ACSL6

Summary

ACSL6 (acyl-CoA synthetase long chain family member 6, HGNC:16496) is a protein-coding gene on chromosome 5q31.1, encoding Long-chain-fatty-acid–CoA ligase 6 (Q9UKU0). Catalyzes the conversion of long-chain fatty acids to their active form acyl-CoA for both synthesis of cellular lipids, and degradation via beta-oxidation.

The protein encoded by this gene catalyzes the formation of acyl-CoA from fatty acids, ATP, and CoA, using magnesium as a cofactor. The encoded protein plays a major role in fatty acid metabolism in the brain. Translocations with the ETV6 gene are causes of myelodysplastic syndrome with basophilia, acute myelogenous leukemia with eosinophilia, and acute eosinophilic leukemia. Several transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 23305 — RefSeq curated summary.

At a glance

• GWAS associations: 11
• Clinical variants (ClinVar): 101 total — 4 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 1
• Druggable target: yes
• Cancer driver (intOGen): activating (oncogene-like) across 1 cancer types
• MANE Select transcript: NM_001009185

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16496
Approved symbol	ACSL6
Name	acyl-CoA synthetase long chain family member 6
Location	5q31.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0837, ACS2, LACS5, LACS2
Ensembl gene	ENSG00000164398
Ensembl biotype	protein_coding
OMIM	604443
Entrez	23305

Gene structure

Transcript identifiers

Ensembl transcripts: 37 — 22 protein_coding, 8 retained_intron, 6 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000296869, ENST00000357096, ENST00000379240, ENST00000379244, ENST00000379246, ENST00000379255, ENST00000414078, ENST00000416557, ENST00000419502, ENST00000430403, ENST00000431707, ENST00000434099, ENST00000441995, ENST00000469164, ENST00000477640, ENST00000484870, ENST00000489047, ENST00000492156, ENST00000493861, ENST00000543479, ENST00000650697, ENST00000650912, ENST00000651086, ENST00000651127, ENST00000651250, ENST00000651269, ENST00000651356, ENST00000651427, ENST00000651454, ENST00000651597, ENST00000651883, ENST00000652375, ENST00000652424, ENST00000652493, ENST00000897429, ENST00000923559, ENST00000959336

RefSeq mRNA: 22 — MANE Select: NM_001009185 NM_001009185, NM_001205247, NM_001205248, NM_001205250, NM_001205251, NM_001405475, NM_001405476, NM_001405477, NM_001405478, NM_001405479, NM_001405480, NM_001405481, NM_001405482, NM_001405483, NM_001405484, NM_001405485, NM_001405486, NM_001405487, NM_001405488, NM_001405489, NM_001405490, NM_015256

CCDS: CCDS34228, CCDS34229, CCDS56381, CCDS56382, CCDS56383

Canonical transcript exons

ENST00000651883 — 21 exons

Exon	Start	End
ENSE00001480341	131974893	131974970
ENSE00003483946	131994031	131994251
ENSE00003775563	131989407	131989508
ENSE00003775662	131990100	131990164
ENSE00003775673	131986822	131986854
ENSE00003776032	131985407	131985458
ENSE00003776301	131970128	131970200
ENSE00003777029	131960520	131960621
ENSE00003777060	131973266	131973400
ENSE00003777232	131988805	131988904
ENSE00003778018	131966416	131966532
ENSE00003778660	131976648	131976721
ENSE00003779963	131990853	131990967
ENSE00003781026	131972724	131972858
ENSE00003781353	131988048	131988226
ENSE00003781470	131971550	131971645
ENSE00003782088	131959536	131959607
ENSE00003782369	131962535	131962678
ENSE00003783375	131967940	131968028
ENSE00003899347	132011505	132011658
ENSE00003901140	131949973	131954371

Expression profiles

Bgee: expression breadth ubiquitous, 210 present calls, max score 95.86.

FANTOM5 (CAGE): breadth broad, TPM avg 2.7717 / max 121.6864, expressed in 249 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
63289	1.1759	149
63279	0.6382	77
63286	0.2660	79
63287	0.1838	72
63283	0.1384	22
63280	0.1236	47
63291	0.0771	42
63290	0.0612	43
63285	0.0467	10
63292	0.0259	16

