ELOVL1 (Q9BW60, HGNC:14418) — review notes

Identity and family

• ELOVL1 = "Very long chain fatty acid elongase 1"; AltNames include "3-keto acyl-CoA synthase ELOVL1", "Very long chain 3-ketoacyl-CoA synthase 1", "Very long chain 3-oxoacyl-CoA synthase 1", "Elongation of very long chain fatty acids protein 1". EC 2.3.1.199. Synonym SSC1; ORF name CGI-88. [file:human/ELOVL1/ELOVL1-uniprot.txt "RecName: Full=Very long chain fatty acid elongase 1"; "AltName: Full=Very long chain 3-oxoacyl-CoA synthase 1"]
• 279 aa, chromosome 1 (ENSG00000066322), MANE NM_022821.4. Multi-pass ER membrane protein (7 predicted TM helices). Belongs to the ELO family, ELOVL1 subfamily. [file:human/ELOVL1/ELOVL1-uniprot.txt "Belongs to the ELO family. ELOVL1 subfamily."]

Molecular function (condensation / first step of the VLCFA elongation cycle)

• ELOVL1 catalyzes the FIRST and RATE-LIMITING of the four reactions of the long-chain fatty acid elongation cycle, an ER-bound process that adds 2 carbons per cycle to long- and very-long-chain fatty acids (VLCFAs). It is a condensing enzyme active toward saturated and monounsaturated acyl-CoA substrates, with highest activity toward C22:0 acyl-CoA. [file:human/ELOVL1/ELOVL1-uniprot.txt "Catalyzes the first and rate-limiting reaction of the four reactions that constitute the long-chain fatty acids elongation cycle"; "Condensing enzyme that exhibits activity toward saturated and monounsaturated acyl-CoA substrates, with the highest activity towards C22:0 acyl-CoA."]
• Catalytic activity (general): a very-long-chain acyl-CoA + malonyl-CoA + H(+) = a very-long-chain 3-oxoacyl-CoA + CO2 + CoA (RHEA:32727, EC 2.3.1.199). Specific reactions in UniProt cover C18→C20, C20→C22, C22→C24, C24→C26, C26→C28, and the monounsaturated equivalents (11Z-C20→C22, 13Z-C22→C24). [file:human/ELOVL1/ELOVL1-uniprot.txt "Reaction=a very-long-chain acyl-CoA + malonyl-CoA + H(+) = a very-long-chain 3-oxoacyl-CoA + CO2 + CoA"]
• GO term GO:0009922 "fatty acid elongase activity" has a definition that IS this exact reaction ("a very-long-chain acyl-CoA + H+ + malonyl-CoA = a very-long-chain 3-oxoacyl-CoA + CO2 + CoA … the first (condensation) step of the four-step fatty acid elongation cycle") [OLS GO:0009922]. This is the correct/best-supported MF for the ELOVL1 condensing step. Chosen as the core MF.

Substrate specificity / chain-length role

• ELOVL1 is the elongase that produces C24–C26 saturated and monounsaturated VLCFAs: it is the single elongase catalyzing synthesis of both saturated C26:0 and monounsaturated C26:1. Overexpression in yeast Δelo3 and in CHO cells markedly increased C24:0, C26:0, C28:0, C26:1; knockdown reduced elongation of C22:0→C26:0 and lowered C26:0 in X-ALD fibroblasts. [PMID:20166112 "We identify ELOVL1 (elongation of very-long-chain-fatty acids) as the single elongase catalysing the synthesis of both saturated VLCFA (C26:0) and mono-unsaturated VLCFA (C26:1)."; "ELOVL1 knockdown reduces elongation of C22:0 to C26:0 and lowers C26:0 levels in X-ALD fibroblasts."]
• In vitro substrate profiling of all seven ELOVLs: ELOVL1 has high activity toward saturated and monounsaturated C20- and C22-CoAs and is essential for production of C24 sphingolipids. PMID:20937905
• ELOVL1 preferentially elongates saturated fatty acyl-CoAs (Unifilter high-density elongase assay). PMID:19575253

