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ACSL5

gene
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Also known as ACS5ACS2

Summary

ACSL5 (acyl-CoA synthetase long chain family member 5, HGNC:16526) is a protein-coding gene on chromosome 10q25.2, encoding Long-chain-fatty-acid–CoA ligase 5 (Q9ULC5). Catalyzes the conversion of long-chain fatty acids to their active form acyl-CoAs for both synthesis of cellular lipids, and degradation via beta-oxidation.

The protein encoded by this gene is an isozyme of the long-chain fatty-acid-coenzyme A ligase family. Although differing in substrate specificity, subcellular localization, and tissue distribution, all isozymes of this family convert free long-chain fatty acids into fatty acyl-CoA esters, and thereby play a key role in lipid biosynthesis and fatty acid degradation. This isozyme is highly expressed in uterus and spleen, and in trace amounts in normal brain, but has markedly increased levels in malignant gliomas. This gene functions in mediating fatty acid-induced glioma cell growth. Three transcript variants encoding two different isoforms have been found for this gene.

Source: NCBI Gene 51703 — RefSeq curated summary.

At a glance

  • Gene–disease (curated): diarrhea 13 (Limited, GenCC)
  • GWAS associations: 9
  • Clinical variants (ClinVar): 121 total — 2 pathogenic
  • GTEx eGene: eQTL in 18 tissues, sQTL in 12 (q < 0.05)
  • Phenotypes (HPO): 9
  • ChEMBL bioactivity: 3 clinical-phase molecules tested; no curated mechanism-of-action drug
  • Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.70 (unconstrained)
  • MANE Select transcript: NM_203379
  • Interaction hub: 1,752 STRING partners (top 10% of genes corpus-wide)
  • Notable: 121 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

FieldValue
HGNC IDHGNC:16526
Approved symbolACSL5
Nameacyl-CoA synthetase long chain family member 5
Location10q25.2
Locus typegene with protein product
StatusApproved
AliasesACS5, ACS2
Ensembl geneENSG00000197142
Ensembl biotypeprotein_coding
OMIM605677
Entrez51703

Gene structure

Transcript identifiers

Ensembl transcripts: 46 — 36 protein_coding, 8 nonsense_mediated_decay, 2 retained_intron

MANE Select: ENST00000354655

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2, TSL 2: 3, TSL 3: 1, TSL 5: 2

ENST00000354655, ENST00000354273, ENST00000356116, ENST00000393081, ENST00000433418, ENST00000467340, ENST00000495539, ENST00000496328, ENST00000861349, ENST00000861350, ENST00000861351, ENST00000861352, ENST00000861353, ENST00000861354, ENST00000861355, ENST00000861356, ENST00000861357, ENST00000861358, ENST00000861359, ENST00000861360, ENST00000861361, ENST00000861362, ENST00000861363, ENST00000861364, ENST00000861365, ENST00000861366, ENST00000861367, ENST00000861368, ENST00000861369, ENST00000954829, ENST00000954830, ENST00000954831, ENST00000954832, ENST00000954833, ENST00000954834, ENST00000954835, ENST00000954836, ENST00000954837, ENST00000993474, ENST00000993475, ENST00000993477, ENST00001043417, ENST00001043419, ENST00001043420, ENST00001043421, ENST00001138580

RefSeq mRNA: 4 — MANE Select: NM_203379 NM_001387037, NM_016234, NM_203379, NM_203380

CCDS: CCDS7572, CCDS7573, CCDS91344

Canonical transcript exons

ENST00000354655 — 21 exons

ExonStartEnd
ENSE00000724257112409507112409685
ENSE00001000193112411456112411529
ENSE00001096563112426258112426359
ENSE00001096573112421593112421665
ENSE00001096575112421947112422035
ENSE00001096579112426788112426859
ENSE00001411902112374116112374269
ENSE00001835863112427218112428376
ENSE00003470738112422325112422441
ENSE00003482344112416888112417022
ENSE00003484218112410463112410495
ENSE00003492611112394918112395102
ENSE00003541113112413173112413307
ENSE00003572499112425338112425481
ENSE00003589092112408422112408521
ENSE00003619593112411902112411979
ENSE00003623182112410584112410635
ENSE00003638097112398901112399009
ENSE00003652803112404511112404575
ENSE00003661740112417846112417941
ENSE00003671255112404705112404806

Expression profiles

Bgee: expression breadth ubiquitous, 267 present calls, max score 99.90.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 23.4060 / max 2111.1540, expressed in 1151 samples.

Highest expression (Bgee): jejunal mucosa, ileal mucosa, corpus epididymis, rectum, mucosa of transverse colon.