Top tissues by expression

295 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
lateral nuclear group of thalamus	UBERON:0002736	95.86	gold quality
Brodmann (1909) area 23	UBERON:0013554	95.54	gold quality
primary visual cortex	UBERON:0002436	93.35	gold quality
right hemisphere of cerebellum	UBERON:0014890	92.94	gold quality
occipital lobe	UBERON:0002021	92.38	gold quality
cerebellar hemisphere	UBERON:0002245	92.33	gold quality
cerebellar cortex	UBERON:0002129	92.28	gold quality
pons	UBERON:0000988	92.12	gold quality
seminal vesicle	UBERON:0000998	91.24	gold quality
cerebellum	UBERON:0002037	91.24	gold quality
Brodmann (1909) area 9	UBERON:0013540	90.17	gold quality
endothelial cell	CL:0000115	90.06	gold quality
right frontal lobe	UBERON:0002810	90.06	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	90.05	gold quality
left testis	UBERON:0004533	89.82	gold quality
prefrontal cortex	UBERON:0000451	89.76	gold quality
lateral globus pallidus	UBERON:0002476	89.75	gold quality
parietal lobe	UBERON:0001872	89.60	gold quality
frontal cortex	UBERON:0001870	89.30	gold quality
postcentral gyrus	UBERON:0002581	89.24	gold quality
caudate nucleus	UBERON:0001873	89.17	gold quality
right testis	UBERON:0004534	89.04	gold quality
superior frontal gyrus	UBERON:0002661	88.99	gold quality
amygdala	UBERON:0001876	88.96	gold quality
neocortex	UBERON:0001950	88.87	gold quality
nucleus accumbens	UBERON:0001882	88.44	gold quality
cingulate cortex	UBERON:0003027	88.25	gold quality
cerebral cortex	UBERON:0000956	88.19	gold quality
telencephalon	UBERON:0001893	88.18	gold quality
anterior cingulate cortex	UBERON:0009835	88.09	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-10283	yes	165.76
E-ANND-3	yes	14.08
E-GEOD-84465	yes	10.66
E-CURD-135	no	1311.49
E-ENAD-27	no	3.43

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): PPARD

miRNA regulators (miRDB)

207 targeting ACSL6, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-5696	99.98	72.36	4487
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-4789-5P	99.98	70.76	2721

Literature-anchored findings (GeneRIF, showing 13)

• The t(5;12)(q23-31;p13)translocation with ETV6-ACSL6 genomic alteration rearrangement in polycythemia vera patients was reported. (PMID:16572202)
• Analyses did not yield convincing evidence for associations of schizophrenia with ACSL6 (PMID:16827919)
• Three ACSL6 spliced variants of a mutually exclusive exon pair are reported, they encode a slightly different short motif which contains a conserved structural domain, the fatty acid Gate domain. (PMID:16834775)
• haplotypes underlying the SPEC2/PDZ-GEF2/ACSL6 region are associated with schizophrenia (PMID:17030554)
• The acyl-coenzyme A synthetase long-chain family member 6 (ACSL6) gene on chromosome 5q31 was associated with premature ovarian failure and identified disease-susceptibility haplotypes. (PMID:18555221)
• ACSL6 is highly associated with schizophrenia and several haplotypes in this haploblock have about twofold to 10-fold increase in the affected subjects in Han Chinese. (PMID:18718982)
• The alternative fatty acid Gate-domain motifs are essential determinants for the activity of the human ACSL6 isoforms, which appear to act as homodimeric enzyme as well as in complex with other spliced forms. (PMID:20429931)
• variations in the ACSL6 gene may contribute to the quantity of cigarettes smoked (PMID:22205969)
• ACSL6 drives acyl-CoA toward lipid synthesis and its downregulation improves mitochondrial biogenesis, respiratory capacity and lipid oxidation (PMID:27647415)
• The results of this study indicate that ACSL6 contributes to the local accumulation of docosahexaenoic acid and docosapentaenoic acid containing phospholipids in spermatids to support normal spermatogenesis (PMID:31648559)
• Substrate Specificity of Human Long-Chain Acyl-CoA Synthetase ACSL6 Variants. (PMID:34602568)
• ETV6::ACSL6 translocation-driven super-enhancer activation leads to eosinophilia in acute lymphoblastic leukemia through IL-3 overexpression. (PMID:38356460)
• ACSL6-activated IL-18R1-NF-kappaB promotes IL-18-mediated tumor immune evasion and tumor progression. (PMID:39292786)

