Functions

FADS1 is the delta-5 fatty acid desaturase that catalyzes the rate-limiting step in PUFA biosynthesis. It introduces a cis double bond at the delta-5 position (8 carbons from an existing double bond, hence "8-3") of C20 polyunsaturated acyl-CoA substrates. Direct enzymatic activity demonstrated by expression in mammalian cells (PMID:10601301, PMID:10769175). By producing arachidonic acid and EPA, FADS1 provides the substrates for all eicosanoid biosynthesis including prostaglandins, leukotrienes, thromboxanes, and specialized pro-resolving mediators. The PUFAs produced are also incorporated into membrane phospholipids and serve as substrates for lipid peroxidation, connecting FADS1 activity to ferroptosis susceptibility.

Molecular Function:

acyl-CoA (8-3)-desaturase activity

References

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000041

Gene Ontology annotation based on UniPathway vocabulary mapping

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:10601301

Cloning, expression, and fatty acid regulation of the human delta-5 desaturase.

FADS1 encodes the delta-5 desaturase, one of two rate-limiting enzymes in PUFA biosynthesis. Expression in CHO cells demonstrated conversion of 20:3(n-6) to 20:4(n-6).

"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"
FADS1 contains two membrane-spanning domains, three histidine-rich regions, and a cytochrome b5 domain.

"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."
Delta-5 and Delta-6 desaturase genes reside head-to-head on chromosome 11 separated by less than 11,000 base pairs.

"the Delta-5 and Delta-6 desaturase genes reside in reverse orientation on chromosome 11 and that they are separated by <11,000 base pairs."
Expression is highest in liver, brain, and heart, and is nutritionally regulated (suppressed by dietary PUFA).

"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"

PMID:10769175

cDNA cloning and characterization of human Delta5-desaturase involved in the biosynthesis of arachidonic acid.

Expression of FADS1 ORF in mouse fibroblast cells demonstrated delta-5 desaturase activity by conversion of DGLA (20:3n-6) to AA (20:4n-6).

"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))."
FADS1 contains an N-terminal cytochrome b5-like domain and three histidine-rich domains.

"The human Delta(5)-desaturase contained a predicted N-terminal cytochrome b(5)-like domain, as well as three histidine-rich domains."
Highly expressed in fetal liver, fetal brain, adult brain, and adrenal gland.

"A tissue expression profile revealed that this gene is highly expressed in fetal liver, fetal brain, adult brain and adrenal gland."

PMID:19946888

Defining the membrane proteome of NK cells.

PMID:22619218

A novel FADS1 isoform potentiates FADS2-mediated production of eicosanoid precursor fatty acids.

Identified alternative FADS1 isoform (FADS1AT1) that lacks catalytic activity but may enhance FADS2 function.

"FADS1 alternative transcript 1 (FADS1AT1) enhances desaturation of FADS2, leading to increased production of eicosanoid precursors, the first case of an isoform modulating the enzymatic activity encoded by another gene."
FADS1 isoform 1 localizes to both ER and mitochondria.

"FADS1, but not FADS1AT1, localizes to endoplasmic reticulum and mitochondria."

Reactome:R-HSA-1989757

Expression of FADS1

Reactome:R-HSA-2046089

Desaturation of eicosatetraenoyl-CoA to eicosapentaenoyl-CoA

Reactome:R-HSA-2046092

Desaturation of dihomo-gamma-lenolenoyl-CoA to arachidonoyl-CoA

Reactome:R-HSA-2046105

Linoleic acid (LA) metabolism

Reactome:R-HSA-2046106

alpha-linolenic acid (ALA) metabolism

file:human/FADS1/FADS1-deep-research-falcon.md

Deep research summary for FADS1

FADS1 performs the delta-5 desaturation step in LC-PUFA biosynthesis, converting DGLA to AA and ETA to EPA.

"FADS1 encodes the microsomal delta-5 desaturase that introduces a double bond at the delta-5 position of C20 polyunsaturated acyl-CoAs. Canonical reactions in humans include dihomo-gamma-linolenic acid (DGLA; 20:3n-6) to arachidonic acid (AA; 20:4n-6) and eicosatetraenoic acid (ETA; 20:4n-3) to eicosapentaenoic acid (EPA; 20:5n-3)."
FADS variants are strong determinants of LC-PUFA biosynthesis with marked frequency differences across ancestries.

"FADS1/FADS2 genotypes show marked frequency differences across ancestries and contribute to gene-diet interactions and evolutionary signatures."
FADS1 upregulation in colorectal cancer increases AA in tumor interstitium and elevates PGE2.

"Xu et al. 2023 demonstrated that FADS1 upregulation is an early event in CRC, increases AA in the tumor interstitium, enriches gram-negative microbes, activates TLR4/MYD88 signaling, and elevates PGE2."
D5D inhibitor (D5D-IN-326) reduced CRC cell/organoid growth, suggesting therapeutic potential of targeting FADS1.

"A D5D inhibitor (D5D-IN-326) reduced CRC cell/organoid growth (e.g., P=0.003 in SW480; 0.008 HCT-116; 0.006 organoid)."

Suggested Experiments

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.

📚 Additional Documentation

Deep Research Falcon

(FADS1-deep-research-falcon.md)

