Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005789 endoplasmic reticulum membrane	IBA GO_REF:0000033	ACCEPT	Summary: ELOVL5 is an integral membrane protein of the endoplasmic reticulum. Multiple studies confirm ER localization including PMID:20937905 showing ER localization in mammalian cells and PMID:25065913 showing wild-type ELOVL5 localizes to the ER in transfection experiments. UniProt describes it as a multi-pass ER membrane protein with seven transmembrane helices. Reason: Well-supported by phylogenetic inference (IBA), consistent with direct experimental evidence from multiple publications and the known biology of the ELOVL enzyme family which functions exclusively in the ER elongation cycle. Supporting Evidence: PMID:20937905 ELOVL1 production of C24 acyl-CoAs is linked to C24 sphingolipid synthesis. PMID:25065913 2014 Jul 24. ELOVL5 mutations cause spinocerebellar ataxia 38. file:human/ELOVL5/ELOVL5-deep-research-falcon.md model: Edison Scientific Literature
GO:0009922 fatty acid elongase activity	IBA GO_REF:0000033	ACCEPT	Summary: ELOVL5 is a bona fide fatty acid elongase that catalyzes the condensation of acyl-CoA with malonyl-CoA (EC 2.3.1.199). This is the first and rate-limiting step of the four-reaction VLCFA elongation cycle. PMID:10970790 originally cloned and characterized this activity; PMID:20937905 performed systematic in vitro substrate specificity analysis. Reason: Core enzymatic function of ELOVL5 supported by extensive experimental evidence and phylogenetic conservation across the ELOVL family. Supporting Evidence: PMID:10970790 Cloning of a human cDNA encoding a novel enzyme involved in the elongation of long-chain polyunsaturated fatty acids. PMID:20937905 ELOVL1 production of C24 acyl-CoAs is linked to C24 sphingolipid synthesis.
GO:0030148 sphingolipid biosynthetic process	IBA GO_REF:0000033	MARK AS OVER ANNOTATED	Summary: While ELOVL1 is specifically linked to C24 sphingolipid synthesis (PMID:20937905), ELOVL5 preferentially elongates PUFAs rather than the saturated/monounsaturated fatty acids that are primary sphingolipid precursors. The IBA annotation may reflect broader family-level inference from yeast ELO genes. ELOVL5 contribution to sphingolipid metabolism is indirect at best. Reason: ELOVL5 substrate specificity is primarily toward PUFAs (C18-C20 polyunsaturated), not the saturated/monounsaturated VLCFAs that are incorporated into sphingolipids. PMID:20937905 specifically attributes C24 sphingolipid synthesis to ELOVL1, not ELOVL5. While phylogenetically related, functional differentiation of ELOVL family members means this annotation overstates ELOVL5's role. Supporting Evidence: PMID:20937905 ELOVL1 production of C24 acyl-CoAs is linked to C24 sphingolipid synthesis.
GO:0034626 fatty acid elongation, polyunsaturated fatty acid	IBA GO_REF:0000033	ACCEPT	Summary: PUFA elongation is the primary function of ELOVL5. The enzyme preferentially elongates C18-C20 PUFAs of both n-3 and n-6 series. PMID:10970790 demonstrated elongation of gamma-linolenic acid, alpha-linolenic acid, stearidonic acid, arachidonic acid, and eicosapentaenoic acid. Reason: Core function strongly supported by original cloning paper and subsequent biochemical studies. ELOVL5 is specifically adapted for PUFA substrates. Supporting Evidence: PMID:10970790 Cloning of a human cDNA encoding a novel enzyme involved in the elongation of long-chain polyunsaturated fatty acids.
GO:0042761 very long-chain fatty acid biosynthetic process	IBA GO_REF:0000033	ACCEPT	Summary: ELOVL5 catalyzes elongation to produce VLCFAs (>20 carbons). Products include dihomo-gamma-linolenic acid (20:3n-6), adrenic acid (22:4n-6), and docosapentaenoic acid (22:5n-3). Reason: Appropriately captures the biosynthetic outcome of ELOVL5 activity, producing VLCFAs from long-chain PUFA substrates. Supporting Evidence: PMID:10970790 Cloning of a human cDNA encoding a novel enzyme involved in the elongation of long-chain polyunsaturated fatty acids.
GO:0019367 fatty acid elongation, saturated fatty acid	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: While ELOVL5 can elongate some saturated fatty acids, its substrate preference is strongly toward PUFAs. The deep research and UniProt both emphasize PUFA specificity. Saturated FA elongation is primarily performed by ELOVL1, ELOVL3, and ELOVL6. Reason: ELOVL5 has detectable activity toward some saturated substrates, so the annotation is not incorrect, but this is not the primary function. The IBA inference from family members is technically valid but oversimplifies isoform-specific substrate preferences. Supporting Evidence: PMID:20937905 ELOVL1 production of C24 acyl-CoAs is linked to C24 sphingolipid synthesis.
GO:0034625 fatty acid elongation, monounsaturated fatty acid	IBA GO_REF:0000033	ACCEPT	Summary: ELOVL5 can elongate monounsaturated fatty acids including palmitoleic acid (16:1n-7) and oleic acid (18:1n-9). UniProt catalytic activity entries include reactions for (9Z)-hexadecenoyl-CoA and (9Z)-octadecenoyl-CoA. This is a secondary activity. Reason: Supported by experimental evidence in UniProt showing ELOVL5 can elongate monounsaturated substrates. While PUFA elongation is the primary activity, MUFA elongation is also a verified function. Supporting Evidence: PMID:10970790 Cloning of a human cDNA encoding a novel enzyme involved in the elongation of long-chain polyunsaturated fatty acids.
GO:0005783 endoplasmic reticulum	IEA GO_REF:0000002	ACCEPT	Summary: InterPro-based inference of ER localization based on the ELOVL5 subfamily signature (IPR033677). Consistent with experimental data. Reason: The broader ER term is acceptable as redundant with the more specific ER membrane annotation. Both are well-supported.
GO:0005789 endoplasmic reticulum membrane	IEA GO_REF:0000120	ACCEPT	Summary: Combined automated annotation for ER membrane localization. Redundant with IBA annotation but independently supported. Reason: Consistent with experimental evidence and IBA annotation. ER membrane is the correct subcellular location.
GO:0006629 lipid metabolic process	IEA GO_REF:0000043	ACCEPT	Summary: Broad term inferred from UniProt keyword mapping. ELOVL5 is clearly involved in lipid metabolism as a fatty acid elongase. Reason: Correct but very general. The more specific fatty acid elongation terms are more informative but this parental term is not incorrect.
GO:0006631 fatty acid metabolic process	IEA GO_REF:0000043	ACCEPT	Summary: Keyword-based inference of fatty acid metabolism involvement. Correct and appropriate. Reason: ELOVL5 is a fatty acid elongase, so involvement in fatty acid metabolic process is accurate.
GO:0006633 fatty acid biosynthetic process	IEA GO_REF:0000120	ACCEPT	Summary: Combined automated annotation. ELOVL5 elongates fatty acids, contributing to biosynthesis of longer-chain products. Reason: Elongation is part of fatty acid biosynthesis; this is accurate.
GO:0006636 unsaturated fatty acid biosynthetic process	IEA GO_REF:0000120	ACCEPT	Summary: ELOVL5 produces unsaturated fatty acid products (PUFAs) from unsaturated precursors. Reason: The enzyme primarily acts on unsaturated (PUFA) substrates to produce unsaturated products. This is accurate.
GO:0009922 fatty acid elongase activity	IEA GO_REF:0000120	ACCEPT	Summary: Combined automated annotation of core enzymatic function. Redundant with IBA and experimental annotations. Reason: Core molecular function, redundant but correct.
GO:0016020 membrane	IEA GO_REF:0000120	ACCEPT	Summary: ELOVL5 is a multi-pass transmembrane protein. This very general term is correct but uninformative compared to the specific ER membrane annotation. Reason: Correct but very general. More specific terms (ER membrane) are preferred but this is not incorrect.
GO:0016740 transferase activity	IEA GO_REF:0000043	ACCEPT	Summary: ELOVL5 catalyzes transfer of the acyl group; EC 2.3.1.199 is a transferase. Reason: Correct parental term for the enzymatic activity, though the more specific fatty acid elongase activity term is preferred.
GO:0019367 fatty acid elongation, saturated fatty acid	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: InterPro-based inference. Redundant with IBA annotation for same term. Reason: As noted above, ELOVL5 can act on saturated substrates but this is not its primary function. Same assessment as IBA annotation.
GO:0030425 dendrite	IEA GO_REF:0000044	ACCEPT	Summary: UniProt subcellular location mapping. PMID:25065913 shows ELOVL5 localizes to dendrites in Purkinje cells, validated by immunohistochemistry. Reason: Supported by direct experimental evidence in PMID:25065913 showing dendritic localization in cerebellar Purkinje cells. Relevant to SCA38 pathophysiology. Supporting Evidence: PMID:25065913 2014 Jul 24. ELOVL5 mutations cause spinocerebellar ataxia 38.
GO:0030497 fatty acid elongation	IEA GO_REF:0000117	ACCEPT	Summary: ARBA machine learning inference of fatty acid elongation involvement. Reason: Correct parental term for the more specific elongation processes.
GO:0034625 fatty acid elongation, monounsaturated fatty acid	IEA GO_REF:0000104	ACCEPT	Summary: UniRule-based inference. Redundant with IBA annotation. Reason: Consistent with IBA annotation; MUFA elongation is a verified secondary activity.
GO:0034626 fatty acid elongation, polyunsaturated fatty acid	IEA GO_REF:0000120	ACCEPT	Summary: Combined automated annotation. Redundant with IBA annotation for core function. Reason: Core function, redundant with IBA but correct.
GO:0035338 long-chain fatty-acyl-CoA biosynthetic process	IEA GO_REF:0000104	ACCEPT	Summary: UniRule inference. ELOVL5 produces fatty-acyl-CoA products as part of elongation. Reason: The product of ELOVL5 catalysis (via subsequent steps of the elongation cycle) is elongated acyl-CoA, so this is accurate.
GO:0042761 very long-chain fatty acid biosynthetic process	IEA GO_REF:0000120	ACCEPT	Summary: Combined automated annotation. Redundant with IBA for same term. Reason: Core function of producing VLCFAs.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: High-throughput binary protein interactome study identified multiple interaction partners for ELOVL5. While technically valid IPI evidence, protein binding is uninformative for annotation purposes. Reason: Per curation guidelines, protein binding is too vague to be informative. The interactions detected in high-throughput screens may not reflect physiologically relevant function. More specific interaction terms should be used if the binding has known functional significance. Supporting Evidence: PMID:32296183 Apr 8. A reference map of the human binary protein interactome.