Cross-species orthologs

30 orthologs

Organism	Symbol	Gene ID
danio_rerio	slc27a2a	ENSDARG00000036237
danio_rerio	acsl2	ENSDARG00000078399
mus_musculus	Acsl6	ENSMUSG00000020333
rattus_norvegicus	Acsl6	ENSRNOG00000026745
drosophila_melanogaster	bgm	FBGN0027348
drosophila_melanogaster	pdgy	FBGN0027601
drosophila_melanogaster	CG8834	FBGN0033733
drosophila_melanogaster	CG17999	FBGN0034552
drosophila_melanogaster	CG9993	FBGN0034553
drosophila_melanogaster	Fatp3	FBGN0034999
drosophila_melanogaster	CG4563	FBGN0035006
drosophila_melanogaster	CG5568	FBGN0035641
drosophila_melanogaster	CG18586	FBGN0035642
drosophila_melanogaster	CG4830	FBGN0037996
drosophila_melanogaster	Acsx1L	FBGN0038730
drosophila_melanogaster	Acsx1R	FBGN0038731
drosophila_melanogaster	Acsx2	FBGN0038732
drosophila_melanogaster	Acsx3	FBGN0038733
drosophila_melanogaster	Acsx4	FBGN0038734
drosophila_melanogaster	Acsl	FBGN0263120
drosophila_melanogaster	Fatp2	FBGN0265187
drosophila_melanogaster	Fatp1	FBGN0267828
drosophila_melanogaster	hll	FBGN0286723
caenorhabditis_elegans		WBGENE00007082
caenorhabditis_elegans		WBGENE00008669
caenorhabditis_elegans		WBGENE00009218
caenorhabditis_elegans		WBGENE00011173
caenorhabditis_elegans		WBGENE00016716
caenorhabditis_elegans		WBGENE00019920
caenorhabditis_elegans		WBGENE00022849

Paralogs (12): ACSL4 (ENSG00000068366), SLC27A5 (ENSG00000083807), ACSBG1 (ENSG00000103740), SLC27A6 (ENSG00000113396), ACSL3 (ENSG00000123983), SLC27A1 (ENSG00000130304), ACSBG2 (ENSG00000130377), SLC27A2 (ENSG00000140284), SLC27A3 (ENSG00000143554), ACSL1 (ENSG00000151726), SLC27A4 (ENSG00000167114), ACSL5 (ENSG00000197142)

Protein

Protein identifiers

Long-chain-fatty-acid–CoA ligase 6 — Q9UKU0 (reviewed: Q9UKU0)

Alternative names: Arachidonate–CoA ligase, Long-chain acyl-CoA synthetase 6

All UniProt accessions (18): A0A494BZW8, A0A494C005, A0A494C046, A0A494C0A5, A0A494C0B6, A0A494C0D5, A0A494C0J9, A0A494C0V0, A0A494C1I9, A0A499FJL5, C9J3Z0, C9J4I1, C9J8C7, C9JK59, C9JPA5, C9JT10, E7ERD7, Q9UKU0

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the conversion of long-chain fatty acids to their active form acyl-CoA for both synthesis of cellular lipids, and degradation via beta-oxidation. Plays an important role in fatty acid metabolism in brain and the acyl-CoAs produced may be utilized exclusively for the synthesis of the brain lipid.

Subcellular location. Mitochondrion outer membrane. Peroxisome membrane. Microsome membrane. Endoplasmic reticulum membrane.

Tissue specificity. Expressed predominantly in erythrocyte precursors, in particular in reticulocytes, fetal blood cells derived from fetal liver, hemopoietic stem cells from cord blood, bone marrow and brain.

Disease relevance. A chromosomal aberration involving ACSL6 may be a cause of myelodysplastic syndrome with basophilia. Translocation t(5;12)(q31;p13) with ETV6. A chromosomal aberration involving ACSL6 may be a cause of acute myelogenous leukemia with eosinophilia. Translocation t(5;12)(q31;p13) with ETV6. A chromosomal aberration involving ACSL6 may be a cause of acute eosinophilic leukemia (AEL). Translocation t(5;12)(q31;p13) with ETV6.

Similarity. Belongs to the ATP-dependent AMP-binding enzyme family.

Isoforms (9)

UniProt ID	Names	Canonical?
Q9UKU0-4	4	yes
Q9UKU0-1	1, Long, v2
Q9UKU0-2	2, Short
Q9UKU0-3	3
Q9UKU0-5	5, v4
Q9UKU0-6	6, v5
Q9UKU0-7	7, v3
Q9UKU0-8	8, v1
Q9UKU0-9	9

RefSeq proteins (22): NP_001009185, NP_001192176, NP_001192177, NP_001192179, NP_001192180, NP_001392404, NP_001392405, NP_001392406, NP_001392407, NP_001392408, NP_001392409, NP_001392410, NP_001392411, NP_001392412, NP_001392413, NP_001392414, NP_001392415, NP_001392416, NP_001392417, NP_001392418, NP_001392419, NP_056071 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000873	AMP-dep_synth/lig_dom	Domain
IPR020845	AMP-binding_CS	Conserved_site
IPR042099	ANL_N_sf	Homologous_superfamily
IPR045311	LC-FACS_euk	Family