Genetic regulation across tissues (GTEx eQTL / sQTL)

ACSL5 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 18 tissues and its splicing (sQTL) in 12 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 30 significant tissue × QTL associations:

TissueQTLq-valueSlopeLead variant
Adipose Visceral Omentumsqtl1.8e-151-2.0410:112426866:G:A
Cells EBV-transformed lymphocytessqtl3.1e-114-2.4810:112426866:G:A
Whole Bloodeqtl2.4e-112-0.4510:112384081:G:T
Colon Transversesqtl4.1e-107+2.1610:112439529:G:A
Liversqtl1.4e-92-2.3110:112426866:G:A
Small Intestine Terminal Ileumsqtl3.6e-43-2.5210:112426866:G:A
Lungsqtl6.8e-10+0.8910:112426866:G:A
Testiseqtl1.8e-09-0.3010:112413796:G:A
Brain Cerebellumeqtl5.1e-08+0.3010:112381487:T:G
Whole Bloodsqtl6.6e-06+0.6710:112426866:G:A
Cells Cultured fibroblastseqtl7.9e-06+0.1710:112375255:C:T
Brain Cerebellar Hemisphereeqtl1.9e-05+0.2410:112406990:C:T
Nerve Tibialeqtl4.0e-05+0.1410:112381487:T:G
Esophagus Mucosaeqtl6.3e-05-0.1910:112325616:C:A
Pancreaseqtl6.4e-05+0.2410:112348992:T:G
Adrenal Glandeqtl7.6e-05+0.3310:112350219:A:G
Brain Putamen basal gangliaeqtl3.8e-04+0.1810:112373303:G:C
Stomacheqtl4.4e-04+0.1210:112335173:A:G
Brain Hippocampuseqtl4.5e-04+0.1810:112364188:C:G
Breast Mammary Tissuesqtl4.6e-04+0.7210:112393875:A:G

FANTOM5 promoters

showing 10 of 28 alternative TSS:

Promoter IDTPM avgSamples expressed
10705015.43391057
1070371.807079
1070511.5061328
1070361.073353
1070411.0643273
1070420.8578220
1070520.244544
1070600.200041
1070400.168665
1070430.163061

Top tissues by expression

showing 100 of 281 tissues by Bgee expression score (0-100, higher = more expressed):