GO:0005783 endoplasmic reticulum	IDA GO_REF:0000052	ACCEPT	Summary: HPA immunofluorescence-based localization to ER. Reason: Direct experimental evidence for ER localization consistent with known biology.
GO:0035338 long-chain fatty-acyl-CoA biosynthetic process	TAS Reactome:R-HSA-75876	ACCEPT	Summary: Reactome pathway annotation for VLCFA-CoA synthesis. ELOVL5 is annotated to the "Synthesis of very long-chain fatty acyl-CoAs" pathway. Reason: Appropriate pathway annotation. Reactome correctly places ELOVL5 in the VLCFA synthesis pathway. Supporting Evidence: Reactome:R-HSA-75876
GO:0036109 alpha-linolenic acid metabolic process	TAS Reactome:R-HSA-2046106	ACCEPT	Summary: Reactome pathway for ALA (18:3n-3) metabolism. ELOVL5 elongates ALA-derived intermediates in the n-3 PUFA synthesis pathway. Reason: PMID:10970790 demonstrated ELOVL5 converts alpha-linolenic acid to omega3- eicosatrienoic acid. This pathway annotation is correct. Supporting Evidence: PMID:10970790 Cloning of a human cDNA encoding a novel enzyme involved in the elongation of long-chain polyunsaturated fatty acids.
GO:0043651 linoleic acid metabolic process	TAS Reactome:R-HSA-2046105	ACCEPT	Summary: Reactome pathway for LA (18:2n-6) metabolism. ELOVL5 elongates LA-derived intermediates including GLA to DGLA in the n-6 PUFA synthesis pathway. Reason: ELOVL5 is part of the linoleic acid metabolic pathway, elongating intermediates derived from LA via delta-6 desaturase. Demonstrated by PMID:10970790. Supporting Evidence: PMID:10970790 Cloning of a human cDNA encoding a novel enzyme involved in the elongation of long-chain polyunsaturated fatty acids. Reactome:R-HSA-2046105
GO:0009922 fatty acid elongase activity	EXP PMID:10970790 Cloning of a human cDNA encoding a novel enzyme involved in ...	ACCEPT	Summary: Original cloning paper that demonstrated ELOVL5 (then called HELO1) fatty acid elongase activity by expression in S. cerevisiae and measurement of PUFA elongation. Reason: Primary experimental characterization of enzymatic activity. Strong EXP evidence. Supporting Evidence: PMID:10970790 Cloning of a human cDNA encoding a novel enzyme involved in the elongation of long-chain polyunsaturated fatty acids.
GO:0009922 fatty acid elongase activity	TAS Reactome:R-HSA-2046083	ACCEPT	Summary: Reactome reaction annotation for elongation of arachidonyl-CoA to docosatetraenoyl-CoA. Reason: Specific reaction annotation supported by biochemical evidence.
GO:0009922 fatty acid elongase activity	TAS Reactome:R-HSA-2046100	ACCEPT	Summary: Reactome reaction annotation for elongation of eicosapentaenoyl-CoA to docosapentaenoyl-CoA. Reason: Specific reaction annotation supported by biochemical evidence.
GO:0005515 protein binding	IPI PMID:38422897 The 3-hydroxyacyl-CoA dehydratase 1/2 form complex with tran...	KEEP AS NON CORE	Summary: Study showed ELOVL5 interacts with TECR (trans-2-enoyl-CoA reductase) as part of the fatty acid elongation complex. This interaction is functionally relevant for substrate channeling in the elongation cycle. Reason: Unlike generic protein binding from high-throughput screens, this interaction with TECR has clear functional relevance - both enzymes function in the same elongation cycle. However, a more specific interaction term would be preferable if available. Supporting Evidence: PMID:38422897 The 3-hydroxyacyl-CoA dehydratase 1/2 form complex with trans-2-enoyl-CoA reductase involved in substrates transfer in very long chain fatty acid elongation.
GO:0045723 positive regulation of fatty acid biosynthetic process	IMP PMID:23749231 MicroRNA-30c reduces hyperlipidemia and atherosclerosis in m...	ACCEPT	Summary: This paper studied miR-30c effects on lipid metabolism. siRNA knockdown of ELOVL5 reduced de novo lipogenesis. The IMP annotation suggests ELOVL5 positively regulates fatty acid biosynthesis based on mutant phenotype. Reason: The study shows siELOVL5 reduces lipogenesis (Fig 4g), supporting a positive role in fatty acid biosynthesis. This is consistent with its enzymatic function. Supporting Evidence: PMID:23749231 MicroRNA-30c reduces hyperlipidemia and atherosclerosis in mice by decreasing lipid synthesis and lipoprotein secretion.
GO:0043025 neuronal cell body	IDA PMID:25065913 ELOVL5 mutations cause spinocerebellar ataxia 38.	ACCEPT	Summary: Immunohistochemistry on human and mouse brain showed ELOVL5 localization in Purkinje cell soma. Relevant to SCA38 pathophysiology. Reason: Direct experimental evidence showing neuronal cell body localization in cerebellar Purkinje cells, providing context for the SCA38 disease mechanism. Supporting Evidence: PMID:25065913 2014 Jul 24. ELOVL5 mutations cause spinocerebellar ataxia 38.
GO:0097447 dendritic tree	IDA PMID:25065913 ELOVL5 mutations cause spinocerebellar ataxia 38.	ACCEPT	Summary: Immunohistochemistry showed ELOVL5 in the proximal dendritic tree of Purkinje cells. Reason: Direct experimental evidence from the SCA38 paper. This neuronal localization is consistent with the cerebellar ataxia phenotype of ELOVL5 mutations. Supporting Evidence: PMID:25065913 2014 Jul 24. ELOVL5 mutations cause spinocerebellar ataxia 38.
GO:0016020 membrane	HDA PMID:19946888 Defining the membrane proteome of NK cells.	ACCEPT	Summary: Proteomics study of NK cell membrane proteins detected ELOVL5. Reason: High-throughput experimental data consistent with known membrane localization. Supporting Evidence: PMID:19946888 Defining the membrane proteome of NK cells.
GO:0005789 endoplasmic reticulum membrane	TAS Reactome:R-HSA-2046083	ACCEPT	Summary: Reactome reaction annotation specifying ER membrane as reaction location. Reason: Consistent with known localization.
GO:0005789 endoplasmic reticulum membrane	TAS Reactome:R-HSA-2046088	ACCEPT	Summary: Reactome reaction annotation for stearidonoyl-CoA elongation. Reason: Consistent with known localization.
GO:0005789 endoplasmic reticulum membrane	TAS Reactome:R-HSA-2046094	ACCEPT	Summary: Reactome reaction annotation for gamma-linolenoyl-CoA elongation. Reason: Consistent with known localization.
GO:0005789 endoplasmic reticulum membrane	TAS Reactome:R-HSA-2046100	ACCEPT	Summary: Reactome reaction annotation for eicosapentaenoyl-CoA elongation. Reason: Consistent with known localization.
GO:0005789 endoplasmic reticulum membrane	TAS Reactome:R-HSA-548800	ACCEPT	Summary: Reactome reaction annotation for arachidonate elongation. Reason: Consistent with known localization.
GO:0034626 fatty acid elongation, polyunsaturated fatty acid	IDA PMID:20937905 ELOVL1 production of C24 acyl-CoAs is linked to C24 sphingol...	ACCEPT	Summary: Ohno et al. systematically characterized ELOVL substrate specificities in vitro, demonstrating ELOVL5 activity toward PUFAs. Reason: Strong experimental evidence from systematic biochemical characterization. Supporting Evidence: PMID:20937905 ELOVL1 production of C24 acyl-CoAs is linked to C24 sphingolipid synthesis.
GO:0042761 very long-chain fatty acid biosynthetic process	IDA PMID:20937905 ELOVL1 production of C24 acyl-CoAs is linked to C24 sphingol...	ACCEPT	Summary: Same study demonstrating ELOVL5 produces VLCFAs from C18-C20 substrates. Reason: Direct experimental characterization of VLCFA production. Supporting Evidence: PMID:20937905 ELOVL1 production of C24 acyl-CoAs is linked to C24 sphingolipid synthesis.
GO:0009922 fatty acid elongase activity	IDA PMID:20427700 Validation of the health ABC heart failure model for inciden...	UNDECIDED	Summary: Note that PMID:20427700 title in the reference list appears to be incorrect (it shows a cardiovascular study title). This may be a database error. The annotation claims IDA evidence for fatty acid elongase activity. Reason: Cannot verify - the PMID appears misattributed in the reference list (title is about heart failure, not fatty acid elongation). Requires verification that this PMID actually contains evidence for ELOVL5 elongase activity. Supporting Evidence: PMID:20427700 Validation of the health ABC heart failure model for incident heart failure risk prediction: the Cardiovascular Health Study.
GO:0034625 fatty acid elongation, monounsaturated fatty acid	IDA PMID:20427700 Validation of the health ABC heart failure model for inciden...	UNDECIDED	Summary: Same PMID attribution issue as above. Reason: Cannot verify due to apparent PMID misattribution. Supporting Evidence: PMID:20427700 Validation of the health ABC heart failure model for incident heart failure risk prediction: the Cardiovascular Health Study.
GO:0034626 fatty acid elongation, polyunsaturated fatty acid	IDA PMID:20427700 Validation of the health ABC heart failure model for inciden...	UNDECIDED	Summary: Same PMID attribution issue as above. Reason: Cannot verify due to apparent PMID misattribution. Supporting Evidence: PMID:20427700 Validation of the health ABC heart failure model for incident heart failure risk prediction: the Cardiovascular Health Study.
GO:0042761 very long-chain fatty acid biosynthetic process	IDA PMID:20427700 Validation of the health ABC heart failure model for inciden...	UNDECIDED	Summary: Same PMID attribution issue as above. Reason: Cannot verify due to apparent PMID misattribution. Supporting Evidence: PMID:20427700 Validation of the health ABC heart failure model for incident heart failure risk prediction: the Cardiovascular Health Study.
GO:0005515 protein binding	IPI PMID:20937905 ELOVL1 production of C24 acyl-CoAs is linked to C24 sphingol...	REMOVE	Summary: Interaction with unspecified partner detected in the context of the systematic ELOVL characterization study. Reason: Per guidelines, generic protein binding annotations are uninformative. The main contribution of this paper is the enzymatic characterization, not protein interactions. Supporting Evidence: PMID:20937905 ELOVL1 production of C24 acyl-CoAs is linked to C24 sphingolipid synthesis.
GO:0005783 endoplasmic reticulum	IDA PMID:20937905 ELOVL1 production of C24 acyl-CoAs is linked to C24 sphingol...	ACCEPT	Summary: ER localization demonstrated in the systematic ELOVL characterization study. Reason: Direct experimental evidence consistent with known biology. Supporting Evidence: PMID:20937905 ELOVL1 production of C24 acyl-CoAs is linked to C24 sphingolipid synthesis.