Pfam: PF00501

Enzyme classification (BRENDA):

• EC 6.2.1.3 — long-chain-fatty-acid-CoA ligase (BRENDA: 48 organisms, 205 substrates, 100 inhibitors, 159 Km, 11 kcat entries)

Substrate kinetics (BRENDA)

48 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.025–12.21	28
COA	0.0005–4.7	21
PALMITATE	0.0002–6	19
OLEATE	0.0014–3	9
ARACHIDONATE	0.0065–9.7	6
STEARATE	0.0002–0.12	6
DECANOATE	0.004–0.0083	4
LAURATE	0.0005–0.002	4
LINOLEATE	0.0022–0.041	4
MYRISTATE	0.0002–0.0024	4
OCTANOATE	0.0007–0.0408	4
LAURIC ACID	0.0017–0.0163	3
LINOLENATE	0.0016–0.0073	2
OCTADECANOATE	0.061–0.072	2
PALMITOLEATE	0.0015–0.002	2

Catalyzed reactions (Rhea), 7 shown:

• a long-chain fatty acid + ATP + CoA = a long-chain fatty acyl-CoA + AMP + diphosphate (RHEA:15421)
• (5Z,8Z,11Z,14Z)-eicosatetraenoate + ATP + CoA = (5Z,8Z,11Z,14Z)-eicosatetraenoyl-CoA + AMP + diphosphate (RHEA:19713)
• hexadecanoate + ATP + CoA = hexadecanoyl-CoA + AMP + diphosphate (RHEA:30751)
• (E)-hexadec-2-enoate + ATP + CoA = (2E)-hexadecenoyl-CoA + AMP + diphosphate (RHEA:36139)
• 5-hydroxy-(6E,8Z,11Z,14Z)-eicosatetraenoate + ATP + CoA = 5-hydroxy-(6E,8Z,11Z,14Z)-eicosatetraenoyl-CoA + AMP + diphosphate (RHEA:52108)
• 12-hydroxy-(5Z,8Z,10E,14Z)-eicosatetraenoate + ATP + CoA = 12-hydroxy-(5Z,8Z,10E,14Z)-eicosatetraenoyl-CoA + AMP + diphosphate (RHEA:52112)
• 15-hydroxy-(5Z,8Z,11Z,13E)-eicosatetraenoate + ATP + CoA = 15-hydroxy-(5Z,8Z,11Z,13E)-eicosatetraenoyl-CoA + AMP + diphosphate (RHEA:52116)

UniProt features (17 total): splice variant 8, sequence conflict 6, chain 1, transmembrane region 1, topological domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UKU0-F1	90.15	0.66

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-75876	Synthesis of very long-chain fatty acyl-CoAs
R-HSA-1430728	Metabolism
R-HSA-556833	Metabolism of lipids
R-HSA-75105	Fatty acyl-CoA biosynthesis
R-HSA-8978868	Fatty acid metabolism

MSigDB gene sets: 250 (showing top): GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_DN, REACTOME_SYNTHESIS_OF_VERY_LONG_CHAIN_FATTY_ACYL_COAS, ACTACCT_MIR196A_MIR196B, KEGG_ADIPOCYTOKINE_SIGNALING_PATHWAY, YAGI_AML_WITH_INV_16_TRANSLOCATION, GOBP_NEUROGENESIS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_LONG_CHAIN_FATTY_ACID_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GNF2_ANK1, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_NEURAL_PRECURSOR_CELL_PROLIFERATION, MODULE_66

GO Biological Process (7): very long-chain fatty acid metabolic process (GO:0000038), long-chain fatty acid metabolic process (GO:0001676), acyl-CoA metabolic process (GO:0006637), neuroblast proliferation (GO:0007405), long-chain fatty-acyl-CoA biosynthetic process (GO:0035338), lipid metabolic process (GO:0006629), fatty acid metabolic process (GO:0006631)

GO Molecular Function (8): long-chain fatty acid-CoA ligase activity (GO:0004467), ATP binding (GO:0005524), enzyme binding (GO:0019899), protein homodimerization activity (GO:0042803), arachidonate-CoA ligase activity (GO:0047676), nucleotide binding (GO:0000166), protein binding (GO:0005515), ligase activity (GO:0016874)