TissueAnatomy IDExpression scoreQuality
jejunal mucosaUBERON:000039999.90gold quality
ileal mucosaUBERON:000033199.27gold quality
corpus epididymisUBERON:000435999.12gold quality
rectumUBERON:000105298.47gold quality
mucosa of transverse colonUBERON:000499198.18gold quality
colonic mucosaUBERON:000031797.97gold quality
mucosa of sigmoid colonUBERON:000499397.73gold quality
duodenumUBERON:000211497.37gold quality
right lobe of liverUBERON:000111496.43gold quality
endometriumUBERON:000129596.17gold quality
small intestine Peyer’s patchUBERON:000345496.08gold quality
small intestineUBERON:000210895.40gold quality
right uterine tubeUBERON:000130294.83gold quality
liverUBERON:000210794.60gold quality
granulocyteCL:000009494.46gold quality
transverse colonUBERON:000115794.27gold quality
caput epididymisUBERON:000435894.14gold quality
upper lobe of left lungUBERON:000895293.38gold quality
upper lobe of lungUBERON:000894893.28gold quality
vermiform appendixUBERON:000115493.04gold quality
gall bladderUBERON:000211092.54gold quality
monocyteCL:000057692.30gold quality
leukocyteCL:000073892.25gold quality
mononuclear cellCL:000084292.13gold quality
colonic epitheliumUBERON:000039791.90gold quality
intestineUBERON:000016091.46gold quality
caecumUBERON:000115391.41gold quality
right lungUBERON:000216791.21gold quality
lower lobe of lungUBERON:000894991.12gold quality
omental fat padUBERON:001041491.03gold quality
peritoneumUBERON:000235891.02gold quality
spleenUBERON:000210690.49gold quality
adipose tissue of abdominal regionUBERON:000780890.49gold quality
cauda epididymisUBERON:000436090.43gold quality
urinary bladderUBERON:000125590.36gold quality
large intestineUBERON:000005990.20gold quality
nasal cavity epitheliumUBERON:000538490.11gold quality
lungUBERON:000204890.10gold quality
lymph nodeUBERON:000002989.85gold quality
colonUBERON:000115589.84gold quality
bloodUBERON:000017888.67gold quality
visceral pleuraUBERON:000240188.44gold quality
body of stomachUBERON:000116188.36gold quality
subcutaneous adipose tissueUBERON:000219088.36gold quality
fallopian tubeUBERON:000388988.14gold quality
olfactory segment of nasal mucosaUBERON:000538687.90gold quality
adipose tissueUBERON:000101387.44gold quality
uterusUBERON:000099587.38gold quality
mucosa of urinary bladderUBERON:000125987.20gold quality
jejunumUBERON:000211587.11gold quality
stomachUBERON:000094586.77gold quality
connective tissueUBERON:000238486.59gold quality
oviduct epitheliumUBERON:000480486.48gold quality
palpebral conjunctivaUBERON:000181286.41gold quality
pleuraUBERON:000097786.39gold quality
nasal cavity mucosaUBERON:000182686.30gold quality
epithelial cell of pancreasCL:000008386.24gold quality
parietal pleuraUBERON:000240085.68gold quality
epithelium of nasopharynxUBERON:000195185.56gold quality
bone marrowUBERON:000237185.37gold quality
spermCL:000001985.22gold quality
bone marrow cellCL:000209284.76gold quality
left uterine tubeUBERON:000130384.41gold quality
left ovaryUBERON:000211984.09gold quality
female reproductive systemUBERON:000047484.01gold quality
seminal vesicleUBERON:000099883.59gold quality
C1 segment of cervical spinal cordUBERON:000646983.49gold quality
pancreatic ductal cellCL:000207983.32silver quality
mucosa of stomachUBERON:000119983.21gold quality
male germ cellCL:000001583.15gold quality
male germ line stem cell (sensu Vertebrata) in testisCL:0000089 ∩ UBERON:000047383.13gold quality
endothelial cellCL:000011583.09gold quality
smooth muscle tissueUBERON:000113583.03gold quality
mucosa of paranasal sinusUBERON:000503083.02gold quality
prostate glandUBERON:000236783.00gold quality
endocervixUBERON:000045882.86gold quality
right ovaryUBERON:000211882.82gold quality
body of uterusUBERON:000985382.62gold quality
superficial temporal arteryUBERON:000161482.54gold quality
cervix squamous epitheliumUBERON:000692282.41gold quality
left testisUBERON:000453382.30gold quality
bronchial epithelial cellCL:000232882.10gold quality
fundus of stomachUBERON:000116082.01gold quality
calcaneal tendonUBERON:000370181.85gold quality
apex of heartUBERON:000209881.80gold quality
vaginaUBERON:000099681.72gold quality
metanephros cortexUBERON:001053381.53gold quality
ovaryUBERON:000099281.48gold quality
right testisUBERON:000453481.32gold quality
testisUBERON:000047381.29gold quality
buccal mucosa cellCL:000233681.25silver quality
spinal cordUBERON:000224081.21gold quality
thoracic mammary glandUBERON:000520081.13gold quality
tonsilUBERON:000237281.08gold quality
epithelium of bronchusUBERON:000203181.05gold quality
mammary glandUBERON:000191181.01gold quality
left coronary arteryUBERON:000162680.98gold quality
germinal epithelium of ovaryUBERON:000130480.93gold quality
heart left ventricleUBERON:000208480.89gold quality
right atrium auricular regionUBERON:000663180.86gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

ExperimentMarker?Max mean expression
E-MTAB-10287yes51.69
E-ANND-3yes18.62
E-MTAB-6142no121.28

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 77 HPA tissues / cells by nTPM:

Tissue / cellAxisnTPMProtein (IHC)
Small intestinetissue405.8high
Duodenumtissue347.8high
Epididymistissue211.6high
Livertissue159.5high
Rectumtissue111.9high
Colontissue107.2high
Urinary bladdertissue71.8medium
Cervixtissue48.9low
Fallopian tubetissue42.6high
Stomach 1tissue42.1low
Frontal cortextissue40.5
Lungtissue34.0high
Endometrium 1tissue28.7high
Appendixtissue28.1medium
Lymph nodetissue26.8not detected
Tonsiltissue26.8not detected
Spleentissue24.6not detected
Breasttissue20.3not detected
Gallbladdertissue20.3medium
Seminal vesicletissue19.2low
Adipose tissuetissue17.9not detected
Caudate putamentissue17.7
Bone marrowtissue15.7not detected
Thymustissue15.4
Smooth muscletissue14.6not detected
Ovarytissue12.6not detected
Prostatetissue11.6not detected
Spinal cordtissue10.8
Testistissue9.2low
Substantia nigratissue9.1
Superior colliculitissue9.0
Tonguetissue8.3
Placentatissue8.1not detected
Esophagustissue7.5not detected
Locus coeruleustissue7.5
Medulla oblongatatissue7.4
Ponstissue7.3
Hippocampustissue7.3not detected
Vaginatissue7.2not detected
Postcentral gyrustissue7.1
Midbraintissue6.9
Thalamustissue6.9
Hypothalamustissue6.8
Kidneytissue6.8medium
Heart muscletissue6.7not detected
Periaqueductal graytissue6.7
Corpus callosumtissue6.5
Septumtissue6.3
Putamentissue6.0
Nucleus accumbenstissue5.6
Cerebral cortextissue5.5not detected
Insular cortextissue5.5
Salivary glandtissue5.3not detected
Pancreastissue5.3low
Ventral forebraintissue5.1
Amygdalatissue4.9
Hippocampal formationtissue4.9
Entorhinal cortextissue4.9
Temporal cortextissue4.9
Basal gangliatissue4.8low