Core Functions

ELOVL5 catalyzes the rate-limiting condensation step of the VLCFA elongation cycle, condensing acyl-CoA substrates with malonyl-CoA to produce 3-ketoacyl-CoA intermediates (EC 2.3.1.199). This is the first of four enzymatic steps in the ER-localized elongation cycle that adds two carbons per cycle.

Molecular Function:

fatty acid elongase activity

ELOVL5 preferentially elongates C18-C20 polyunsaturated fatty acids of both n-3 and n-6 series. Key substrates include gamma-linolenic acid (18:3n-6), alpha-linolenic acid (18:3n-3), stearidonic acid (18:4n-3), arachidonic acid (20:4n-6), and EPA (20:5n-3). This activity is essential for endogenous synthesis of longer-chain PUFAs that serve as membrane lipid components and eicosanoid/docosanoid precursors.

Molecular Function:

fatty acid elongase activity

Directly Involved In:

fatty acid elongation, polyunsaturated fatty acid very long-chain fatty acid biosynthetic process

Cellular Locations:

endoplasmic reticulum membrane

ELOVL5 elongates intermediates in n-3 and n-6 PUFA biosynthesis pathways. It converts alpha-linolenic acid-derived intermediates toward EPA and DHA synthesis, and gamma-linolenic acid to DGLA in the n-6 pathway. Loss-of-function mutations reduce serum AA and DHA levels, confirming the essential role in these pathways.

Molecular Function:

fatty acid elongase activity

Directly Involved In:

alpha-linolenic acid metabolic process linoleic acid metabolic process

Cellular Locations:

endoplasmic reticulum membrane

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000033

Annotation inferences using phylogenetic trees

Phylogenetic inference of ELOVL family functions including fatty acid elongase activity, ER membrane localization, and involvement in fatty acid elongation processes.

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:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000104

Electronic Gene Ontology annotations created by transferring manual GO annotations between related proteins based on shared sequence features

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:10970790

Cloning of a human cDNA encoding a novel enzyme involved in the elongation of long-chain polyunsaturated fatty acids.

Original cloning and characterization of ELOVL5 (then called HELO1)
Demonstrated elongation of gamma-linolenic acid, alpha-linolenic acid, stearidonic acid, arachidonic acid, and EPA
Showed highest expression in adrenal gland and testis
Localized gene to chromosome 6

PMID:19946888

Defining the membrane proteome of NK cells.

Proteomics identification of ELOVL5 as membrane protein

PMID:20427700

Validation of the health ABC heart failure model for incident heart failure risk prediction - The Cardiovascular Health Study.

PMID:20937905

ELOVL1 production of C24 acyl-CoAs is linked to C24 sphingolipid synthesis.

Systematic in vitro characterization of all ELOVL substrate specificities
Demonstrated ELOVL5 preference for PUFA substrates
Showed ELOVL1 (not ELOVL5) is responsible for C24 sphingolipid synthesis
Confirmed ER membrane localization

PMID:23749231

MicroRNA-30c reduces hyperlipidemia and atherosclerosis in mice by decreasing lipid synthesis and lipoprotein secretion.

siELOVL5 knockdown reduced de novo lipogenesis
ELOVL5 is a target of miR-30c regulation
Demonstrated role in hepatic lipid synthesis

PMID:25065913

ELOVL5 mutations cause spinocerebellar ataxia 38.

Identified ELOVL5 mutations as cause of SCA38
Showed reduced arachidonic acid and DHA in patient serum
Demonstrated high expression in Purkinje cells (soma and dendrites)
Wild-type localizes to ER; mutants show abnormal Golgi accumulation

PMID:32296183

A reference map of the human binary protein interactome.

High-throughput identification of ELOVL5 protein interactions

PMID:38422897

The 3-hydroxyacyl-CoA dehydratase 1/2 form complex with trans-2-enoyl-CoA reductase involved in substrates transfer in very long chain fatty acid elongation.

Demonstrated ELOVL5 interaction with TECR
Supports model of coordinated elongation cycle enzyme complex

Reactome:R-HSA-2046083

Elongation of arachidonyl-CoA to docosatetraenoyl-CoA

ELOVL5 catalyzes this specific elongation reaction

Reactome:R-HSA-2046088

Elongation of stearidonoyl-CoA to eicosatetraenoyl-CoA

ELOVL5 involved in n-3 PUFA pathway

Reactome:R-HSA-2046094

Elongation of gamma-lenolenoyl-CoA to dihomo-gamma-lenolenoyl-CoA

Key step in n-6 PUFA pathway (GLA to DGLA)

Reactome:R-HSA-2046100

Elongation of eicosapentaenoyl-CoA to docosapentaenoyl-CoA

ELOVL5 elongates EPA toward DHA synthesis

Reactome:R-HSA-2046105

Linoleic acid (LA) metabolism

ELOVL5 functions in n-6 PUFA synthesis pathway from dietary linoleic acid

Reactome:R-HSA-2046106

alpha-linolenic acid (ALA) metabolism

ELOVL5 functions in n-3 PUFA synthesis pathway from dietary ALA

Reactome:R-HSA-548800

ELOVL1,2,3,5 elongate AA-CoA and Mal-CoA to 3ODCT-CoA

ELOVL5 contributes to arachidonate elongation

Reactome:R-HSA-75876

Synthesis of very long-chain fatty acyl-CoAs

ELOVL5 is one of seven ELOVL elongases in the VLCFA synthesis pathway

file:human/ELOVL5/ELOVL5-deep-research-falcon.md

Deep research report on ELOVL5

Suggested Experiments

Experiment: Lipidomic profiling of membrane phospholipids in ELOVL5 knockout/knockdown cells compared to wild-type, with particular attention to PUFA-containing species that are susceptible to lipid peroxidation.

Hypothesis: ELOVL5 deficiency will reduce incorporation of C20-C22 PUFAs into membrane phospholipids, potentially altering membrane fluidity and susceptibility to oxidative damage.

Experiment: Test whether DHA supplementation can rescue ELOVL5 deficiency phenotypes, since ELOVL5 is upstream of DHA synthesis.

Hypothesis: Exogenous DHA should bypass the need for ELOVL5-dependent elongation and restore normal membrane lipid composition and cellular function.

📚 Additional Documentation

Deep Research Falcon

(ELOVL5-deep-research-falcon.md)

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template_file: templates/gene_research_go_focused.md
template_variables:
organism: human
gene_id: ELOVL5
gene_symbol: ELOVL5
uniprot_accession: Q9NYP7
protein_description: 'RecName: Full=Very long chain fatty acid elongase 5 {ECO:0000255|HAMAP-Rule:MF_03205};
EC=2.3.1.199 {ECO:0000255|HAMAP-Rule:MF_03205, ECO:0000269|PubMed:10970790, ECO:0000269|PubMed:19575253,
ECO:0000269|PubMed:20937905}; AltName: Full=3-keto acyl-CoA synthase ELOVL5 {ECO:0000255|HAMAP-Rule:MF_03205};
AltName: Full=ELOVL fatty acid elongase 5 {ECO:0000255|HAMAP-Rule:MF_03205}; Short=ELOVL
FA elongase 5 {ECO:0000255|HAMAP-Rule:MF_03205}; AltName: Full=Elongation of very
long chain fatty acids protein 5 {ECO:0000255|HAMAP-Rule:MF_03205}; AltName: Full=Fatty
acid elongase 1; Short=hELO1; AltName: Full=Very long chain 3-ketoacyl-CoA synthase
5 {ECO:0000255|HAMAP-Rule:MF_03205}; AltName: Full=Very long chain 3-oxoacyl-CoA
synthase 5 {ECO:0000255|HAMAP-Rule:MF_03205};'
gene_info: Name=ELOVL5 {ECO:0000255|HAMAP-Rule:MF_03205}; Synonyms=ELOVL2; ORFNames=PRO0530;
organism_full: Homo sapiens (Human).
protein_family: Belongs to the ELO family. ELOVL5 subfamily.
protein_domains: ELO_fam. (IPR002076); ELOVL5. (IPR033677); ELO (PF01151)
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citation_count: 17

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: Q9NYP7
Protein Description: RecName: Full=Very long chain fatty acid elongase 5 {ECO:0000255|HAMAP-Rule:MF_03205}; EC=2.3.1.199 {ECO:0000255|HAMAP-Rule:MF_03205, ECO:0000269|PubMed:10970790, ECO:0000269|PubMed:19575253, ECO:0000269|PubMed:20937905}; AltName: Full=3-keto acyl-CoA synthase ELOVL5 {ECO:0000255|HAMAP-Rule:MF_03205}; AltName: Full=ELOVL fatty acid elongase 5 {ECO:0000255|HAMAP-Rule:MF_03205}; Short=ELOVL FA elongase 5 {ECO:0000255|HAMAP-Rule:MF_03205}; AltName: Full=Elongation of very long chain fatty acids protein 5 {ECO:0000255|HAMAP-Rule:MF_03205}; AltName: Full=Fatty acid elongase 1; Short=hELO1; AltName: Full=Very long chain 3-ketoacyl-CoA synthase 5 {ECO:0000255|HAMAP-Rule:MF_03205}; AltName: Full=Very long chain 3-oxoacyl-CoA synthase 5 {ECO:0000255|HAMAP-Rule:MF_03205};
Gene Information: Name=ELOVL5 {ECO:0000255|HAMAP-Rule:MF_03205}; Synonyms=ELOVL2; ORFNames=PRO0530;
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the ELO family. ELOVL5 subfamily.
Key Domains: ELO_fam. (IPR002076); ELOVL5. (IPR033677); ELO (PF01151)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "ELOVL5" 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 'ELOVL5' 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 ELOVL5 (gene ID: ELOVL5, UniProt: Q9NYP7) 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: Q9NYP7
Protein Description: RecName: Full=Very long chain fatty acid elongase 5 {ECO:0000255|HAMAP-Rule:MF_03205}; EC=2.3.1.199 {ECO:0000255|HAMAP-Rule:MF_03205, ECO:0000269|PubMed:10970790, ECO:0000269|PubMed:19575253, ECO:0000269|PubMed:20937905}; AltName: Full=3-keto acyl-CoA synthase ELOVL5 {ECO:0000255|HAMAP-Rule:MF_03205}; AltName: Full=ELOVL fatty acid elongase 5 {ECO:0000255|HAMAP-Rule:MF_03205}; Short=ELOVL FA elongase 5 {ECO:0000255|HAMAP-Rule:MF_03205}; AltName: Full=Elongation of very long chain fatty acids protein 5 {ECO:0000255|HAMAP-Rule:MF_03205}; AltName: Full=Fatty acid elongase 1; Short=hELO1; AltName: Full=Very long chain 3-ketoacyl-CoA synthase 5 {ECO:0000255|HAMAP-Rule:MF_03205}; AltName: Full=Very long chain 3-oxoacyl-CoA synthase 5 {ECO:0000255|HAMAP-Rule:MF_03205};
Gene Information: Name=ELOVL5 {ECO:0000255|HAMAP-Rule:MF_03205}; Synonyms=ELOVL2; ORFNames=PRO0530;
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the ELO family. ELOVL5 subfamily.
Key Domains: ELO_fam. (IPR002076); ELOVL5. (IPR033677); ELO (PF01151)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "ELOVL5" 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 ELOVL5 (gene ID: ELOVL5, UniProt: Q9NYP7) 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.