provider: falcon
model: Edison Scientific Literature
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template_variables:
organism: human
gene_id: FADS1
gene_symbol: FADS1
uniprot_accession: O60427
protein_description: 'RecName: Full=Acyl-CoA (8-3)-desaturase {ECO:0000305}; EC=1.14.19.44
{ECO:0000269|PubMed:10601301, ECO:0000269|PubMed:10769175}; AltName: Full=Delta(5)
fatty acid desaturase; Short=D5D {ECO:0000250|UniProtKB:Q920L1}; Short=Delta(5)
desaturase {ECO:0000250|UniProtKB:Q920L1}; Short=Delta-5 desaturase {ECO:0000303|PubMed:10601301,
ECO:0000303|PubMed:10769175}; AltName: Full=Fatty acid desaturase 1 {ECO:0000303|PubMed:10860662};'
gene_info: Name=FADS1 {ECO:0000303|PubMed:10860662, ECO:0000312|HGNC:HGNC:3574};
Synonyms=FADSD5;
organism_full: Homo sapiens (Human).
protein_family: Belongs to the fatty acid desaturase type 1 family.
protein_domains: Cyt_B5-like_heme/steroid-bd. (IPR001199); Cyt_B5-like_heme/steroid_sf.
(IPR036400); FA_desaturase_dom. (IPR005804); Fatty_acid_desaturase. (IPR012171);
Cyt-b5 (PF00173)
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Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: O60427
Protein Description: RecName: Full=Acyl-CoA (8-3)-desaturase {ECO:0000305}; EC=1.14.19.44 {ECO:0000269|PubMed:10601301, ECO:0000269|PubMed:10769175}; AltName: Full=Delta(5) fatty acid desaturase; Short=D5D {ECO:0000250|UniProtKB:Q920L1}; Short=Delta(5) desaturase {ECO:0000250|UniProtKB:Q920L1}; Short=Delta-5 desaturase {ECO:0000303|PubMed:10601301, ECO:0000303|PubMed:10769175}; AltName: Full=Fatty acid desaturase 1 {ECO:0000303|PubMed:10860662};
Gene Information: Name=FADS1 {ECO:0000303|PubMed:10860662, ECO:0000312|HGNC:HGNC:3574}; Synonyms=FADSD5;
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the fatty acid desaturase type 1 family.
Key Domains: Cyt_B5-like_heme/steroid-bd. (IPR001199); Cyt_B5-like_heme/steroid_sf. (IPR036400); FA_desaturase_dom. (IPR005804); Fatty_acid_desaturase. (IPR012171); Cyt-b5 (PF00173)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "FADS1" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'FADS1' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene FADS1 (gene ID: FADS1, UniProt: O60427) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: O60427
Protein Description: RecName: Full=Acyl-CoA (8-3)-desaturase {ECO:0000305}; EC=1.14.19.44 {ECO:0000269|PubMed:10601301, ECO:0000269|PubMed:10769175}; AltName: Full=Delta(5) fatty acid desaturase; Short=D5D {ECO:0000250|UniProtKB:Q920L1}; Short=Delta(5) desaturase {ECO:0000250|UniProtKB:Q920L1}; Short=Delta-5 desaturase {ECO:0000303|PubMed:10601301, ECO:0000303|PubMed:10769175}; AltName: Full=Fatty acid desaturase 1 {ECO:0000303|PubMed:10860662};
Gene Information: Name=FADS1 {ECO:0000303|PubMed:10860662, ECO:0000312|HGNC:HGNC:3574}; Synonyms=FADSD5;
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the fatty acid desaturase type 1 family.
Key Domains: Cyt_B5-like_heme/steroid-bd. (IPR001199); Cyt_B5-like_heme/steroid_sf. (IPR036400); FA_desaturase_dom. (IPR005804); Fatty_acid_desaturase. (IPR012171); Cyt-b5 (PF00173)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "FADS1" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Please provide a comprehensive research report on the gene FADS1 (gene ID: FADS1, UniProt: O60427) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Plan and verification
- Target confirmed: Human FADS1 (UniProt O60427), also called delta-5 desaturase (D5D), EC 1.14.19.44. Literature places FADS1 in the endoplasmic reticulum (ER) membrane with an N‑terminal cytochrome b5–like domain and conserved His boxes shared across FADS1/2/3; electrons are supplied by the cytochrome b5/NADH–cytochrome b5 reductase system. These features align with the UniProt description and the fatty acid desaturase type 1 family membership (human) (koletzko2019fads1andfads2 pages 3-4, majou2021synthesisofdha pages 10-10, park2018thebiochemistryand pages 13-14, koletzko2019fads1andfads2 pages 1-3).

Comprehensive research report: FADS1 (Fatty Acid Desaturase 1; O60427)

1) Key concepts and definitions
- Molecular identity and reaction. FADS1 encodes the microsomal Δ5 desaturase that introduces a double bond at the Δ5 position of C20 polyunsaturated acyl-CoAs. Canonical reactions in humans include: (i) dihomo-γ-linolenic acid (DGLA; 20:3n‑6) → arachidonic acid (AA; 20:4n‑6); and (ii) eicosatetraenoic acid (ETA; 20:4n‑3) → eicosapentaenoic acid (EPA; 20:5n‑3). These Δ5 steps sit within the long‑chain PUFA (LC‑PUFA) biosynthetic pathway that converts dietary linoleic acid (LA; 18:2n‑6) and α‑linolenic acid (ALA; 18:3n‑3) to AA, EPA, and DHA via alternating desaturation/elongation (FADS2 Δ6/Δ8 and ELOVL) (Koletzko 2019 review) (https://doi.org/10.1146/annurev-nutr-082018-124250, Aug 2019) (koletzko2019fads1andfads2 pages 3-4, koletzko2019fads1andfads2 pages 1-3).
- Subcellular localization and domains. FADS1 is an ER membrane enzyme bearing an N‑terminal cytochrome b5–like domain; mammalian desaturation requires the cytochrome b5/cytochrome b5 reductase electron donor system on the ER. FADS genes share cytochrome b5 domain and three conserved histidine boxes critical for catalysis (Brenna et al. 2010; Chen et al. 2013) (https://doi.org/10.1016/j.plefa.2010.02.011, Apr 2010; https://doi.org/10.1016/j.bbrc.2013.09.127, Nov 2013) (majou2021synthesisofdha pages 10-10, park2018thebiochemistryand pages 13-14).
- FADS gene cluster and regulation. FADS1 and FADS2 lie head‑to‑head on chr11q12‑q13 with numerous common variants that modulate desaturase activities and tissue/blood LC‑PUFA levels. These genotypes show marked frequency differences across ancestries and contribute to gene–diet interactions and evolutionary signatures (Koletzko 2019; Romero‑Hidalgo 2024) (https://doi.org/10.1146/annurev-nutr-082018-124250; https://doi.org/10.1016/j.heliyon.2024.e35477) (koletzko2019fads1andfads2 pages 1-3, romerohidalgo2024selectionscanin pages 15-16).
- Alternative isoforms. A non‑catalytic FADS1 alternative transcript (FADS1AT1) modulates FADS2‑mediated desaturation and displays distinct organelle localization (ER and mitochondria), suggesting isoform‑level regulation of LC‑PUFA biosynthesis (Park et al. 2012) (https://doi.org/10.1194/jlr.m025312, Aug 2012) (park2018thebiochemistryand pages 13-14).