GO Cellular Component (8): mitochondrial outer membrane (GO:0005741), peroxisomal membrane (GO:0005778), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), membrane (GO:0016020), mitochondrion (GO:0005739), peroxisome (GO:0005777)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Fatty acyl-CoA biosynthesis	1
Metabolism	1
Fatty acid metabolism	1
Metabolism of lipids	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
fatty acid metabolic process	2
cytoplasm	2
intracellular membrane-bounded organelle	2
nucleoside phosphate metabolic process	1
sulfur compound metabolic process	1
purine-containing compound metabolic process	1
generation of neurons	1
neural precursor cell proliferation	1
long-chain fatty-acyl-CoA metabolic process	1
fatty-acyl-CoA biosynthetic process	1
primary metabolic process	1
lipid metabolic process	1
monocarboxylic acid metabolic process	1
long-chain fatty acid metabolic process	1
fatty acid-CoA ligase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
protein binding	1
identical protein binding	1
protein dimerization activity	1
long-chain fatty acid-CoA ligase activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
catalytic activity	1
mitochondrial membrane	1
organelle outer membrane	1
peroxisome	1
microbody membrane	1
endomembrane system	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
membrane	1
cell periphery	1
cellular anatomical structure	1
microbody	1

Protein interactions and networks

STRING

2212 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ACSL6	CPT1A	P50416	852
ACSL6	DGAT1	O75907	821
ACSL6	AASDH	Q4L235	769
ACSL6	ETV6	P41212	706
ACSL6	ABCD1	P33897	695
ACSL6	PHYH	O14832	690
ACSL6	ACACA	Q13085	656
ACSL6	ABCD3	P28288	642
ACSL6	COASY	Q13057	642
ACSL6	ACSS1	Q9NUB1	632
ACSL6	CDC42SE2	Q9NRR3	599
ACSL6	ABL2	P42684	587
ACSL6	CD36	P16671	574
ACSL6	MN1	Q10571	571
ACSL6	SIRT3	Q9NTG7	564

IntAct

10 interactions, top by confidence:

A	B	Type	Score
ZNF16	ACSL6	psi-mi:“MI:0915”(physical association)	0.370
PB2	SEC15L3	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
PRPH2	TOR1A	psi-mi:“MI:0914”(association)	0.350
MFSD6L	ESYT2	psi-mi:“MI:0914”(association)	0.350
SLC10A2	CLGN	psi-mi:“MI:0914”(association)	0.350
SLC35F1	C15orf61	psi-mi:“MI:0914”(association)	0.350

BioGRID (14): ZNF655 (Two-hybrid), PCMTD2 (Two-hybrid), ACSL6 (Affinity Capture-MS), ACSL6 (Affinity Capture-MS), ACSL6 (Affinity Capture-MS), ACSL6 (Proximity Label-MS), ACSL6 (Affinity Capture-MS), ACSL6 (Affinity Capture-MS), ACSL6 (Affinity Capture-MS), ACSL6 (Affinity Capture-MS), ACSL6 (Reconstituted Complex), ACSL6 (Two-hybrid), ACSL6 (Reconstituted Complex), ACSL6 (Co-purification)

ESM2 similar proteins: A0A0U1WZ18, A3QK15, B9N1F9, D3ZVR9, E0CSI1, O70196, P00503, P00504, P05201, P08906, P33121, P33124, P40142, P50137, P50554, P54767, P61922, P78330, P80147, Q07346, Q14410, Q15124, Q1W377, Q28BL6, Q2KHU0, Q2KIG0, Q42472, Q42521, Q4R4D5, Q4R5L1, Q5R691, Q5RB83, Q5ZLG0, Q6P1N9, Q6P8M1, Q7TN78, Q80W40, Q86V21, Q8BZF8, Q8K183

Diamond homologs: A0A0C1BUW8, A0A0C1E3B7, A0A0S1RUN4, A0A0S2E7V8, A0A0S2E7W3, A0A0S2E7W7, A0A0S2E7X0, A0A0S2E7Z1, A0A1B5L6A0, A0A336U965, A0A6F9DYX9, A7XRY0, B2HGV4, B7STY1, B8MYS6, F8P1W3, I6NXV7, I6X8D2, J4UHQ6, M4IS92, O53521, P39581, P44446, P9WES4, P9WEZ0, Q03133, Q0CBN5, Q0CRX1, Q0CT94, Q0CU19, Q0CWD0, Q0D034, Q0D1N9, Q0UI00, Q1MWN4, Q5B7T4, Q65DH1, Q7TYX8, Q8W471, Q9FFE9

SIGNOR signaling

0 interactions.

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 1 cancer types — LIPO.