Research report: Human ELOVL5 (UniProt: Q9NYP7) — functional annotation, pathways, regulation, and recent advances (2023–2025)

Verification of target identity and family/domain alignment
- Symbol match and organism: ELOVL5 is a human member of the ELOVL (elongation of very-long-chain fatty acids) family of integral ER membrane enzymes that catalyze the rate-limiting condensation step in fatty acid chain elongation, consistent with the UniProt description of ELOVL5 as a 3‑ketoacyl‑CoA synthase for VLCFA elongation (EC 2.3.1.199) (wang2023) (wang2023acomprehensivereview pages 2-4, wang2023acomprehensivereview pages 1-2).
- Family/domains and localization: ELOVL enzymes are multi-pass ER membrane proteins with conserved elongase motifs; ELOVL5 is grouped with ELOVL2 as the principal PUFA-elongating isoforms localized to endoplasmic reticulum, in agreement with the ELO family/domain annotations (wang2023; Vaz et al., 2025) (wang2023acomprehensivereview pages 2-4, vaz2025disordersoffatty pages 9-11).

Key concepts and definitions
- Enzyme class and reaction: ELOVL5 is the condensing enzyme of the microsomal fatty acid elongation (FACES) cycle. It catalyzes the Claisen-type condensation of an acyl‑CoA (chain length n) with malonyl‑CoA to form 3‑ketoacyl‑CoA (n+2). This is the first and rate-determining step of the four‑reaction ER elongation cycle (condensation by ELOVLs; then 3‑ketoacyl‑CoA reductase/KAR; hydroxyacyl‑CoA dehydratase/HACD1–4; trans‑2‑enoyl‑CoA reductase/TECR), integrated with high cytosolic NADPH/NADP+ to drive reductions (Kato et al., 2024 JBC; Vaz et al., 2025) (vaz2025disordersoffatty pages 9-11). URL: https://doi.org/10.1016/j.jbc.2024.105656 (Feb 2024); https://doi.org/10.1002/jimd.12734 (May 2025).
- Substrate specificity: Among human ELOVLs, ELOVL5 preferentially elongates C18–C20 polyunsaturated fatty acids (PUFAs), working in tandem with ELOVL2 (which extends C20–C22/C24). This positions ELOVL5 as the principal elongase for 18:3n‑3/18:2n‑6–derived intermediates to C20 products (e.g., 20:5n‑3/EPA precursors, 20:4n‑6 AA precursors), and onward toward docosapentaenoic acid (22:5n‑3) via sequential desaturation/elongation (Vaz et al., 2025; Loukil et al., 2024) (vaz2025disordersoffatty pages 9-11, loukil2024geneticassociationbetween pages 1-3). URL: https://doi.org/10.1186/s12263-024-00747-4 (Jun 2024).
- Pathway context with desaturases: Long‑chain PUFA biosynthesis from essential precursors (ALA 18:3n‑3; LA 18:2n‑6) proceeds via alternating desaturation (FADS2 Δ6, FADS1 Δ5) and elongation (ELOVL5, then ELOVL2). Human conversion of dietary ALA to EPA/DHA is limited (~5% to EPA; ~0.5% to DHA, influenced by diet and FADS variation), underscoring the pathway’s tight regulation and substrate competition (Loukil et al., 2024) (loukil2024geneticassociationbetween pages 1-3).
- Cellular localization: ELOVL5 functions on the cytosolic face of the endoplasmic reticulum, consistent with the ER-resident ELOVL family and the arrangement of the four‑enzyme elongation cycle in ER membranes (wang2023; Vaz et al., 2025) (wang2023acomprehensivereview pages 2-4, vaz2025disordersoffatty pages 9-11).

Recent developments and latest research (emphasis 2023–2024)
- Mechanistic and structural context for the elongation cycle: 2024 biochemical work refined the catalytic understanding of the terminal reductase step (TECR) and its coordination with ELOVL condensing enzymes during ER VLCFA elongation, supporting the canonical four‑step cycle and the rate‑limiting role of ELOVL enzymes (Kato et al., 2024 JBC) (vaz2025disordersoffatty pages 9-11). URL: https://doi.org/10.1016/j.jbc.2024.105656 (Feb 2024).
- Family‑level updates: A 2023 comprehensive review synthesized isoform‑specific roles: ELOVL5 as a core PUFA‑elongating enzyme with broad human tissue expression (highest in testis/epididymis), regulation intersecting with PPARα, and disease relevance across metabolic, neurologic, and cancer contexts (Wang et al., 2023) (wang2023acomprehensivereview pages 2-4, wang2023acomprehensivereview pages 4-5). URL: https://doi.org/10.1186/s40001-023-01523-7 (Nov 2023).
- Human genetic and nutrigenomic insights: A 2024 scoping review concluded that FADS genetic variants strongly influence circulating EPA/DHA, while evidence for ELOVL polymorphisms remains limited; nevertheless, ELOVL5 is positioned upstream of EPA/DHA synthesis as the principal C18→C20 elongase interacting with FADS1/2 (Loukil et al., 2024) (loukil2024geneticassociationbetween pages 1-3). URL: https://doi.org/10.1186/s12263-024-00747-4 (Jun 2024).
- Cancer biology: 2023–2024 literature highlighted elevated ELOVL5 expression and functional roles across cancers. In colorectal cancer, analyses show higher ELOVL5 with co‑upregulation of desaturation/elongation partners (FADS2, TECR), and SNPs near ELOVL5 associated with poor survival in mCRC cohorts (Moon, 2023) (moon2023emergingrolesof pages 5-7). In breast cancer cells, ELOVL5 knockdown modulated PUFA composition and increased sensitivity to ferroptosis, suggesting a role in redox‑lipid homeostasis and therapeutic vulnerability (Nikulin et al., 2023) (nikulin2023elovl5andigfbp6 pages 1-2). URLs: https://doi.org/10.1080/19768354.2023.2189933 (Mar 2023); https://doi.org/10.3389/fmolb.2023.1075704 (Jan 2023).

Current applications and real‑world implementations
- Nutritional genomics and risk stratification: Given ELOVL5’s place in endogenous EPA/DHA synthesis, population data emphasize that genetic variation in upstream FADS and dietary n‑6/n‑3 ratios constrain conversion, informing dietary recommendations that prioritize direct LC‑PUFA intake (e.g., EPA/DHA) over relying on ALA conversion. The scoping review reports typical conversion estimates (~5% EPA; ~0.5% DHA) and notes substrate competition (high LA) reduces n‑3 LC‑PUFA synthesis—parameters used in nutritional counseling and trial design (Loukil et al., 2024) (loukil2024geneticassociationbetween pages 1-3).
- Oncology: PUFA remodeling and ferroptosis. Experimental evidence that lowering ELOVL5 can sensitize breast cancer cells to ferroptosis suggests potential combination strategies with exogenous PUFAs or ferroptosis inducers; although still preclinical, such approaches guide biomarker‑driven trials and combination regimens being explored across tumor types (Nikulin et al., 2023; Moon, 2023) (nikulin2023elovl5andigfbp6 pages 1-2, moon2023emergingrolesof pages 5-7).

Expert opinions and authoritative synthesis
- The 2023 European Journal of Medical Research review emphasizes ELOVL5’s central role in PUFA elongation, ER localization, and its regulation and disease associations, framing ELOVL5 as a plausible therapeutic target where lipid composition contributes to pathophysiology (Wang et al., 2023) (wang2023acomprehensivereview pages 2-4, wang2023acomprehensivereview pages 1-2, wang2023acomprehensivereview pages 4-5). URL: https://doi.org/10.1186/s40001-023-01523-7 (Nov 2023).
- The 2025 JIMD review situates ELOVL5 within inherited disorders of FA homeostasis and clarifies biochemical drivers (malonyl‑CoA, NADPH dependence; ER cycle) and isoform preferences (C18–C20 PUFA for ELOVL5), supporting mechanistic annotations used in clinical genetics and metabolic medicine (Vaz et al., 2025) (vaz2025disordersoffatty pages 9-11). URL: https://doi.org/10.1002/jimd.12734 (May 2025).

Relevant statistics and quantitative data
- Endogenous n‑3 LC‑PUFA synthesis efficiency: Estimated conversion of ALA to EPA/DHA in humans is low—approximately 5% to EPA and 0.5% to DHA—with variation due to FADS genotypes, sex, age, and dietary LA competition; this contextualizes the metabolic leverage and limitations of ELOVL5 in systemic EPA/DHA status (Loukil et al., 2024) (loukil2024geneticassociationbetween pages 1-3).
- Expression landscape: Family‑level surveys report ELOVL5 detected in multiple human tissues, with highest mRNA in testis/epididymis, aligning with tissues enriched in docosapentaenoic acids and reflecting the physiological demand for PUFA elongation during spermatogenesis (Wang et al., 2023) (wang2023acomprehensivereview pages 4-5).

Function, substrates, products, and cofactors (concise synthesis)
- Function: ER condensing enzyme initiating two‑carbon elongation of long‑chain PUFAs (EC 2.3.1.199) (Vaz et al., 2025; Wang et al., 2023) (vaz2025disordersoffatty pages 9-11, wang2023acomprehensivereview pages 2-4).
- Substrate specificity: Prefers 18–20 carbon n‑3/n‑6 PUFAs (e.g., 18:3n‑3, 18:2n‑6, 20:4n‑6, 20:5n‑3), producing longer 3‑ketoacyl‑CoAs that are processed to C20/C22 PUFAs (e.g., precursors of AA, EPA; pathway to 22:5n‑3) (Vaz et al., 2025; Loukil et al., 2024) (vaz2025disordersoffatty pages 9-11, loukil2024geneticassociationbetween pages 1-3).
- Pathway partners: FADS2 (Δ6), FADS1 (Δ5), ELOVL2 (C20→C24), plus KAR, HACD1–4, TECR (ER elongation steps) (Kato et al., 2024; Vaz et al., 2025) (vaz2025disordersoffatty pages 9-11).
- Cofactors and substrates: Malonyl‑CoA (from ACC1/ACACA) as the C2 donor; reducing equivalents (NADPH) required downstream for KAR/TECR steps; acyl‑CoA substrates provided by FASN and dietary uptake (Vaz et al., 2025) (vaz2025disordersoffatty pages 9-11).
- Localization: Endoplasmic reticulum membrane (Wang et al., 2023; Vaz et al., 2025) (wang2023acomprehensivereview pages 2-4, vaz2025disordersoffatty pages 9-11).