2) Recent developments (2023–2024) and latest research
- Cancer biology: colorectal cancer (CRC) FADS1–AA axis. Xu et al. 2023 demonstrated that FADS1 upregulation is an early event in CRC, increases AA in the tumor interstitium, enriches gram‑negative microbes, activates TLR4/MYD88 signaling, and elevates PGE2; dietary AA feeding promoted tumorigenesis in AOM/DSS and Apc−/− models. Knockdown of FADS1 lowered AA (without changing EPA), reduced AA/EPA ratio, and attenuated tumor growth; a D5D inhibitor (D5D‑IN‑326) reduced CRC cell/organoid growth (e.g., P=0.003 in SW480; 0.008 HCT‑116; 0.006 organoid). High FADS1 expression associated with poorer outcomes in a clinical cohort (multivariable HRs reported for tumor features) (https://doi.org/10.1038/s41467-023-37590-x, Apr 2023) (xu2023fads1arachidonicacidaxis pages 1-2, xu2023fads1arachidonicacidaxis pages 4-5, xu2023fads1arachidonicacidaxis pages 11-11, xu2023fads1arachidonicacidaxis pages 3-4).
- Lipidomics/GWAS and gene–supplement interactions. A 2024 UK Biobank GWIS of 200,060 Europeans found genome‑wide significant FADS1/FADS2 interactions with fish oil supplementation for omega‑3%, DHA%, total omega‑3 and the omega‑6:omega‑3 ratio. For omega‑3%, lead variant rs35473591 had smaller genetic effect in supplement users (β 0.35) than non‑users (β 0.42), and supplement effect sizes varied across genotypes (β 0.45, 0.50, 0.59 by genotype), underscoring personalized responses (medRxiv, Dec 2024) (https://doi.org/10.1101/2024.12.12.24318956) (sun2024leveraginggeneticdata pages 72-77).
- Lipid species GWAS. A 2024 population lipidomics GWAS (Rhineland Study) identified 51 loci for complex lipid species, including signals at FADS2/FADS1 pivotal for fatty acid metabolism, reinforcing the centrality of this locus in human lipid architecture (medRxiv, Dec 2024) (https://doi.org/10.1101/2024.12.04.24318368) (sun2024leveraginggeneticdata pages 72-77).
- Clinical lipid associations and risk. UK Biobank prospective analysis linked higher plasma n‑3 and n‑6 PUFA with lower incident hepatocellular carcinoma (HCC) risk (HR Q4 vs Q1: 0.48 for both) and markedly lower chronic liver disease mortality (HR 0.21 for n‑3 PUFA; 0.15 for n‑6 PUFA), while saturated fat was associated with higher risk (Nature Communications, May 2024); discussion highlights roles of fatty acid desaturases (FADS1/2) in PUFA biology (https://doi.org/10.1038/s41467-024-47960-8) (sun2024leveraginggeneticdata pages 72-77).
- Genotype–phenotype in humans. In 2024, Rabehl et al. reported that homozygous ancestral (minor) FADS1 genotypes had significantly lower blood AA, with trends toward lower arachidonic‑derived oxylipins; liver fat did not differ by genotype in this 85‑patient cohort (Frontiers in Nutrition, Jul 2024) (https://doi.org/10.3389/fnut.2024.1356986) (rabehl2024effectoffads1 pages 7-8). Reyes‑Pérez et al. (2024) found in 76 adults with obesity that EPA+DHA supplementation raised the omega‑3 index across all, but carriers of FADS1 rs174547 CC (ancestral) showed smaller increases in n‑6, n‑3, total PUFA, EPA, DHA and omega‑3 index than TT (Nutrients, Oct 2024) (https://doi.org/10.3390/nu16203522) (reyesperez2024fads1geneticvariant pages 13-13). A 2024 scoping review concluded that 47 FADS SNPs associate with EPA/DHA levels, with consistent effects for rs174537/rs174547/rs174556/rs174561 (minor alleles → lower EPA/DHA) (Genes & Nutrition, Jun 2024) (https://doi.org/10.1186/s12263-024-00747-4) (loukil2024geneticassociationbetween pages 23-23).
- Functional and cellular effects. An exploratory 2024 JLR study linked FADS1 rs174550 genotype to differences in mitochondrial function in human adipocytes and genotype‑diet interactions under ALA‑enriched diet, tying FADS variation to bioenergetics (https://doi.org/10.1016/j.jlr.2024.100638, Oct 2024) (sun2024leveraginggeneticdata pages 72-77). In a rat Western diet model, hepatocyte‑specific AAV8‑Fads1 overexpression improved glucose tolerance and insulin signaling (low‑fat/high‑fructose diet) and reduced plasma triglyceride (~50%) and hepatic cholesterol (~25%) under high‑fat/high‑fructose; AA/DGLA ratio was restored, nominating FADS1 as a diet‑dependent MASLD target (IJMS, Apr 2024) (https://doi.org/10.3390/ijms25094836) (sun2024leveraginggeneticdata pages 72-77).
- Evolution and population differences. A 2024 selection scan in Native Americans highlighted FADS2 rs174616 with gene–diet interactions altering lipid levels and desaturase activity, consistent with strong selection at the FADS locus and population‑specific nutrigenomic implications (Heliyon, Aug 2024) (https://doi.org/10.1016/j.heliyon.2024.e35477) (romerohidalgo2024selectionscanin pages 15-16).

3) Current applications and real‑world implementations
- Nutrigenomics/precision nutrition. Multiple recent human studies and reviews show FADS1 variants strongly influence PUFA status and modify responses to diet or supplementation, supporting genotype‑aware recommendations (e.g., UK Biobank GWIS: genotype‑dependent fish oil effects; rs174547/rs174550 associations with altered response to omega‑3 or linoleic/ALA‑rich diets) (https://doi.org/10.1101/2024.12.12.24318956; https://doi.org/10.3390/nu16203522; https://doi.org/10.3389/fnut.2024.1356986) (sun2024leveraginggeneticdata pages 72-77, reyesperez2024fads1geneticvariant pages 13-13, rabehl2024effectoffads1 pages 7-8). The 2024 scoping review synthesizes 40 studies linking FADS1/2 variants to circulating EPA/DHA, endorsing their use in stratified nutrition (https://doi.org/10.1186/s12263-024-00747-4) (loukil2024geneticassociationbetween pages 23-23). The broader expert review (Koletzko 2019) frames FADS genotype as a foundation for precision nutrition at individual/population scales (https://doi.org/10.1146/annurev-nutr-082018-124250) (koletzko2019fads1andfads2 pages 1-3).
- Oncology targeting. Preclinical CRC data implicate the FADS1–AA–PGE2 axis as druggable: genetic knockdown and a D5D inhibitor reduced growth in CRC models, suggesting FADS1 inhibition and AA–PGE2 pathway modulation as candidate strategies, potentially in combination with microbiome‑informed approaches (https://doi.org/10.1038/s41467-023-37590-x) (xu2023fads1arachidonicacidaxis pages 1-2, xu2023fads1arachidonicacidaxis pages 11-11).
- Liver–metabolic disease. Proof‑of‑concept gene therapy (AAV8‑Fads1) improved metabolic features and hepatic lipid composition in diet‑induced models, nominating FADS1 for MASLD‑oriented therapeutics (https://doi.org/10.3390/ijms25094836) (sun2024leveraginggeneticdata pages 72-77). Observational data link higher circulating PUFAs to substantially lower HCC incidence and CLD mortality, aligning with mechanisms governed by FADS1/2 (https://doi.org/10.1038/s41467-024-47960-8) (sun2024leveraginggeneticdata pages 72-77).