Clinical variants and AI predictions

ClinVar

101 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	2
Uncertain significance	73
Likely benign	7
Benign	4

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
2506534	GRCh37/hg19 5q23.3-31.1(chr5:127800418-134002686)	Pathogenic
3242297	GRCh37/hg19 5q23.2-31.1(chr5:124864529-134720575)x1	Pathogenic
59673	GRCh38/hg38 5q23.1-31.1(chr5:116677122-132686163)x1	Pathogenic
830550	NC_000005.9:g.(?130497712)(131729974_?)del	Pathogenic
545310	NC_000005.10:g.(?131428263)(132208822_?)del	Likely pathogenic
624508	GRCh37/hg19 5q23.2-31.2(chr5:126377719-136270989)x1	Likely pathogenic

SpliceAI

3990 predictions. Top by Δscore:

Variant	Effect	Δscore
5:131954224:T:A	donor_gain	1.0000
5:131959619:CA:C	acceptor_gain	1.0000
5:131959620:A:C	acceptor_gain	1.0000
5:131972718:TCTTA:T	donor_loss	1.0000
5:131972719:CTTA:C	donor_loss	1.0000
5:131972720:TTA:T	donor_loss	1.0000
5:131972720:TTAC:T	donor_loss	1.0000
5:131972721:TA:T	donor_loss	1.0000
5:131972722:A:AG	donor_loss	1.0000
5:131972723:C:A	donor_loss	1.0000
5:131972856:GATC:G	acceptor_loss	1.0000
5:131972859:C:CC	acceptor_gain	1.0000
5:131972859:C:T	acceptor_loss	1.0000
5:131972860:T:G	acceptor_loss	1.0000
5:131973262:TTA:T	donor_loss	1.0000
5:131973262:TTAC:T	donor_loss	1.0000
5:131973263:TA:T	donor_loss	1.0000
5:131973264:A:AC	donor_gain	1.0000
5:131973264:AC:A	donor_gain	1.0000
5:131973265:C:A	donor_loss	1.0000
5:131973265:C:CT	donor_gain	1.0000
5:131973265:CC:C	donor_gain	1.0000
5:131973265:CCT:C	donor_gain	1.0000
5:131973265:CCTT:C	donor_gain	1.0000
5:131973265:CCTTG:C	donor_gain	1.0000
5:131973397:CAGA:C	acceptor_gain	1.0000
5:131973399:GA:G	acceptor_gain	1.0000
5:131973400:ACT:A	acceptor_loss	1.0000
5:131973401:C:A	acceptor_loss	1.0000
5:131973401:C:CC	acceptor_gain	1.0000

AlphaMissense

4719 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:131985415:C:T	G278D	1.000
5:131954303:T:A	K675N	0.999
5:131954303:T:G	K675N	0.999
5:131962634:T:A	K561N	0.999
5:131962634:T:G	K561N	0.999
5:131962636:T:C	K561E	0.999
5:131962653:C:G	R555P	0.999
5:131966436:C:G	D540H	0.999
5:131966519:C:T	G512E	0.999
5:131966520:C:G	G512R	0.999
5:131966520:C:T	G512R	0.999
5:131968019:C:T	G481E	0.999
5:131968020:C:A	G481W	0.999
5:131968020:C:G	G481R	0.999
5:131968020:C:T	G481R	0.999
5:131970163:C:T	G466E	0.999
5:131970171:G:C	C463W	0.999
5:131970184:C:T	G459D	0.999
5:131985416:C:G	G278R	0.999
5:131985417:G:C	S277R	0.999
5:131985417:G:T	S277R	0.999
5:131985419:T:G	S277R	0.999
5:131985428:A:G	C274R	0.999
5:131954304:T:A	K675I	0.998
5:131954305:T:C	K675E	0.998
5:131954319:A:G	L670P	0.998
5:131962614:A:T	V568D	0.998
5:131962632:A:G	L562P	0.998
5:131962668:A:T	L550H	0.998
5:131966424:A:G	W544R	0.998

dbSNP variants (sampled 300 via entrez): RS1000084300 (5:131984638 G>A), RS1000084358 (5:131952511 A>G), RS1000293556 (5:132010223 G>C,T), RS1000321415 (5:131980687 T>C), RS1000331249 (5:132007541 C>T), RS1000335874 (5:131977368 T>A), RS1000344371 (5:131966960 C>T), RS1000483953 (5:131986241 G>A), RS1000530874 (5:131988851 G>A,C), RS1000542938 (5:131956998 A>G,T), RS1000559732 (5:131992553 C>G), RS1000723445 (5:131975955 T>A,C,G), RS1000775705 (5:131976423 A>G), RS1000788519 (5:132001556 T>C), RS1000849949 (5:131961537 A>T)