Biological process

• VLCFA biosynthesis / fatty acid elongation: ELOVL1 with ELOVL6 accounts for elongation from LCFA to VLCFA; ELOVL6 does C18:0–C22:0, ELOVL1 does C24:0–C26:0. PMID:20166112
• Sphingolipid / ceramide biosynthesis: ELOVL1's C24-CoA production is linked to C24 sphingolipid synthesis and is co-regulated with the ceramide synthase CERS2. Loss of ELOVL1 activity (p.S165F) reduces ≥C24 ceramides and sphingomyelins. [PMID:20937905 "ELOVL1 production of C24 acyl-CoAs is linked to C24 sphingolipid synthesis"; "essential for the production of C24 sphingolipids"] PMID:30487246
• Skin barrier: VLCFAs/omega-O-acylceramides are important for the epidermal permeability barrier; the disease shows ichthyosis (epidermal hyperproliferation, increased keratinisation), and transcriptomics shows upregulation of epidermal-development/keratinisation modules. PMID:30487246

Subcellular location

• Endoplasmic reticulum membrane; multi-pass membrane protein; a C-terminal di-lysine motif may confer ER localization. [file:human/ELOVL1/ELOVL1-uniprot.txt "SUBCELLULAR LOCATION: Endoplasmic reticulum membrane"; "Multi-pass membrane protein"]

Interactions (elongase complex)

• Interacts with LASS2 (CERS2), HSD17B12 (KAR), and TECR — components of the ER VLCFA elongation machinery. [file:human/ELOVL1/ELOVL1-uniprot.txt "SUBUNIT: Interacts with LASS2 and HSD17B12. Interacts with TECR (PubMed:20937905, PubMed:38422897)."]
• The VLCFA elongation machinery is a four-component ER-membrane system: FA elongase (ELOVL), 3-ketoacyl-CoA reductase (KAR), 3-hydroxyacyl-CoA dehydratase (HACD), trans-2-enoyl-CoA reductase (TECR). PMID:38422897
• A physical interaction with GLP1R (P43220) was reported in a MYTH interactome screen (IntAct-sourced IPI). ELOVL1 is a bystander ER enzyme in that dataset, not a GLP-1 signaling component; bare "protein binding". [PMID:23864651 abstract: 38 novel GLP-1R interactor candidates from a MYTH screen]

Disease

• ELOVL1 variants cause Ichthyotic keratoderma, spasticity, hypomyelination, and dysmorphic facies (IKSHD; MIM:618527), autosomal dominant. Recurrent de novo p.Ser165Phe abrogates elongase activity (loss of function). [file:human/ELOVL1/ELOVL1-uniprot.txt "Ichthyotic keratoderma, spasticity, hypomyelination, and dysmorphic facies (IKSHD)"] PMID:29496980 PMID:30487246

Annotation review flags

• PMID:10970790 (Leonard et al. 2000, "HELO1"): the cached abstract describes cloning of a 299-aa human elongase on chromosome 6 that elongates long-chain POLYUNSATURATED FAs (GLA→DGLA etc.) — i.e. ELOVL5, NOT ELOVL1 (279 aa, chr 1, saturated/monounsaturated VLCFA). The GO:0009922 EXP annotation to ELOVL1 assigned by Reactome citing this paper appears to rest on a mis-attributed reference. Per curation policy an EXP annotation is not REMOVED on the basis of an abstract; the MF term itself (fatty acid elongase activity) is correct for ELOVL1 and abundantly supported by other EXP/IDA papers, so the annotation is kept (KEEP_AS_NON_CORE as a redundant EXP for the same MF) and the reference is flagged WRONG_IDENTIFIER/MISCITED in reference_review.
• GO:0034626 "fatty acid elongation, polyunsaturated fatty acid" (IBA only): ELOVL1 is specific for SATURATED and MONOUNSATURATED VLCFAs; PUFA elongation is the role of ELOVL2/ELOVL5. This IBA is an over-broad phylogenetic propagation → MARK_AS_OVER_ANNOTATED.
• Reactome LA/ALA metabolism TAS terms (GO:0043651 linoleic acid metabolic process; GO:0036109 alpha-linolenic acid metabolic process) and the two Reactome elongation reactions R-HSA-2046088/2046094 place ELOVL1 in PUFA (n-3/n-6) elongation pathways. ELOVL1 is not the principal PUFA elongase; keep as non-core (Reactome groups all four ELOVLs in these generic reactions).
• Bare "protein binding" GO:0005515 IPI (GLP1R PMID:23864651; TECR PMID:38422897; and PMID:20937905 with Q53GQ0/Q96G23/Q99190) → MARK_AS_OVER_ANNOTATED (uninformative; the biologically meaningful interactions with the elongase machinery are captured in notes/core functions).
• GO:0016020 "membrane" (IEA GO_REF:0000120; HDA PMID:19946888 NK-cell membrane proteomics) → too general vs ER membrane; MODIFY to endoplasmic reticulum membrane (GO:0005789).