4) Expert opinions and analysis from authoritative sources
- Annual Review of Nutrition (2019): FADS variants are strong determinants of LC‑PUFA biosynthesis; genotype distribution differences reflect evolutionary adaptation and underpin robust gene–diet interactions; precision nutrition strategies should incorporate FADS genotypes (https://doi.org/10.1146/annurev-nutr-082018-124250) (koletzko2019fads1andfads2 pages 1-3, koletzko2019fads1andfads2 pages 3-4).
- 2024 scoping review (Genes & Nutrition): Across 40 studies, consistent associations for key FADS1 variants (rs174537, rs174547, rs174556, rs174561) with lower EPA/DHA in minor‑allele carriers; high LD across the locus complicates isolation of single causal variants, but translational relevance for genotype‑guided omega‑3 status is clear (https://doi.org/10.1186/s12263-024-00747-4) (loukil2024geneticassociationbetween pages 23-23).
- Population genetics (2024 Heliyon): Selection at the FADS locus and gene–diet interactions emphasize the necessity of ancestry‑sensitive dietary guidance and clinical trial interpretation (https://doi.org/10.1016/j.heliyon.2024.e35477) (romerohidalgo2024selectionscanin pages 15-16).

5) Relevant statistics and data from recent studies
- Cancer (CRC) mechanistic study (Xu 2023). AA increases from normal to adenoma to CRC; AA feeding accelerates tumorigenesis in AOM/DSS and Apc−/− models; D5D inhibitor reduced growth in CRC cells/organoids with P values ~0.003–0.008; FADS1 high expression associated with worse clinical features; shFADS1 lowered interstitial AA and blunted LPS‑induced PGE2 increase (https://doi.org/10.1038/s41467-023-37590-x, Apr 2023) (xu2023fads1arachidonicacidaxis pages 1-2, xu2023fads1arachidonicacidaxis pages 4-5, xu2023fads1arachidonicacidaxis pages 11-11, xu2023fads1arachidonicacidaxis pages 3-4).
- Human lipidomics/GWIS (UKB, 200,060 participants). FADS1/FADS2 fish‑oil interactions genome‑wide significant; for omega‑3% lead SNP rs35473591 had β 0.35 (supplement users) vs 0.42 (non‑users); fish‑oil effects varied by genotype (β 0.45/0.50/0.59) (medRxiv, Dec 2024) (https://doi.org/10.1101/2024.12.12.24318956) (sun2024leveraginggeneticdata pages 72-77).
- Prospective liver outcomes (UK Biobank; N=252,398). Highest quartile versus lowest for plasma n‑3 PUFA: HCC HR 0.48 (95% CI 0.33–0.69); CLD mortality HR 0.21 (0.13–0.33). For n‑6 PUFA: HCC HR 0.48 (0.28–0.81); CLD mortality HR 0.15 (0.08–0.30). Saturated fat showed increased risk (Nature Communications, May 2024) (https://doi.org/10.1038/s41467-024-47960-8) (sun2024leveraginggeneticdata pages 72-77).
- Human genotype–biomarker cohorts. Rabehl 2024: ancestral FADS1 genotype associated with lower blood AA; oxylipin trends lower; no significant genotype differences in liver fat (N=85) (https://doi.org/10.3389/fnut.2024.1356986) (rabehl2024effectoffads1 pages 7-8). Reyes‑Pérez 2024: N=76 obesity; 1.5 g/day omega‑3 for 4 months; all groups increased omega‑3 index, but rs174547 CC showed smaller EPA/DHA gains than TT (https://doi.org/10.3390/nu16203522) (reyesperez2024fads1geneticvariant pages 13-13).
- Evidence synthesis. Loukil 2024: 40 studies, 47 FADS SNPs; rs174537/rs174547/rs174556/rs174561 most studied; minor alleles associate with lower EPA/DHA; high LD noted (https://doi.org/10.1186/s12263-024-00747-4) (loukil2024geneticassociationbetween pages 23-23).

Biological pathways and cellular context
- Pathway placement. FADS1 performs the Δ5 desaturation in ER‑based LC‑PUFA biosynthesis, downstream of FADS2 (Δ6/Δ8) and ELOVL elongases, governing AA and EPA availability for oxylipin biosynthesis (e.g., prostaglandins, leukotrienes, specialized pro‑resolving mediators) (Koletzko 2019) (https://doi.org/10.1146/annurev-nutr-082018-124250) (koletzko2019fads1andfads2 pages 1-3, koletzko2019fads1andfads2 pages 3-4).
- Enzyme system. FADS1 requires the ER cytochrome b5 electron shuttle and NADH‑cytochrome b5 reductase; cytochrome b5 domain and His‑box motifs are characteristic of human FADS desaturases (Brenna 2010; Chen 2013) (https://doi.org/10.1016/j.plefa.2010.02.011; https://doi.org/10.1016/j.bbrc.2013.09.127) (majou2021synthesisofdha pages 10-10, park2018thebiochemistryand pages 13-14).

Conclusions and implications
- FADS1 is a validated human ER Δ5 desaturase controlling AA and EPA synthesis and thereby oxylipin signaling. Recent human lipidomics and GWIS strengthen evidence for genotype‑dependent dietary responses, supporting precision nutrition. Translational oncology (CRC) identifies a FADS1–AA–microbiome–PGE2 axis amenable to pharmacologic inhibition. Population genetics and cohort data emphasize ancestry‑specific allele frequencies and diet interactions, necessitating thoughtful trial design and dietary guidance. Together, mechanistic, genetic, and interventional lines of evidence integrate FADS1 into cardiometabolic, hepatic, and oncologic pathways in humans (xu2023fads1arachidonicacidaxis pages 1-2, sun2024leveraginggeneticdata pages 72-77, loukil2024geneticassociationbetween pages 23-23, koletzko2019fads1andfads2 pages 1-3).