Disease associations

OMIM: gene MIM:604443 | disease phenotypes: MIM:618354, MIM:181500, MIM:212140

GenCC curated gene-disease

Mondo (3): Houge-Janssens syndrome 3 (MONDO:0032697), schizophrenia (MONDO:0005090), systemic primary carnitine deficiency disease (MONDO:0008919)

Orphanet (2): Systemic primary carnitine deficiency (Orphanet:158), NON RARE IN EUROPE: Schizophrenia (Orphanet:3140)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0100753	Schizophrenia

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST001438_16	Crohn’s disease	4.000000e-08
GCST001725_83	Inflammatory bowel disease	1.000000e-52
GCST002817_22	Alzheimer’s disease in APOE e4- carriers	3.000000e-07
GCST002817_6	Alzheimer’s disease in APOE e4- carriers	2.000000e-07
GCST004131_32	Inflammatory bowel disease	4.000000e-27
GCST004132_10	Crohn’s disease	6.000000e-36
GCST004133_36	Ulcerative colitis	2.000000e-06
GCST004864_32	Perceived unattractiveness to mosquitoes	1.000000e-09
GCST010701_41	Cortical surface area (MOSTest)	1.000000e-20
GCST010702_96	Subcortical volume (MOSTest)	2.000000e-08
GCST010703_160	Brain morphology (MOSTest)	3.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0008380	perceived unattractiveness to mosquitos measurement
EFO:0004346	neuroimaging measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C536778	Systemic carnitine deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4680042 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

1 potent at pChembl≥5 of 3 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.21	IC50	6200	nM	CHEMBL4776019

PubChem BioAssay actives

1 with measured affinity, of 10 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
7-(9-oxoxanthen-2-yl)oxyheptanoic acid	1684043: Inhibition of recombinant human ACSL6 assessed as reduction in acetyl-coA prodution incubated for 60 mins in presence of Coenzyme A, ATP and MgCl2 by MALDI-TOF MS analysis	ic50	6.2000	uM

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, affects cotreatment, decreases expression, increases expression	3
Tetrachlorodibenzodioxin	increases expression	3
Valproic Acid	increases expression, increases methylation	3
bisphenol F	affects cotreatment, decreases methylation	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
benzo(b)fluoranthene	affects cotreatment, decreases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
methylparaben	increases expression	1
benz(a)anthracene	affects cotreatment, decreases expression	1
chrysene	affects cotreatment, decreases expression	1
butylparaben	increases expression	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
obeticholic acid	increases expression	1
nutlin 3	increases expression, affects cotreatment	1
quinocetone	increases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Acetaminophen	increases expression	1
Dactinomycin	affects cotreatment, increases expression	1
Diuron	decreases expression	1
Methamphetamine	affects response to substance	1
Methotrexate	increases expression	1
Quercetin	decreases expression	1
Urethane	decreases expression	1
Cyclosporine	decreases expression	1
Aflatoxin B1	decreases expression	1
Okadaic Acid	decreases expression	1
Copper Sulfate	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4678694	Binding	Inhibition of recombinant human ACSL6 assessed as reduction in acetyl-coA prodution incubated for 60 mins in presence of Coenzyme A, ATP and MgCl2 by MALDI-TOF MS analysis	Discovery of a benzimidazole series as the first highly potent and selective ACSL1 inhibitors. — Bioorg Med Chem Lett