Disease associations and physiology
- Inherited disease: The 2025 JIMD review catalogs ELOVL family gene disorders and notes the specific substrate preference of ELOVL5 but does not detail ELOVL5‑specific Mendelian disease in its excerpt; nonetheless, ELOVL family pathogenic variants establish the clinical relevance of this pathway (Vaz et al., 2025) (vaz2025disordersoffatty pages 9-11).
- Cancer: Multiple lines of evidence link ELOVL5 to tumor lipid remodeling and phenotypes—elevated expression in colorectal cancer and other tumors; genetic associations with survival in mCRC cohorts; and functional data in breast cancer indicating roles in ferroptosis susceptibility (Moon, 2023; Nikulin et al., 2023) (moon2023emergingrolesof pages 5-7, nikulin2023elovl5andigfbp6 pages 1-2).
- Immunology and metabolism: Family‑level syntheses highlight ELOVL roles in membrane lipid composition, signaling lipids (eicosanoids/docosanoids), and PPARα‑linked regulation, implying ELOVL5 activity can influence inflammatory and metabolic signaling outputs (Wang et al., 2023) (wang2023acomprehensivereview pages 1-2, wang2023acomprehensivereview pages 4-5).

Regulation
- Transcriptional/metabolic regulation: Reviews report that ELOVL family members intersect with lipid‑sensing transcription factors, including PPARα and SREBP1c (family‑level), and that PUFA elongation impacts PPARα activity. While isoform‑specific regulatory maps remain incomplete, ELOVL5 has been noted among ELOVLs stimulated by PPARα in some tissues, consistent with its role in fatty acid remodeling (Wang et al., 2023) (wang2023acomprehensivereview pages 2-4, wang2023acomprehensivereview pages 1-2).

Notes on symbol ambiguity and scope
- The collected evidence specifically addresses human ELOVL5 as an ER VLC‑PUFA elongase. No conflicting gene with identical symbol in a different organism was used as the primary basis for claims. Family and domain features, catalytic role, and localization consistently match the UniProt description (Wang et al., 2023; Vaz et al., 2025) (wang2023acomprehensivereview pages 2-4, vaz2025disordersoffatty pages 9-11).

References with URLs and dates
- Wang X et al. A comprehensive review of the family of very-long-chain fatty acid elongases. European Journal of Medical Research. Nov 2023. URL: https://doi.org/10.1186/s40001-023-01523-7 (Accessed 2025). (wang2023acomprehensivereview pages 2-4, wang2023acomprehensivereview pages 1-2, wang2023acomprehensivereview pages 4-5)
- Kato R et al. Catalytic mechanism of trans-2-enoyl-CoA reductases in the fatty acid elongation cycle. J Biol Chem. Feb 2024. URL: https://doi.org/10.1016/j.jbc.2024.105656 (vaz2025disordersoffatty pages 9-11)
- Loukil I et al. 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 (loukil2024geneticassociationbetween pages 1-3)
- Moon Y‑A. Emerging roles of polyunsaturated fatty acid synthesis pathway in colorectal cancer. Animal Cells and Systems. Mar 2023. URL: https://doi.org/10.1080/19768354.2023.2189933 (moon2023emergingrolesof pages 5-7)
- Nikulin S et al. ELOVL5 and IGFBP6 genes modulate sensitivity of breast cancer cells to ferroptosis. Frontiers in Molecular Biosciences. Jan 2023. URL: https://doi.org/10.3389/fmolb.2023.1075704 (nikulin2023elovl5andigfbp6 pages 1-2)
- Vaz FM et al. Disorders of fatty acid homeostasis. Journal of Inherited Metabolic Disease. May 2025. URL: https://doi.org/10.1002/jimd.12734 (vaz2025disordersoffatty pages 9-11)

Summary
Human ELOVL5 (Q9NYP7) is an ER-resident condensing enzyme (EC 2.3.1.199) that preferentially elongates 18–20 carbon n‑3/n‑6 PUFAs, operating with FADS1/2 and ELOVL2 to generate LC‑PUFAs including AA/EPA/DPA/DHA precursors. Its activity depends on malonyl‑CoA and NADPH‑driven downstream reductions within the ER elongation cycle. Recent reviews and mechanistic work (2023–2024) consolidate its biochemical role, regulation, and disease relevance. In cancer, ELOVL5 aligns with altered PUFA metabolism and ferroptosis sensitivity, while nutrigenomic evidence underscores constraints on endogenous EPA/DHA production that implicate ELOVL5 within broader genetic and dietary determinants of PUFA status (wang2023acomprehensivereview pages 2-4, loukil2024geneticassociationbetween pages 1-3, moon2023emergingrolesof pages 5-7, nikulin2023elovl5andigfbp6 pages 1-2, vaz2025disordersoffatty pages 9-11).

References

(wang2023acomprehensivereview pages 2-4): Xiangyu Wang, Hao Yu, Rong Gao, Ming Liu, and Wenli Xie. A comprehensive review of the family of very-long-chain fatty acid elongases: structure, function, and implications in physiology and pathology. European Journal of Medical Research, Nov 2023. URL: https://doi.org/10.1186/s40001-023-01523-7, doi:10.1186/s40001-023-01523-7. This article has 61 citations and is from a peer-reviewed journal.
(wang2023acomprehensivereview pages 1-2): Xiangyu Wang, Hao Yu, Rong Gao, Ming Liu, and Wenli Xie. A comprehensive review of the family of very-long-chain fatty acid elongases: structure, function, and implications in physiology and pathology. European Journal of Medical Research, Nov 2023. URL: https://doi.org/10.1186/s40001-023-01523-7, doi:10.1186/s40001-023-01523-7. This article has 61 citations and is from a peer-reviewed journal.
(vaz2025disordersoffatty pages 9-11): Frédéric M. Vaz, Sacha Ferdinandusse, Gajja S. Salomons, and Ronald J. A. Wanders. Disorders of fatty acid homeostasis. Journal of Inherited Metabolic Disease, May 2025. URL: https://doi.org/10.1002/jimd.12734, doi:10.1002/jimd.12734. This article has 10 citations and is from a peer-reviewed journal.
(loukil2024geneticassociationbetween pages 1-3): 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.
(wang2023acomprehensivereview pages 4-5): Xiangyu Wang, Hao Yu, Rong Gao, Ming Liu, and Wenli Xie. A comprehensive review of the family of very-long-chain fatty acid elongases: structure, function, and implications in physiology and pathology. European Journal of Medical Research, Nov 2023. URL: https://doi.org/10.1186/s40001-023-01523-7, doi:10.1186/s40001-023-01523-7. This article has 61 citations and is from a peer-reviewed journal.
(moon2023emergingrolesof pages 5-7): Young-Ah Moon. Emerging roles of polyunsaturated fatty acid synthesis pathway in colorectal cancer. Animal Cells and Systems, 27:61-71, Mar 2023. URL: https://doi.org/10.1080/19768354.2023.2189933, doi:10.1080/19768354.2023.2189933. This article has 13 citations and is from a peer-reviewed journal.
(nikulin2023elovl5andigfbp6 pages 1-2): Sergey Nikulin, Alexandra Razumovskaya, Andrey Poloznikov, Galina Zakharova, Boris Alekseev, and Alexander Tonevitsky. Elovl5 and igfbp6 genes modulate sensitivity of breast cancer cells to ferroptosis. Frontiers in Molecular Biosciences, Jan 2023. URL: https://doi.org/10.3389/fmolb.2023.1075704, doi:10.3389/fmolb.2023.1075704. This article has 23 citations and is from a poor quality or predatory journal.

Citations

vaz2025disordersoffatty pages 9-11
loukil2024geneticassociationbetween pages 1-3
moon2023emergingrolesof pages 5-7
wang2023acomprehensivereview pages 4-5
wang2023acomprehensivereview pages 2-4
wang2023acomprehensivereview pages 1-2
https://doi.org/10.1016/j.jbc.2024.105656
https://doi.org/10.1002/jimd.12734
https://doi.org/10.1186/s12263-024-00747-4
https://doi.org/10.1186/s40001-023-01523-7
https://doi.org/10.1080/19768354.2023.2189933
https://doi.org/10.3389/fmolb.2023.1075704
https://doi.org/10.1186/s40001-023-01523-7,
https://doi.org/10.1002/jimd.12734,
https://doi.org/10.1186/s12263-024-00747-4,
https://doi.org/10.1080/19768354.2023.2189933,
https://doi.org/10.3389/fmolb.2023.1075704,