Data availability and key URLs
- Koletzko et al., Annual Review of Nutrition 2019: https://doi.org/10.1146/annurev-nutr-082018-124250 (Aug 2019) (koletzko2019fads1andfads2 pages 3-4, koletzko2019fads1andfads2 pages 1-3)
- Brenna et al., Prostaglandins Leukot Essent Fatty Acids 2010: https://doi.org/10.1016/j.plefa.2010.02.011 (Apr 2010) (majou2021synthesisofdha pages 10-10)
- Chen et al., Biochem Biophys Res Commun 2013: https://doi.org/10.1016/j.bbrc.2013.09.127 (Nov 2013) (park2018thebiochemistryand pages 13-14)
- Park et al., J Lipid Res 2012: https://doi.org/10.1194/jlr.m025312 (Aug 2012) (park2018thebiochemistryand pages 13-14)
- Xu et al., Nature Communications 2023: https://doi.org/10.1038/s41467-023-37590-x (Apr 2023) (xu2023fads1arachidonicacidaxis pages 1-2, xu2023fads1arachidonicacidaxis pages 4-5, xu2023fads1arachidonicacidaxis pages 11-11, xu2023fads1arachidonicacidaxis pages 3-4)
- Ihejirika et al., medRxiv 2024: https://doi.org/10.1101/2024.12.12.24318956 (Dec 2024) (sun2024leveraginggeneticdata pages 72-77)
- Landstra et al., medRxiv 2024: https://doi.org/10.1101/2024.12.04.24318368 (Dec 2024) (sun2024leveraginggeneticdata pages 72-77)
- Liu et al., Nature Communications 2024: https://doi.org/10.1038/s41467-024-47960-8 (May 2024) (sun2024leveraginggeneticdata pages 72-77)
- Rabehl et al., Frontiers in Nutrition 2024: https://doi.org/10.3389/fnut.2024.1356986 (Jul 2024) (rabehl2024effectoffads1 pages 7-8)
- Reyes‑Pérez et al., Nutrients 2024: https://doi.org/10.3390/nu16203522 (Oct 2024) (reyesperez2024fads1geneticvariant pages 13-13)
- Loukil et al., Genes & Nutrition 2024: https://doi.org/10.1186/s12263-024-00747-4 (Jun 2024) (loukil2024geneticassociationbetween pages 23-23)
- Romero‑Hidalgo et al., Heliyon 2024: https://doi.org/10.1016/j.heliyon.2024.e35477 (Aug 2024) (romerohidalgo2024selectionscanin pages 15-16)
- Ghooray et al., IJMS 2024: https://doi.org/10.3390/ijms25094836 (Apr 2024) (sun2024leveraginggeneticdata pages 72-77)

References

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(romerohidalgo2024selectionscanin pages 15-16): Sandra Romero-Hidalgo, Janine Sagaceta-Mejía, Marisela Villalobos-Comparán, María Elizabeth Tejero, Mayra Domínguez-Pérez, Leonor Jacobo-Albavera, Rosalinda Posadas-Sánchez, Gilberto Vargas-Alarcón, Carlos Posadas-Romero, Luis Macías-Kauffer, Felipe Vadillo-Ortega, Miguel Angel Contreras-Sieck, Víctor Acuña-Alonzo, Rodrigo Barquera, Gastón Macín, Aristea Binia, Jose Guadalupe Guevara-Chávez, Leticia Sebastián-Medina, Martha Menjívar, Samuel Canizales-Quinteros, Alessandra Carnevale, and Teresa Villarreal-Molina. Selection scan in native americans of mexico identifies fads2 rs174616: evidence of gene-diet interactions affecting lipid levels and delta-6-desaturase activity. Heliyon, 10:e35477, Aug 2024. URL: https://doi.org/10.1016/j.heliyon.2024.e35477, doi:10.1016/j.heliyon.2024.e35477. This article has 4 citations and is from a peer-reviewed journal.
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(xu2023fads1arachidonicacidaxis pages 3-4): Chunjie Xu, Lei Gu, Lipeng Hu, Chun-hui Jiang, Qing Li, Long-ci Sun, Hong Zhou, Ye Liu, Hanbing Xue, Jun Li, Zhi-gang Zhang, Xueli Zhang, and Qing Xu. Fads1-arachidonic acid axis enhances arachidonic acid metabolism by altering intestinal microecology in colorectal cancer. Nature Communications, Apr 2023. URL: https://doi.org/10.1038/s41467-023-37590-x, doi:10.1038/s41467-023-37590-x. This article has 80 citations and is from a highest quality peer-reviewed journal.
(sun2024leveraginggeneticdata pages 72-77): Y Sun. Leveraging genetic data to unravel the health effects of polyunsaturated fatty acids. Unknown journal, 2024.
(rabehl2024effectoffads1 pages 7-8): Miriam Rabehl, Zeren Wei, Can G. Leineweber, Jörg Enssle, Michael Rothe, Adelheid Jung, Christoph Schmöcker, Ulf Elbelt, Karsten H. Weylandt, and Anne Pietzner. Effect of fads1 snps rs174546, rs174547 and rs174550 on blood fatty acid profiles and plasma free oxylipins. Frontiers in Nutrition, Jul 2024. URL: https://doi.org/10.3389/fnut.2024.1356986, doi:10.3389/fnut.2024.1356986. This article has 3 citations and is from a poor quality or predatory journal.
(reyesperez2024fads1geneticvariant pages 13-13): Samantha Desireé Reyes-Pérez, Karina González-Becerra, Elisa Barrón-Cabrera, José Francisco Muñoz-Valle, Juan Armendáriz-Borunda, and Erika Martínez-López. Fads1 genetic variant and omega-3 supplementation are associated with changes in fatty acid composition in red blood cells of subjects with obesity. Nutrients, 16:3522, Oct 2024. URL: https://doi.org/10.3390/nu16203522, doi:10.3390/nu16203522. This article has 13 citations and is from a poor quality or predatory journal.
(loukil2024geneticassociationbetween pages 23-23): Insaf Loukil, David M. Mutch, and Mélanie Plourde. Genetic association between fads and elovl polymorphisms and the circulating levels of epa/dha in humans: a scoping review. Genes & Nutrition, Jun 2024. URL: https://doi.org/10.1186/s12263-024-00747-4, doi:10.1186/s12263-024-00747-4. This article has 20 citations and is from a peer-reviewed journal.

Citations

park2018thebiochemistryand pages 13-14
sun2024leveraginggeneticdata pages 72-77
loukil2024geneticassociationbetween pages 23-23
romerohidalgo2024selectionscanin pages 15-16
majou2021synthesisofdha pages 10-10
https://doi.org/10.1146/annurev-nutr-082018-124250,
https://doi.org/10.1016/j.plefa.2010.02.011,
https://doi.org/10.1016/j.bbrc.2013.09.127,
https://doi.org/10.1146/annurev-nutr-082018-124250;
https://doi.org/10.1016/j.heliyon.2024.e35477
https://doi.org/10.1194/jlr.m025312,
https://doi.org/10.1038/s41467-023-37590-x,
https://doi.org/10.1101/2024.12.12.24318956
https://doi.org/10.1101/2024.12.04.24318368
https://doi.org/10.1038/s41467-024-47960-8
https://doi.org/10.3389/fnut.2024.1356986
https://doi.org/10.3390/nu16203522
https://doi.org/10.1186/s12263-024-00747-4
https://doi.org/10.1016/j.jlr.2024.100638,
https://doi.org/10.3390/ijms25094836
https://doi.org/10.1101/2024.12.12.24318956;
https://doi.org/10.3390/nu16203522;
https://doi.org/10.1146/annurev-nutr-082018-124250
https://doi.org/10.1038/s41467-023-37590-x
https://doi.org/10.1016/j.plefa.2010.02.011;
https://doi.org/10.1016/j.bbrc.2013.09.127
https://doi.org/10.1016/j.plefa.2010.02.011
https://doi.org/10.1194/jlr.m025312
https://doi.org/10.1051/ocl/2021030,
https://doi.org/10.1016/b978-0-12-811230-4.00005-3,
https://doi.org/10.1016/j.heliyon.2024.e35477,
https://doi.org/10.3389/fnut.2024.1356986,
https://doi.org/10.3390/nu16203522,
https://doi.org/10.1186/s12263-024-00747-4,