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00000374	PHASE4	COMPLETED	Treatment for First-Episode Schizophrenia
NCT00001656	PHASE4	COMPLETED	Comparison of Clozapine vs Olanzapine in Childhood-Onset Psychotic Disorders
NCT00007774	PHASE4	COMPLETED	To Determine if Olanzapine is More Cost Effective Than Haloperidol for the Treatment of Schizophrenia
NCT00014001	PHASE4	COMPLETED	CATIE- Schizophrenia Trial
NCT00018668	PHASE4	COMPLETED	Antipsychotic Response in Schizophrenia
NCT00034801	PHASE4	COMPLETED	Olanzapine Versus Active Comparator in the Treatment of Depression in Patients With Schizophrenia
NCT00034905	PHASE4	COMPLETED	A Comparison of Seroquel vs. Risperidone in Schizophrenia
NCT00036088	PHASE4	COMPLETED	Olanzapine Versus An Active Comparator in the Treatment of Schizophrenia
NCT00044187	PHASE4	COMPLETED	The Assessment of a Weight-Gain Agent for the Treatment of Olanzapine-Associated Anti-Obesity Agent in Patients With Schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, and Bipolar I Disorder
NCT00044655	PHASE4	COMPLETED	Switching Medication to Treat Schizophrenia
NCT00048828	PHASE4	COMPLETED	Treating Drug-Resistant Childhood Schizophrenia
NCT00053703	PHASE4	COMPLETED	Treatment of Early Onset Schizophrenia Spectrum Disorders (TEOSS)
NCT00056498	PHASE4	COMPLETED	Risperidone Treatment in Schizophrenia Patients Who Are Currently Taking Clozapine
NCT00061802	PHASE4	COMPLETED	Efficacy and Safety of Two Atypical Antipsychotics vs. Placebo in Patients With an Acute Exacerbation of Either Schizophrenia or Schizoaffective Disorder
NCT00080327	PHASE4	COMPLETED	Study of Three Doses of Aripiprazole in Patients With Acute Schizophrenia
NCT00088049	PHASE4	COMPLETED	Study of Olanzapine vs. Aripiprazole in the Treatment of Schizophrenia
NCT00090012	PHASE4	COMPLETED	Comparison of Continuing Olanzapine to Switching to Quetiapine in Overweight or Obese Patients With Schizophrenia and Schizoaffective Disorder
NCT00100776	PHASE4	COMPLETED	Efficacy of High Dose Olanzapine for the Treatment of Schizophrenia and Schizoaffective Disorder
NCT00103571	PHASE4	COMPLETED	Olanzapine Versus Aripiprazole in the Treatment of Acutely Ill Patients With Schizophrenia
NCT00108368	PHASE4	COMPLETED	The Effects of Risperidone and Olanzapine on Thinking
NCT00114595	PHASE4	COMPLETED	Ethyl-Eicosapentaenoic Acid and Tardive Dyskinesia
NCT00130923	PHASE4	COMPLETED	Risperidone Long-acting Versus Oral Risperidone in Patients With Schizophrenia and Alcohol Use Disorder
NCT00137020	PHASE4	COMPLETED	Clinical Effect Of Cross Titration Of Antipsychotics With Ziprasidone In Schizophrenia Or Schizoaffective Disorder
NCT00140166	PHASE4	COMPLETED	Treatment of Acute Schizophrenia With Vitamin Therapy
NCT00145847	PHASE4	COMPLETED	Naltrexone Treatment of Alcohol Abuse in Schizophrenia
NCT00148564	PHASE4	COMPLETED	Energy Homeostasis Under Treatment With Atypical Antipsychotics
NCT00156715	PHASE4	COMPLETED	Efficacy of Quetiapine in the Treatment of Patients With Schizophrenia and a Comorbid Substance Use Disorder
NCT00158223	PHASE4	COMPLETED	Effectiveness of Pimozide in Augmenting the Effects of Clozapine in the Treatment of Schizophrenia
NCT00159081	PHASE4	COMPLETED	One Year Drug Treatment in First-Episode Schizophrenia
NCT00159120	PHASE4	COMPLETED	Maintenance Treatment vs. Stepwise Drug Discontinuation in First-Episode Schizophrenia
NCT00159133	PHASE4	COMPLETED	Prodrome-Based Early Intervention With Antipsychotics vs. Benzodiazepines in First-Episode Schizophrenia
NCT00159757	PHASE4	TERMINATED	12 Week Open, Non-Comparative Switch Study Of Oral Ziprazidone In Previously Treated Schizophrenic Patients
NCT00167817	PHASE4	COMPLETED	Effect of Switch to Aripiprazole on Health and Smoking Parameters in Patients With Schizophrenia: A Pilot Study
NCT00169026	PHASE4	TERMINATED	Alcoholism and Schizophrenia: Effects of Clozapine
NCT00169039	PHASE4	TERMINATED	Clozapine Versus Chlorpromazine for Treatment-Unresponsive Schizophrenia
NCT00169065	PHASE4	COMPLETED	Effectiveness of Clozapine Versus Olanzapine for Treatment-resistant Schizophrenia
NCT00169091	PHASE4	TERMINATED	Clozapine Versus Haloperidol for Treating the First Episode of Schizophrenia
NCT00176423	PHASE4	COMPLETED	Efficacy Study of Galantamine for Cognitive Impairments in Schizophrenia
NCT00176436	PHASE4	COMPLETED	Atomoxetine for Treatment of Weight Gain in Olanzapine or Clozapine Patients
NCT00177008	PHASE4	COMPLETED	Aripiprazole for the Treatment of Schizophrenia With Co-Morbid Social Anxiety