📄 View Raw YAML

id: Q9NYP7
gene_symbol: ELOVL5
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: ELOVL5 (Very long chain fatty acid elongase 5) is an endoplasmic 
  reticulum membrane-resident enzyme that catalyzes the rate-limiting 
  condensation step in the elongation of C18-C20 polyunsaturated fatty acids 
  (PUFAs). It preferentially acts on n-3 and n-6 PUFAs including gamma-linolenic
  acid (18:3n-6), alpha-linolenic acid (18:3n-3), and arachidonic acid 
  (20:4n-6), adding two carbons per elongation cycle by condensing acyl-CoA 
  substrates with malonyl-CoA. ELOVL5 works in concert with FADS1/FADS2 
  desaturases and ELOVL2 to generate long-chain PUFAs that serve as precursors 
  for membrane phospholipids and eicosanoid/docosanoid lipid mediators. 
  Mutations in ELOVL5 cause spinocerebellar ataxia type 38 (SCA38). Recent 
  studies link ELOVL5 to ferroptosis sensitivity through its role in determining
  membrane PUFA composition.
existing_annotations:
  - term:
      id: GO:0005789
      label: endoplasmic reticulum membrane
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: ELOVL5 is an integral membrane protein of the endoplasmic 
        reticulum. Multiple studies confirm ER localization including 
        PMID:20937905 showing ER localization in mammalian cells and 
        PMID:25065913 showing wild-type ELOVL5 localizes to the ER in 
        transfection experiments. UniProt describes it as a multi-pass ER 
        membrane protein with seven transmembrane helices.
      action: ACCEPT
      reason: Well-supported by phylogenetic inference (IBA), consistent with 
        direct experimental evidence from multiple publications and the known 
        biology of the ELOVL enzyme family which functions exclusively in the ER
        elongation cycle.
      supported_by:
        - reference_id: PMID:20937905
          supporting_text: ELOVL1 production of C24 acyl-CoAs is linked to C24 
            sphingolipid synthesis.
        - reference_id: PMID:25065913
          supporting_text: 2014 Jul 24. ELOVL5 mutations cause spinocerebellar 
            ataxia 38.
        - reference_id: file:human/ELOVL5/ELOVL5-deep-research-falcon.md
          supporting_text: 'model: Edison Scientific Literature'
  - term:
      id: GO:0009922
      label: fatty acid elongase activity
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: ELOVL5 is a bona fide fatty acid elongase that catalyzes the 
        condensation of acyl-CoA with malonyl-CoA (EC 2.3.1.199). This is the 
        first and rate-limiting step of the four-reaction VLCFA elongation 
        cycle. PMID:10970790 originally cloned and characterized this activity; 
        PMID:20937905 performed systematic in vitro substrate specificity 
        analysis.
      action: ACCEPT
      reason: Core enzymatic function of ELOVL5 supported by extensive 
        experimental evidence and phylogenetic conservation across the ELOVL 
        family.
      supported_by:
        - reference_id: PMID:10970790
          supporting_text: Cloning of a human cDNA encoding a novel enzyme 
            involved in the elongation of long-chain polyunsaturated fatty 
            acids.
        - reference_id: PMID:20937905
          supporting_text: ELOVL1 production of C24 acyl-CoAs is linked to C24 
            sphingolipid synthesis.
  - term:
      id: GO:0030148
      label: sphingolipid biosynthetic process
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: While ELOVL1 is specifically linked to C24 sphingolipid synthesis
        (PMID:20937905), ELOVL5 preferentially elongates PUFAs rather than the 
        saturated/monounsaturated fatty acids that are primary sphingolipid 
        precursors. The IBA annotation may reflect broader family-level 
        inference from yeast ELO genes. ELOVL5 contribution to sphingolipid 
        metabolism is indirect at best.
      action: MARK_AS_OVER_ANNOTATED
      reason: ELOVL5 substrate specificity is primarily toward PUFAs (C18-C20 
        polyunsaturated), not the saturated/monounsaturated VLCFAs that are 
        incorporated into sphingolipids. PMID:20937905 specifically attributes 
        C24 sphingolipid synthesis to ELOVL1, not ELOVL5. While phylogenetically
        related, functional differentiation of ELOVL family members means this 
        annotation overstates ELOVL5's role.
      supported_by:
        - reference_id: PMID:20937905
          supporting_text: ELOVL1 production of C24 acyl-CoAs is linked to C24 
            sphingolipid synthesis.
  - term:
      id: GO:0034626
      label: fatty acid elongation, polyunsaturated fatty acid
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: PUFA elongation is the primary function of ELOVL5. The enzyme 
        preferentially elongates C18-C20 PUFAs of both n-3 and n-6 series. 
        PMID:10970790 demonstrated elongation of gamma-linolenic acid, 
        alpha-linolenic acid, stearidonic acid, arachidonic acid, and 
        eicosapentaenoic acid.
      action: ACCEPT
      reason: Core function strongly supported by original cloning paper and 
        subsequent biochemical studies. ELOVL5 is specifically adapted for PUFA 
        substrates.
      supported_by:
        - reference_id: PMID:10970790
          supporting_text: Cloning of a human cDNA encoding a novel enzyme 
            involved in the elongation of long-chain polyunsaturated fatty 
            acids.
  - term:
      id: GO:0042761
      label: very long-chain fatty acid biosynthetic process
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: ELOVL5 catalyzes elongation to produce VLCFAs (>20 carbons). 
        Products include dihomo-gamma-linolenic acid (20:3n-6), adrenic acid 
        (22:4n-6), and docosapentaenoic acid (22:5n-3).
      action: ACCEPT
      reason: Appropriately captures the biosynthetic outcome of ELOVL5 
        activity, producing VLCFAs from long-chain PUFA substrates.
      supported_by:
        - reference_id: PMID:10970790
          supporting_text: Cloning of a human cDNA encoding a novel enzyme 
            involved in the elongation of long-chain polyunsaturated fatty 
            acids.
  - term:
      id: GO:0019367
      label: fatty acid elongation, saturated fatty acid
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: While ELOVL5 can elongate some saturated fatty acids, its 
        substrate preference is strongly toward PUFAs. The deep research and 
        UniProt both emphasize PUFA specificity. Saturated FA elongation is 
        primarily performed by ELOVL1, ELOVL3, and ELOVL6.
      action: KEEP_AS_NON_CORE
      reason: ELOVL5 has detectable activity toward some saturated substrates, 
        so the annotation is not incorrect, but this is not the primary 
        function. The IBA inference from family members is technically valid but
        oversimplifies isoform-specific substrate preferences.
      supported_by:
        - reference_id: PMID:20937905
          supporting_text: ELOVL1 production of C24 acyl-CoAs is linked to C24 
            sphingolipid synthesis.
  - term:
      id: GO:0034625
      label: fatty acid elongation, monounsaturated fatty acid
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: ELOVL5 can elongate monounsaturated fatty acids including 
        palmitoleic acid (16:1n-7) and oleic acid (18:1n-9). UniProt catalytic 
        activity entries include reactions for (9Z)-hexadecenoyl-CoA and 
        (9Z)-octadecenoyl-CoA. This is a secondary activity.
      action: ACCEPT
      reason: Supported by experimental evidence in UniProt showing ELOVL5 can 
        elongate monounsaturated substrates. While PUFA elongation is the 
        primary activity, MUFA elongation is also a verified function.
      supported_by:
        - reference_id: PMID:10970790
          supporting_text: Cloning of a human cDNA encoding a novel enzyme 
            involved in the elongation of long-chain polyunsaturated fatty 
            acids.
  - term:
      id: GO:0005783
      label: endoplasmic reticulum
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: InterPro-based inference of ER localization based on the ELOVL5 
        subfamily signature (IPR033677). Consistent with experimental data.
      action: ACCEPT
      reason: The broader ER term is acceptable as redundant with the more 
        specific ER membrane annotation. Both are well-supported.
  - term:
      id: GO:0005789
      label: endoplasmic reticulum membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: Combined automated annotation for ER membrane localization. 
        Redundant with IBA annotation but independently supported.
      action: ACCEPT
      reason: Consistent with experimental evidence and IBA annotation. ER 
        membrane is the correct subcellular location.
  - term:
      id: GO:0006629
      label: lipid metabolic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: Broad term inferred from UniProt keyword mapping. ELOVL5 is 
        clearly involved in lipid metabolism as a fatty acid elongase.
      action: ACCEPT
      reason: Correct but very general. The more specific fatty acid elongation 
        terms are more informative but this parental term is not incorrect.
  - term:
      id: GO:0006631
      label: fatty acid metabolic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: Keyword-based inference of fatty acid metabolism involvement. 
        Correct and appropriate.
      action: ACCEPT
      reason: ELOVL5 is a fatty acid elongase, so involvement in fatty acid 
        metabolic process is accurate.
  - term:
      id: GO:0006633
      label: fatty acid biosynthetic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: Combined automated annotation. ELOVL5 elongates fatty acids, 
        contributing to biosynthesis of longer-chain products.
      action: ACCEPT
      reason: Elongation is part of fatty acid biosynthesis; this is accurate.
  - term:
      id: GO:0006636
      label: unsaturated fatty acid biosynthetic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: ELOVL5 produces unsaturated fatty acid products (PUFAs) from 
        unsaturated precursors.
      action: ACCEPT
      reason: The enzyme primarily acts on unsaturated (PUFA) substrates to 
        produce unsaturated products. This is accurate.
  - term:
      id: GO:0009922
      label: fatty acid elongase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: Combined automated annotation of core enzymatic function. 
        Redundant with IBA and experimental annotations.
      action: ACCEPT
      reason: Core molecular function, redundant but correct.
  - term:
      id: GO:0016020
      label: membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: ELOVL5 is a multi-pass transmembrane protein. This very general 
        term is correct but uninformative compared to the specific ER membrane 
        annotation.
      action: ACCEPT
      reason: Correct but very general. More specific terms (ER membrane) are 
        preferred but this is not incorrect.
  - term:
      id: GO:0016740
      label: transferase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: ELOVL5 catalyzes transfer of the acyl group; EC 2.3.1.199 is a 
        transferase.
      action: ACCEPT
      reason: Correct parental term for the enzymatic activity, though the more 
        specific fatty acid elongase activity term is preferred.
  - term:
      id: GO:0019367
      label: fatty acid elongation, saturated fatty acid
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: InterPro-based inference. Redundant with IBA annotation for same 
        term.
      action: KEEP_AS_NON_CORE
      reason: As noted above, ELOVL5 can act on saturated substrates but this is
        not its primary function. Same assessment as IBA annotation.
  - term:
      id: GO:0030425
      label: dendrite
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: UniProt subcellular location mapping. PMID:25065913 shows ELOVL5 
        localizes to dendrites in Purkinje cells, validated by 
        immunohistochemistry.
      action: ACCEPT
      reason: Supported by direct experimental evidence in PMID:25065913 showing
        dendritic localization in cerebellar Purkinje cells. Relevant to SCA38 
        pathophysiology.
      supported_by:
        - reference_id: PMID:25065913
          supporting_text: 2014 Jul 24. ELOVL5 mutations cause spinocerebellar 
            ataxia 38.
  - term:
      id: GO:0030497
      label: fatty acid elongation
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: ARBA machine learning inference of fatty acid elongation 
        involvement.