📄 View Raw YAML

id: O60427
gene_symbol: FADS1
aliases:
  - FADSD5
  - D5D
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 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.
existing_annotations:
  - term:
      id: GO:0006629
      label: lipid metabolic process
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      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.
      action: ACCEPT
      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).
      supported_by:
        - reference_id: PMID:10601301
          supporting_text: 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
        - reference_id: file:human/FADS1/FADS1-deep-research-falcon.md
          supporting_text: 'model: Edison Scientific Literature'
  - term:
      id: GO:0016020
      label: membrane
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      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.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:10601301
          supporting_text: 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.
  - term:
      id: GO:0016717
      label: 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
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      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.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:10769175
          supporting_text: The human Delta(5)-desaturase contained a predicted 
            N-terminal cytochrome b(5)-like domain, as well as three 
            histidine-rich domains.
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: Some evidence supports mitochondrial localization of FADS1, 
        particularly for the alternative isoform 2.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:22619218
          supporting_text: FADS1, but not FADS1AT1, localizes to endoplasmic 
            reticulum and mitochondria.
  - term:
      id: GO:0005789
      label: endoplasmic reticulum membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: FADS1 is a multi-pass transmembrane protein primarily localized 
        to the ER membrane where it performs fatty acid desaturation.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:10601301
          supporting_text: 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.
  - term:
      id: GO:0006629
      label: lipid metabolic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: Redundant with the IBA annotation for lipid metabolic process. 
        Both are correct annotations.
      action: ACCEPT
      reason: This IEA annotation from combined automated methods correctly 
        identifies FADS1's role in lipid metabolism. Duplicates with different 
        evidence codes are acceptable.
  - term:
      id: GO:0006631
      label: fatty acid metabolic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: FADS1 is specifically involved in fatty acid metabolism as a 
        fatty acid desaturase.
      action: ACCEPT
      reason: This is a core function of FADS1. The enzyme desaturates fatty 
        acyl-CoA substrates, making fatty acid metabolic process an accurate 
        annotation.
      supported_by:
        - reference_id: PMID:10601301
          supporting_text: 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).
  - term:
      id: GO:0006633
      label: fatty acid biosynthetic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: FADS1 participates in the biosynthesis of long-chain 
        polyunsaturated fatty acids by introducing double bonds into fatty acid 
        precursors.
      action: ACCEPT
      reason: FADS1 is directly involved in fatty acid biosynthesis - 
        specifically the biosynthesis of highly unsaturated fatty acids (HUFAs) 
        from dietary PUFA precursors.
      supported_by:
        - reference_id: PMID:10769175
          supporting_text: 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)).
  - term:
      id: GO:0016491
      label: oxidoreductase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: FADS1 is an oxidoreductase enzyme. This is a parent term of the 
        more specific desaturase activities.
      action: ACCEPT
      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.
  - term:
      id: GO:0062076
      label: acyl-CoA (8-3)-desaturase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: This is the specific molecular function term for FADS1's 
        enzymatic activity, describing the delta-5 desaturase reaction on 
        acyl-CoA substrates.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:10769175
          supporting_text: 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)).
  - term:
      id: GO:0036109
      label: alpha-linolenic acid metabolic process
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2046106
    review:
      summary: FADS1 participates in alpha-linolenic acid (ALA, 18:3n-3) 
        metabolism by performing the delta-5 desaturation step in the omega-3 
        pathway.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:10769175
          supporting_text: 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)).
  - term:
      id: GO:0043651
      label: linoleic acid metabolic process
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2046105
    review:
      summary: FADS1 participates in linoleic acid (LA, 18:2n-6) metabolism by 
        performing the delta-5 desaturation step in the omega-6 pathway.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:10601301
          supporting_text: 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).
  - term:
      id: GO:0006636
      label: unsaturated fatty acid biosynthetic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000041
    review:
      summary: FADS1 is directly involved in unsaturated fatty acid biosynthesis
        by introducing cis double bonds into fatty acid substrates.
      action: ACCEPT
      reason: This is a core function of FADS1. The enzyme specifically 
        introduces double bonds to create polyunsaturated fatty acids.
  - term:
      id: GO:0005789
      label: endoplasmic reticulum membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1989757
    review:
      summary: ER membrane localization for FADS1 expression and function.
      action: ACCEPT
      reason: Reactome pathway information correctly places FADS1 at the ER 
        membrane, consistent with its function as a microsomal desaturase.
  - term:
      id: GO:0005789
      label: endoplasmic reticulum membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2046089
    review:
      summary: ER membrane localization for the omega-3 desaturation reaction.
      action: ACCEPT
      reason: Duplicate ER membrane annotation from different Reactome reactions
        is acceptable as it provides pathway context.
  - term:
      id: GO:0005789
      label: endoplasmic reticulum membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2046092
    review:
      summary: ER membrane localization for the omega-6 desaturation reaction.
      action: ACCEPT
      reason: Duplicate ER membrane annotation from different Reactome reactions
        is acceptable as it provides pathway context.
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: Mitochondrial localization supported by sequence similarity to 
        characterized orthologs.
      action: ACCEPT
      reason: ISS annotation based on sequence similarity is consistent with 
        experimental evidence for mitochondrial localization (PMID:22619218). 
        Both ER and mitochondrial localizations are documented.
  - term:
      id: GO:0005789
      label: endoplasmic reticulum membrane
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: ER membrane localization supported by sequence similarity to 
        characterized orthologs.
      action: ACCEPT
      reason: ISS annotation correctly identifies primary localization of FADS1.
  - term:
      id: GO:0062076
      label: acyl-CoA (8-3)-desaturase activity
    evidence_type: IDA
    original_reference_id: PMID:10769175
    review:
      summary: Direct experimental demonstration of delta-5 desaturase activity 
        by expression in mammalian cells.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:10769175
          supporting_text: 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)).
  - term:
      id: GO:0045485
      label: omega-6 fatty acid desaturase activity
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2046089
    review:
      summary: FADS1 acts on omega-6 fatty acid substrates (DGLA) to produce 
        arachidonic acid.
      action: ACCEPT
      reason: FADS1 desaturates both omega-6 (DGLA to AA) and omega-3 (ETA to 
        EPA) substrates. The omega-6 desaturase activity is well documented.
      supported_by:
        - reference_id: PMID:10601301
          supporting_text: 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).
  - term:
      id: GO:0045485
      label: omega-6 fatty acid desaturase activity
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2046092
    review:
      summary: Duplicate annotation for omega-6 fatty acid desaturase activity 
        from different Reactome reaction.
      action: ACCEPT
      reason: Consistent with FADS1 function in omega-6 PUFA biosynthesis.
  - term:
      id: GO:0006636
      label: unsaturated fatty acid biosynthetic process
    evidence_type: IDA
    original_reference_id: PMID:10601301
    review:
      summary: Direct experimental evidence for involvement in unsaturated fatty
        acid biosynthesis from the original cloning paper.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:10601301
          supporting_text: 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).
  - term:
      id: GO:0016213
      label: acyl-CoA 6-desaturase activity
    evidence_type: IDA
    original_reference_id: PMID:10601301
    review:
      summary: This annotation appears to be an error. FADS1 has delta-5 
        desaturase activity, not delta-6. FADS2 has delta-6 desaturase activity.
      action: REMOVE
      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.
      supported_by:
        - reference_id: PMID:10601301
          supporting_text: 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.
  - term:
      id: GO:0042759
      label: long-chain fatty acid biosynthetic process
    evidence_type: IDA
    original_reference_id: PMID:10601301
    review:
      summary: FADS1 participates in long-chain fatty acid biosynthesis by 
        desaturating C20 fatty acid substrates.
      action: ACCEPT
      reason: The substrates and products of FADS1 (DGLA, AA, ETA, EPA) are all 
        long-chain fatty acids (C20), making this annotation accurate.
      supported_by:
        - reference_id: PMID:10601301
          supporting_text: 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).
  - term:
      id: GO:0016020
      label: membrane
    evidence_type: HDA
    original_reference_id: PMID:19946888
    review:
      summary: High-throughput data confirms membrane localization of FADS1 in 
        NK cells.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:19946888
          supporting_text: Defining the membrane proteome of NK cells.
  - term:
      id: GO:0000248
      label: C-5 sterol desaturase activity
    evidence_type: TAS
    original_reference_id: PMID:10601301
    review:
      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.
      action: REMOVE
      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.
      supported_by:
        - reference_id: PMID:10601301
          supporting_text: 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).
  - term:
      id: GO:0006355
      label: regulation of DNA-templated transcription
    evidence_type: NAS
    original_reference_id: PMID:10601301
    review:
      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.
      action: REMOVE
      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.
      supported_by:
        - reference_id: PMID:10601301
          supporting_text: 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.
  - term:
      id: GO:0006636
      label: unsaturated fatty acid biosynthetic process
    evidence_type: TAS
    original_reference_id: PMID:10601301
    review:
      summary: TAS annotation for unsaturated fatty acid biosynthesis from the 
        original characterization paper.
      action: ACCEPT
      reason: Accurate annotation based on the functional characterization of 
        FADS1.
      supported_by:
        - reference_id: PMID:10601301
          supporting_text: Cloning, expression, and fatty acid regulation of the
            human delta-5 desaturase.
  - term:
      id: GO:0007267
      label: cell-cell signaling
    evidence_type: NAS
    original_reference_id: PMID:10601301
    review:
      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.
      action: MARK_AS_OVER_ANNOTATED
      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.
      supported_by:
        - reference_id: PMID:10601301
          supporting_text: Cloning, expression, and fatty acid regulation of the
            human delta-5 desaturase.
  - term:
      id: GO:0008654
      label: phospholipid biosynthetic process
    evidence_type: TAS
    original_reference_id: PMID:10601301
    review:
      summary: FADS1 products (AA, EPA) are incorporated into membrane 
        phospholipids, but FADS1 itself does not directly synthesize 
        phospholipids.
      action: KEEP_AS_NON_CORE
      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.
      supported_by:
        - reference_id: PMID:10601301
          supporting_text: Cloning, expression, and fatty acid regulation of the
            human delta-5 desaturase.
  - term:
      id: GO:0009267
      label: cellular response to starvation
    evidence_type: IDA
    original_reference_id: PMID:10601301
    review:
      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.
      action: REMOVE
      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.
      supported_by:
        - reference_id: PMID:10601301
          supporting_text: 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
  - term:
      id: GO:0016020
      label: membrane
    evidence_type: NAS
    original_reference_id: PMID:10601301
    review:
      summary: General membrane localization from the original characterization.
      action: ACCEPT
      reason: Accurate annotation based on the structural characterization 
        showing membrane-spanning domains.
      supported_by:
        - reference_id: PMID:10601301
          supporting_text: 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.
  - term:
      id: GO:0016020
      label: membrane
    evidence_type: TAS
    original_reference_id: PMID:10601301
    review:
      summary: TAS annotation for membrane localization from the original paper.
      action: ACCEPT
      reason: Accurate annotation based on structural characterization.
      supported_by:
        - reference_id: PMID:10601301
          supporting_text: Cloning, expression, and fatty acid regulation of the
            human delta-5 desaturase.
  - term:
      id: GO:0016491
      label: oxidoreductase activity
    evidence_type: IDA
    original_reference_id: PMID:10601301
    review:
      summary: Direct experimental demonstration of oxidoreductase (desaturase) 
        activity.
      action: ACCEPT
      reason: The functional expression experiments demonstrated enzymatic 
        activity, confirming FADS1 as an oxidoreductase.
      supported_by:
        - reference_id: PMID:10601301
          supporting_text: Cloning, expression, and fatty acid regulation of the
            human delta-5 desaturase.
  - term:
      id: GO:0043231
      label: intracellular membrane-bounded organelle
    evidence_type: NAS
    original_reference_id: PMID:10601301
    review:
      summary: General term for localization to membrane-bounded organelles (ER,
        mitochondria).
      action: ACCEPT
      reason: This is a parent term of the more specific ER membrane annotation.
        Accurate but not highly informative.
      supported_by:
        - reference_id: PMID:10601301
          supporting_text: Cloning, expression, and fatty acid regulation of the
            human delta-5 desaturase.
  - term:
      id: GO:0045595
      label: regulation of cell differentiation
    evidence_type: NAS
    original_reference_id: PMID:10601301
    review:
      summary: This annotation suggests FADS1 regulates cell differentiation. 
        The cited paper does not provide evidence for this function.
      action: MARK_AS_OVER_ANNOTATED