      action: ACCEPT
      reason: Correct parental term for the more specific elongation processes.
  - term:
      id: GO:0034625
      label: fatty acid elongation, monounsaturated fatty acid
    evidence_type: IEA
    original_reference_id: GO_REF:0000104
    review:
      summary: UniRule-based inference. Redundant with IBA annotation.
      action: ACCEPT
      reason: Consistent with IBA annotation; MUFA elongation is a verified 
        secondary activity.
  - term:
      id: GO:0034626
      label: fatty acid elongation, polyunsaturated fatty acid
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: Combined automated annotation. Redundant with IBA annotation for 
        core function.
      action: ACCEPT
      reason: Core function, redundant with IBA but correct.
  - term:
      id: GO:0035338
      label: long-chain fatty-acyl-CoA biosynthetic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000104
    review:
      summary: UniRule inference. ELOVL5 produces fatty-acyl-CoA products as 
        part of elongation.
      action: ACCEPT
      reason: The product of ELOVL5 catalysis (via subsequent steps of the 
        elongation cycle) is elongated acyl-CoA, so this is accurate.
  - term:
      id: GO:0042761
      label: very long-chain fatty acid biosynthetic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: Combined automated annotation. Redundant with IBA for same term.
      action: ACCEPT
      reason: Core function of producing VLCFAs.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:32296183
    review:
      summary: High-throughput binary protein interactome study identified 
        multiple interaction partners for ELOVL5. While technically valid IPI 
        evidence, protein binding is uninformative for annotation purposes.
      action: REMOVE
      reason: Per curation guidelines, protein binding is too vague to be 
        informative. The interactions detected in high-throughput screens may 
        not reflect physiologically relevant function. More specific interaction
        terms should be used if the binding has known functional significance.
      supported_by:
        - reference_id: PMID:32296183
          supporting_text: Apr 8. A reference map of the human binary protein 
            interactome.
  - term:
      id: GO:0005783
      label: endoplasmic reticulum
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: HPA immunofluorescence-based localization to ER.
      action: ACCEPT
      reason: Direct experimental evidence for ER localization consistent with 
        known biology.
  - term:
      id: GO:0035338
      label: long-chain fatty-acyl-CoA biosynthetic process
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-75876
    review:
      summary: Reactome pathway annotation for VLCFA-CoA synthesis. ELOVL5 is 
        annotated to the "Synthesis of very long-chain fatty acyl-CoAs" pathway.
      action: ACCEPT
      reason: Appropriate pathway annotation. Reactome correctly places ELOVL5 
        in the VLCFA synthesis pathway.
      supported_by:
        - reference_id: Reactome:R-HSA-75876
  - term:
      id: GO:0036109
      label: alpha-linolenic acid metabolic process
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2046106
    review:
      summary: Reactome pathway for ALA (18:3n-3) metabolism. ELOVL5 elongates 
        ALA-derived intermediates in the n-3 PUFA synthesis pathway.
      action: ACCEPT
      reason: PMID:10970790 demonstrated ELOVL5 converts alpha-linolenic acid to
        omega3- eicosatrienoic acid. This pathway annotation is correct.
      supported_by:
        - reference_id: PMID:10970790
          supporting_text: Cloning of a human cDNA encoding a novel enzyme 
            involved in the elongation of long-chain polyunsaturated fatty 
            acids.
  - term:
      id: GO:0043651
      label: linoleic acid metabolic process
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2046105
    review:
      summary: Reactome pathway for LA (18:2n-6) metabolism. ELOVL5 elongates 
        LA-derived intermediates including GLA to DGLA in the n-6 PUFA synthesis
        pathway.
      action: ACCEPT
      reason: ELOVL5 is part of the linoleic acid metabolic pathway, elongating 
        intermediates derived from LA via delta-6 desaturase. Demonstrated by 
        PMID:10970790.
      supported_by:
        - reference_id: PMID:10970790
          supporting_text: Cloning of a human cDNA encoding a novel enzyme 
            involved in the elongation of long-chain polyunsaturated fatty 
            acids.
        - reference_id: Reactome:R-HSA-2046105
  - term:
      id: GO:0009922
      label: fatty acid elongase activity
    evidence_type: EXP
    original_reference_id: PMID:10970790
    review:
      summary: Original cloning paper that demonstrated ELOVL5 (then called 
        HELO1) fatty acid elongase activity by expression in S. cerevisiae and 
        measurement of PUFA elongation.
      action: ACCEPT
      reason: Primary experimental characterization of enzymatic activity. 
        Strong EXP evidence.
      supported_by:
        - reference_id: PMID:10970790
          supporting_text: Cloning of a human cDNA encoding a novel enzyme 
            involved in the elongation of long-chain polyunsaturated fatty 
            acids.
  - term:
      id: GO:0009922
      label: fatty acid elongase activity
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2046083
    review:
      summary: Reactome reaction annotation for elongation of arachidonyl-CoA to
        docosatetraenoyl-CoA.
      action: ACCEPT
      reason: Specific reaction annotation supported by biochemical evidence.
  - term:
      id: GO:0009922
      label: fatty acid elongase activity
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2046100
    review:
      summary: Reactome reaction annotation for elongation of 
        eicosapentaenoyl-CoA to docosapentaenoyl-CoA.
      action: ACCEPT
      reason: Specific reaction annotation supported by biochemical evidence.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:38422897
    review:
      summary: Study showed ELOVL5 interacts with TECR (trans-2-enoyl-CoA 
        reductase) as part of the fatty acid elongation complex. This 
        interaction is functionally relevant for substrate channeling in the 
        elongation cycle.
      action: KEEP_AS_NON_CORE
      reason: Unlike generic protein binding from high-throughput screens, this 
        interaction with TECR has clear functional relevance - both enzymes 
        function in the same elongation cycle. However, a more specific 
        interaction term would be preferable if available.
      supported_by:
        - reference_id: PMID:38422897
          supporting_text: The 3-hydroxyacyl-CoA dehydratase 1/2 form complex 
            with trans-2-enoyl-CoA reductase involved in substrates transfer in 
            very long chain fatty acid elongation.
  - term:
      id: GO:0045723
      label: positive regulation of fatty acid biosynthetic process
    evidence_type: IMP
    original_reference_id: PMID:23749231
    review:
      summary: This paper studied miR-30c effects on lipid metabolism. siRNA 
        knockdown of ELOVL5 reduced de novo lipogenesis. The IMP annotation 
        suggests ELOVL5 positively regulates fatty acid biosynthesis based on 
        mutant phenotype.
      action: ACCEPT
      reason: The study shows siELOVL5 reduces lipogenesis (Fig 4g), supporting 
        a positive role in fatty acid biosynthesis. This is consistent with its 
        enzymatic function.
      supported_by:
        - reference_id: PMID:23749231
          supporting_text: MicroRNA-30c reduces hyperlipidemia and 
            atherosclerosis in mice by decreasing lipid synthesis and 
            lipoprotein secretion.
  - term:
      id: GO:0043025
      label: neuronal cell body
    evidence_type: IDA
    original_reference_id: PMID:25065913
    review:
      summary: Immunohistochemistry on human and mouse brain showed ELOVL5 
        localization in Purkinje cell soma. Relevant to SCA38 pathophysiology.
      action: ACCEPT
      reason: Direct experimental evidence showing neuronal cell body 
        localization in cerebellar Purkinje cells, providing context for the 
        SCA38 disease mechanism.
      supported_by:
        - reference_id: PMID:25065913
          supporting_text: 2014 Jul 24. ELOVL5 mutations cause spinocerebellar 
            ataxia 38.
  - term:
      id: GO:0097447
      label: dendritic tree
    evidence_type: IDA
    original_reference_id: PMID:25065913
    review:
      summary: Immunohistochemistry showed ELOVL5 in the proximal dendritic tree
        of Purkinje cells.
      action: ACCEPT
      reason: Direct experimental evidence from the SCA38 paper. This neuronal 
        localization is consistent with the cerebellar ataxia phenotype of 
        ELOVL5 mutations.
      supported_by:
        - reference_id: PMID:25065913
          supporting_text: 2014 Jul 24. ELOVL5 mutations cause spinocerebellar 
            ataxia 38.
  - term:
      id: GO:0016020
      label: membrane
    evidence_type: HDA
    original_reference_id: PMID:19946888
    review:
      summary: Proteomics study of NK cell membrane proteins detected ELOVL5.
      action: ACCEPT
      reason: High-throughput experimental data consistent with known membrane 
        localization.
      supported_by:
        - reference_id: PMID:19946888
          supporting_text: Defining the membrane proteome of NK cells.
  - term:
      id: GO:0005789
      label: endoplasmic reticulum membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2046083
    review:
      summary: Reactome reaction annotation specifying ER membrane as reaction 
        location.
      action: ACCEPT
      reason: Consistent with known localization.
  - term:
      id: GO:0005789
      label: endoplasmic reticulum membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2046088
    review:
      summary: Reactome reaction annotation for stearidonoyl-CoA elongation.
      action: ACCEPT
      reason: Consistent with known localization.
  - term:
      id: GO:0005789
      label: endoplasmic reticulum membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2046094
    review:
      summary: Reactome reaction annotation for gamma-linolenoyl-CoA elongation.
      action: ACCEPT
      reason: Consistent with known localization.
  - term:
      id: GO:0005789
      label: endoplasmic reticulum membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2046100
    review:
      summary: Reactome reaction annotation for eicosapentaenoyl-CoA elongation.
      action: ACCEPT
      reason: Consistent with known localization.
  - term:
      id: GO:0005789
      label: endoplasmic reticulum membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-548800
    review:
      summary: Reactome reaction annotation for arachidonate elongation.
      action: ACCEPT
      reason: Consistent with known localization.
  - term:
      id: GO:0034626
      label: fatty acid elongation, polyunsaturated fatty acid
    evidence_type: IDA
    original_reference_id: PMID:20937905
    review:
      summary: Ohno et al. systematically characterized ELOVL substrate 
        specificities in vitro, demonstrating ELOVL5 activity toward PUFAs.
      action: ACCEPT
      reason: Strong experimental evidence from systematic biochemical 
        characterization.
      supported_by:
        - reference_id: PMID:20937905
          supporting_text: ELOVL1 production of C24 acyl-CoAs is linked to C24 
            sphingolipid synthesis.
  - term:
      id: GO:0042761
      label: very long-chain fatty acid biosynthetic process
    evidence_type: IDA
    original_reference_id: PMID:20937905
    review:
      summary: Same study demonstrating ELOVL5 produces VLCFAs from C18-C20 
        substrates.
      action: ACCEPT
      reason: Direct experimental characterization of VLCFA production.
      supported_by:
        - reference_id: PMID:20937905
          supporting_text: ELOVL1 production of C24 acyl-CoAs is linked to C24 
            sphingolipid synthesis.
  - term:
      id: GO:0009922
      label: fatty acid elongase activity
    evidence_type: IDA
    original_reference_id: PMID:20427700
    review:
      summary: Note that PMID:20427700 title in the reference list appears to be
        incorrect (it shows a cardiovascular study title). This may be a 
        database error. The annotation claims IDA evidence for fatty acid 
        elongase activity.
      action: UNDECIDED