      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.'
      supported_by:
        - reference_id: PMID:10601301
          supporting_text: Cloning, expression, and fatty acid regulation of the
            human delta-5 desaturase.
  - term:
      id: GO:0046456
      label: icosanoid biosynthetic process
    evidence_type: TAS
    original_reference_id: PMID:10601301
    review:
      summary: FADS1 synthesizes arachidonic acid and EPA, which are the 
        precursors for icosanoid (eicosanoid) biosynthesis.
      action: ACCEPT
      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."
      supported_by:
        - reference_id: PMID:10601301
          supporting_text: 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.
references:
  - id: GO_REF:0000024
    title: Manual transfer of experimentally-verified manual GO annotation data 
      to orthologs by curator judgment of sequence similarity
    findings: []
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings: []
  - id: GO_REF:0000041
    title: Gene Ontology annotation based on UniPathway vocabulary mapping
    findings: []
  - id: GO_REF:0000043
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword 
      mapping
    findings: []
  - id: GO_REF:0000044
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular 
      Location vocabulary mapping
    findings: []
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods
    findings: []
  - id: PMID:10601301
    title: Cloning, expression, and fatty acid regulation of the human delta-5 
      desaturase.
    findings:
      - statement: FADS1 encodes the delta-5 desaturase, one of two 
          rate-limiting enzymes in PUFA biosynthesis. Expression in CHO cells 
          demonstrated conversion of 20:3(n-6) to 20:4(n-6).
        supporting_text: 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
      - statement: FADS1 contains two membrane-spanning domains, three 
          histidine-rich regions, and a cytochrome b5 domain.
        supporting_text: 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.
      - statement: Delta-5 and Delta-6 desaturase genes reside head-to-head on 
          chromosome 11 separated by less than 11,000 base pairs.
        supporting_text: the Delta-5 and Delta-6 desaturase genes reside in 
          reverse orientation on chromosome 11 and that they are separated by 
          <11,000 base pairs.
      - statement: Expression is highest in liver, brain, and heart, and is 
          nutritionally regulated (suppressed by dietary PUFA).
        supporting_text: 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
  - id: PMID:10769175
    title: cDNA cloning and characterization of human Delta5-desaturase involved
      in the biosynthesis of arachidonic acid.
    findings:
      - statement: Expression of FADS1 ORF in mouse fibroblast cells 
          demonstrated delta-5 desaturase activity by conversion of DGLA 
          (20:3n-6) to AA (20:4n-6).
        supporting_text: 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)).
      - statement: FADS1 contains an N-terminal cytochrome b5-like domain and 
          three histidine-rich domains.
        supporting_text: The human Delta(5)-desaturase contained a predicted 
          N-terminal cytochrome b(5)-like domain, as well as three 
          histidine-rich domains.
      - statement: Highly expressed in fetal liver, fetal brain, adult brain, 
          and adrenal gland.
        supporting_text: A tissue expression profile revealed that this gene is 
          highly expressed in fetal liver, fetal brain, adult brain and adrenal 
          gland.
  - id: PMID:19946888
    title: Defining the membrane proteome of NK cells.
    findings: []
  - id: PMID:22619218
    title: A novel FADS1 isoform potentiates FADS2-mediated production of 
      eicosanoid precursor fatty acids.
    findings:
      - statement: Identified alternative FADS1 isoform (FADS1AT1) that lacks 
          catalytic activity but may enhance FADS2 function.
        supporting_text: FADS1 alternative transcript 1 (FADS1AT1) enhances 
          desaturation of FADS2, leading to increased production of eicosanoid 
          precursors, the first case of an isoform modulating the enzymatic 
          activity encoded by another gene.
      - statement: FADS1 isoform 1 localizes to both ER and mitochondria.
        supporting_text: FADS1, but not FADS1AT1, localizes to endoplasmic 
          reticulum and mitochondria.
  - id: Reactome:R-HSA-1989757
    title: Expression of FADS1
    findings: []
  - id: Reactome:R-HSA-2046089
    title: Desaturation of eicosatetraenoyl-CoA to eicosapentaenoyl-CoA
    findings: []
  - id: Reactome:R-HSA-2046092
    title: Desaturation of dihomo-gamma-lenolenoyl-CoA to arachidonoyl-CoA
    findings: []
  - id: Reactome:R-HSA-2046105
    title: Linoleic acid (LA) metabolism
    findings: []
  - id: Reactome:R-HSA-2046106
    title: alpha-linolenic acid (ALA) metabolism
    findings: []
  - id: file:human/FADS1/FADS1-deep-research-falcon.md
    title: Deep research summary for FADS1
    findings:
      - statement: FADS1 performs the delta-5 desaturation step in LC-PUFA 
          biosynthesis, converting DGLA to AA and ETA to EPA.
        supporting_text: FADS1 encodes the microsomal delta-5 desaturase that 
          introduces a double bond at the delta-5 position of C20 
          polyunsaturated acyl-CoAs. Canonical reactions in humans include 
          dihomo-gamma-linolenic acid (DGLA; 20:3n-6) to arachidonic acid (AA; 
          20:4n-6) and eicosatetraenoic acid (ETA; 20:4n-3) to eicosapentaenoic 
          acid (EPA; 20:5n-3).
      - statement: FADS variants are strong determinants of LC-PUFA biosynthesis
          with marked frequency differences across ancestries.
        supporting_text: FADS1/FADS2 genotypes show marked frequency differences
          across ancestries and contribute to gene-diet interactions and 
          evolutionary signatures.
      - statement: FADS1 upregulation in colorectal cancer increases AA in tumor
          interstitium and elevates PGE2.
        supporting_text: Xu et al. 2023 demonstrated that FADS1 upregulation is 
          an early event in CRC, increases AA in the tumor interstitium, 
          enriches gram-negative microbes, activates TLR4/MYD88 signaling, and 
          elevates PGE2.
      - statement: D5D inhibitor (D5D-IN-326) reduced CRC cell/organoid growth, 
          suggesting therapeutic potential of targeting FADS1.
        supporting_text: A D5D inhibitor (D5D-IN-326) reduced CRC cell/organoid 
          growth (e.g., P=0.003 in SW480; 0.008 HCT-116; 0.006 organoid).
core_functions:
  - molecular_function:
      id: GO:0062076
      label: acyl-CoA (8-3)-desaturase activity
    description: FADS1 is the delta-5 fatty acid desaturase that catalyzes the 
      rate-limiting step in PUFA biosynthesis. It introduces a cis double bond 
      at the delta-5 position (8 carbons from an existing double bond, hence 
      "8-3") of C20 polyunsaturated acyl-CoA substrates. Direct enzymatic 
      activity demonstrated by expression in mammalian cells (PMID:10601301, 
      PMID:10769175). By producing arachidonic acid and EPA, FADS1 provides the 
      substrates for all eicosanoid biosynthesis including prostaglandins, 
      leukotrienes, thromboxanes, and specialized pro-resolving mediators. The 
      PUFAs produced are also incorporated into membrane phospholipids and serve
      as substrates for lipid peroxidation, connecting FADS1 activity to 
      ferroptosis susceptibility.
proposed_new_terms: []
suggested_questions:
  - question: What is the relative contribution of FADS1 vs FADS2 to membrane 
      PUFA composition and ferroptosis sensitivity?
  - question: Is FADS1 activity or expression altered in ferroptosis-resistant 
      cancer cells?
  - question: What is the functional significance of FADS1 mitochondrial 
      localization?
suggested_experiments:
  - description: 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.
  - description: 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.
tags:
  - ferroptosis

FADS1

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Gene Research for Functional Annotation

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