      reason: Cannot verify - the PMID appears misattributed in the reference 
        list (title is about heart failure, not fatty acid elongation). Requires
        verification that this PMID actually contains evidence for ELOVL5 
        elongase activity.
      supported_by:
        - reference_id: PMID:20427700
          supporting_text: 'Validation of the health ABC heart failure model for incident
            heart failure risk prediction: the Cardiovascular Health Study.'
  - term:
      id: GO:0034625
      label: fatty acid elongation, monounsaturated fatty acid
    evidence_type: IDA
    original_reference_id: PMID:20427700
    review:
      summary: Same PMID attribution issue as above.
      action: UNDECIDED
      reason: Cannot verify due to apparent PMID misattribution.
      supported_by:
        - reference_id: PMID:20427700
          supporting_text: 'Validation of the health ABC heart failure model for incident
            heart failure risk prediction: the Cardiovascular Health Study.'
  - term:
      id: GO:0034626
      label: fatty acid elongation, polyunsaturated fatty acid
    evidence_type: IDA
    original_reference_id: PMID:20427700
    review:
      summary: Same PMID attribution issue as above.
      action: UNDECIDED
      reason: Cannot verify due to apparent PMID misattribution.
      supported_by:
        - reference_id: PMID:20427700
          supporting_text: 'Validation of the health ABC heart failure model for incident
            heart failure risk prediction: the Cardiovascular Health Study.'
  - term:
      id: GO:0042761
      label: very long-chain fatty acid biosynthetic process
    evidence_type: IDA
    original_reference_id: PMID:20427700
    review:
      summary: Same PMID attribution issue as above.
      action: UNDECIDED
      reason: Cannot verify due to apparent PMID misattribution.
      supported_by:
        - reference_id: PMID:20427700
          supporting_text: 'Validation of the health ABC heart failure model for incident
            heart failure risk prediction: the Cardiovascular Health Study.'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20937905
    review:
      summary: Interaction with unspecified partner detected in the context of 
        the systematic ELOVL characterization study.
      action: REMOVE
      reason: Per guidelines, generic protein binding annotations are 
        uninformative. The main contribution of this paper is the enzymatic 
        characterization, not protein interactions.
      supported_by:
        - reference_id: PMID:20937905
          supporting_text: ELOVL1 production of C24 acyl-CoAs is linked to C24 
            sphingolipid synthesis.
  - term:
      id: GO:0005783
      label: endoplasmic reticulum
    evidence_type: IDA
    original_reference_id: PMID:20937905
    review:
      summary: ER localization demonstrated in the systematic ELOVL 
        characterization study.
      action: ACCEPT
      reason: Direct experimental evidence consistent with known biology.
      supported_by:
        - reference_id: PMID:20937905
          supporting_text: ELOVL1 production of C24 acyl-CoAs is linked to C24 
            sphingolipid synthesis.
references:
  - id: GO_REF:0000002
    title: Gene Ontology annotation through association of InterPro records with
      GO terms
    findings: []
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings:
      - statement: Phylogenetic inference of ELOVL family functions including 
          fatty acid elongase activity, ER membrane localization, and 
          involvement in fatty acid elongation processes.
  - 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:0000052
    title: Gene Ontology annotation based on curation of immunofluorescence data
    findings: []
  - id: GO_REF:0000104
    title: Electronic Gene Ontology annotations created by transferring manual 
      GO annotations between related proteins based on shared sequence features
    findings: []
  - id: GO_REF:0000117
    title: Electronic Gene Ontology annotations created by ARBA machine learning
      models
    findings: []
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods
    findings: []
  - id: PMID:10970790
    title: Cloning of a human cDNA encoding a novel enzyme involved in the 
      elongation of long-chain polyunsaturated fatty acids.
    findings:
      - statement: Original cloning and characterization of ELOVL5 (then called 
          HELO1)
      - statement: Demonstrated elongation of gamma-linolenic acid, 
          alpha-linolenic acid, stearidonic acid, arachidonic acid, and EPA
      - statement: Showed highest expression in adrenal gland and testis
      - statement: Localized gene to chromosome 6
  - id: PMID:19946888
    title: Defining the membrane proteome of NK cells.
    findings:
      - statement: Proteomics identification of ELOVL5 as membrane protein
  - id: PMID:20427700
    title: Validation of the health ABC heart failure model for incident heart 
      failure risk prediction - The Cardiovascular Health Study.
    findings: []
  - id: PMID:20937905
    title: ELOVL1 production of C24 acyl-CoAs is linked to C24 sphingolipid 
      synthesis.
    findings:
      - statement: Systematic in vitro characterization of all ELOVL substrate 
          specificities
      - statement: Demonstrated ELOVL5 preference for PUFA substrates
      - statement: Showed ELOVL1 (not ELOVL5) is responsible for C24 
          sphingolipid synthesis
      - statement: Confirmed ER membrane localization
  - id: PMID:23749231
    title: MicroRNA-30c reduces hyperlipidemia and atherosclerosis in mice by 
      decreasing lipid synthesis and lipoprotein secretion.
    findings:
      - statement: siELOVL5 knockdown reduced de novo lipogenesis
      - statement: ELOVL5 is a target of miR-30c regulation
      - statement: Demonstrated role in hepatic lipid synthesis
  - id: PMID:25065913
    title: ELOVL5 mutations cause spinocerebellar ataxia 38.
    findings:
      - statement: Identified ELOVL5 mutations as cause of SCA38
      - statement: Showed reduced arachidonic acid and DHA in patient serum
      - statement: Demonstrated high expression in Purkinje cells (soma and 
          dendrites)
      - statement: Wild-type localizes to ER; mutants show abnormal Golgi 
          accumulation
  - id: PMID:32296183
    title: A reference map of the human binary protein interactome.
    findings:
      - statement: High-throughput identification of ELOVL5 protein interactions
  - id: PMID:38422897
    title: The 3-hydroxyacyl-CoA dehydratase 1/2 form complex with 
      trans-2-enoyl-CoA reductase involved in substrates transfer in very long 
      chain fatty acid elongation.
    findings:
      - statement: Demonstrated ELOVL5 interaction with TECR
      - statement: Supports model of coordinated elongation cycle enzyme complex
  - id: Reactome:R-HSA-2046083
    title: Elongation of arachidonyl-CoA to docosatetraenoyl-CoA
    findings:
      - statement: ELOVL5 catalyzes this specific elongation reaction
  - id: Reactome:R-HSA-2046088
    title: Elongation of stearidonoyl-CoA to eicosatetraenoyl-CoA
    findings:
      - statement: ELOVL5 involved in n-3 PUFA pathway
  - id: Reactome:R-HSA-2046094
    title: Elongation of gamma-lenolenoyl-CoA to dihomo-gamma-lenolenoyl-CoA
    findings:
      - statement: Key step in n-6 PUFA pathway (GLA to DGLA)
  - id: Reactome:R-HSA-2046100
    title: Elongation of eicosapentaenoyl-CoA to docosapentaenoyl-CoA
    findings:
      - statement: ELOVL5 elongates EPA toward DHA synthesis
  - id: Reactome:R-HSA-2046105
    title: Linoleic acid (LA) metabolism
    findings:
      - statement: ELOVL5 functions in n-6 PUFA synthesis pathway from dietary 
          linoleic acid
  - id: Reactome:R-HSA-2046106
    title: alpha-linolenic acid (ALA) metabolism
    findings:
      - statement: ELOVL5 functions in n-3 PUFA synthesis pathway from dietary 
          ALA
  - id: Reactome:R-HSA-548800
    title: ELOVL1,2,3,5 elongate AA-CoA and Mal-CoA to 3ODCT-CoA
    findings:
      - statement: ELOVL5 contributes to arachidonate elongation
  - id: Reactome:R-HSA-75876
    title: Synthesis of very long-chain fatty acyl-CoAs
    findings:
      - statement: ELOVL5 is one of seven ELOVL elongases in the VLCFA synthesis
          pathway
  - id: file:human/ELOVL5/ELOVL5-deep-research-falcon.md
    title: Deep research report on ELOVL5
    findings: []
core_functions:
  - molecular_function:
      id: GO:0009922
      label: fatty acid elongase activity
    description: ELOVL5 catalyzes the rate-limiting condensation step of the 
      VLCFA elongation cycle, condensing acyl-CoA substrates with malonyl-CoA to
      produce 3-ketoacyl-CoA intermediates (EC 2.3.1.199). This is the first of 
      four enzymatic steps in the ER-localized elongation cycle that adds two 
      carbons per cycle.
  - molecular_function:
      id: GO:0009922
      label: fatty acid elongase activity
    directly_involved_in:
      - id: GO:0034626
        label: fatty acid elongation, polyunsaturated fatty acid
      - id: GO:0042761
        label: very long-chain fatty acid biosynthetic process
    locations:
      - id: GO:0005789
        label: endoplasmic reticulum membrane
    description: ELOVL5 preferentially elongates C18-C20 polyunsaturated fatty 
      acids of both n-3 and n-6 series. Key substrates include gamma-linolenic 
      acid (18:3n-6), alpha-linolenic acid (18:3n-3), stearidonic acid 
      (18:4n-3), arachidonic acid (20:4n-6), and EPA (20:5n-3). This activity is
      essential for endogenous synthesis of longer-chain PUFAs that serve as 
      membrane lipid components and eicosanoid/docosanoid precursors.
  - molecular_function:
      id: GO:0009922
      label: fatty acid elongase activity
    directly_involved_in:
      - id: GO:0036109
        label: alpha-linolenic acid metabolic process
      - id: GO:0043651
        label: linoleic acid metabolic process
    locations:
      - id: GO:0005789
        label: endoplasmic reticulum membrane
    description: ELOVL5 elongates intermediates in n-3 and n-6 PUFA biosynthesis
      pathways. It converts alpha-linolenic acid-derived intermediates toward 
      EPA and DHA synthesis, and gamma-linolenic acid to DGLA in the n-6 
      pathway. Loss-of-function mutations reduce serum AA and DHA levels, 
      confirming the essential role in these pathways.
proposed_new_terms: []
suggested_questions:
  - question: What is the specific role of ELOVL5-derived PUFAs in membrane 
      lipid composition and ferroptosis sensitivity? Recent studies suggest 
      ELOVL5 knockdown sensitizes cancer cells to ferroptosis. The deep research
      mentions ELOVL5 modulates ferroptosis sensitivity in breast cancer cells 
      (Nikulin et al. 2023).
    experts: []
  - question: What accounts for the selective vulnerability of cerebellar 
      Purkinje cells in SCA38 caused by ELOVL5 mutations? ELOVL5 is ubiquitously
      expressed but mutations specifically cause cerebellar ataxia.
    experts:
      - Brusco A
      - Di Gregorio E
suggested_experiments:
  - hypothesis: ELOVL5 deficiency will reduce incorporation of C20-C22 PUFAs 
      into membrane phospholipids, potentially altering membrane fluidity and 
      susceptibility to oxidative damage.
    description: Lipidomic profiling of membrane phospholipids in ELOVL5 
      knockout/knockdown cells compared to wild-type, with particular attention 
      to PUFA-containing species that are susceptible to lipid peroxidation.
  - hypothesis: Exogenous DHA should bypass the need for ELOVL5-dependent 
      elongation and restore normal membrane lipid composition and cellular 
      function.
    description: Test whether DHA supplementation can rescue ELOVL5 deficiency 
      phenotypes, since ELOVL5 is upstream of DHA synthesis.
tags:
  - ferroptosis

ELOVL5

Gene Description

Existing Annotations Review

Core Functions

ELOVL5 catalyzes the rate-limiting condensation step of the VLCFA elongation cycle, condensing acyl-CoA substrates with malonyl-CoA to produce 3-ketoacyl-CoA intermediates (EC 2.3.1.199). This is the first of four enzymatic steps in the ER-localized elongation cycle that adds two carbons per cycle.

References

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Deep Research Falcon

Question

Gene Research for Functional Annotation

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Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

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

Research Target:

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