Brain sub-regions (HPA Brain Atlas): detected in 190; highest nTPM — Posterior thalamic nucleus (15.1), Dorsal cochlear nucleus (13.9), Area parastriata, superior (12.3), Nucleus cuneatus (12.3), Cervical spinal cord, ventral horn (11.9).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ERF, FOXO1, MYOD1, SREBF1, TCF12

miRNA regulators (miRDB)

Targeting ACSL5 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 52 miRNAs:

miRNAMax scoreAvg scoremiRNA target_count
HSA-MIR-450A-1-3P100.0069.331837
HSA-MIR-6870-5P99.9968.552115
HSA-MIR-428299.9975.366408
HSA-MIR-569699.9872.364487
HSA-MIR-998599.9872.112939
HSA-MIR-4723-5P99.9768.702034
HSA-MIR-569899.9768.492029
HSA-MIR-7111-5P99.9768.482062
HSA-MIR-426799.9666.532368
HSA-MIR-311999.9271.342390
HSA-MIR-368699.9070.532432
HSA-MIR-808799.9069.551351
HSA-MIR-612499.8769.783551
HSA-MIR-205-5P99.8170.051557
HSA-MIR-6739-5P99.8067.872806
HSA-MIR-6733-5P99.7467.942759
HSA-MIR-4446-5P99.7269.192544
HSA-MIR-7161-5P99.6868.921592
HSA-MIR-1212499.6869.172700
HSA-MIR-46699.6770.852863
HSA-MIR-509399.6769.262291
HSA-MIR-548U99.6567.781463
HSA-MIR-315399.5567.592337
HSA-MIR-766-5P99.4767.912225
HSA-MIR-569799.3967.741249
HSA-MIR-446099.3768.52615
HSA-MIR-135A-5P99.3671.851601
HSA-MIR-135B-5P99.3671.631613
HSA-MIR-6507-5P99.3670.462524
HSA-MIR-4520-2-3P99.1469.281009

Functional genomics

gnomAD constraint: pLI 1.45e-07, LOEUF 0.702, missense Z 1.25 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000354655 — one region, missense o/e 0.93.

Literature-anchored findings (GeneRIF, showing 35)

  • expression of ACS5 in the gastric body and the small intestine with metaplasia or heterotopia (PMID:15736044)
  • ACS5 is a very suitable marker molecule for the detection of villus atrophy in the small intestine. (PMID:15809837)
  • SREBP-1c-mediated insulin regulation of acyl-CoA synthestase 5 expression indicate that ACS-5 is involved in the anabolic fate of fatty acids. (PMID:16198472)
  • Existence of a link between ACSL5 genotype and diet responsiveness. (PMID:17495181)
  • Suggest an ACSL5-dependent regulatory mechanism that contributes to the cellular renewal along the crypt-villus axis in human small intestine. (PMID:17681178)
  • Oncostatin M directly lowers the plasma triglycerides in hyperlipidemia by stimulating the transcription of ACSL3/5 in the liver. (PMID:17761945)
  • Expression of ACSL5 in human epidermis is reported. (PMID:18228202)
  • These results indicate that ACSL5 is a critical factor for survival of glioma cells under acidic tumor microenvironment. (PMID:18806831)
  • These results reveal a mechanism for elevated transcription of ACSL5 in skeletal muscle of carriers of the rs2419621(T) allele, associated with more rapid diet-induced weight loss. (PMID:19218499)
  • Increased ACSL5 is associated with Fatty Liver. (PMID:20470896)
  • High ACSL5 transcript levels associate with systemic lupus erythematosus and apoptosis in Jurkat T lymphocytes and peripheral blood cells (PMID:22163040)
  • The data strongly indicate that human but not rat acyl-CoA synthetase 5 is sensitive to triacsin C and does not compensate for other triacsin C-sensitive ACSL isoforms. (PMID:22171129)
  • Levels of acyl-coenzyme A synthetase 5 in urothelial cells and corresponding neoplasias reflect cellular differentiation. (PMID:23348389)
  • Down-regulation of ACSL5 is associated with colorectal cancer. (PMID:24222123)
  • Uncoupling of ACSL5 and mitochondrial mortalin by mutated TP53 could be important in colorectal carcinogenesis. (PMID:24770931)
  • ACSL5 mediates antiproliferative activities via Wnt2B palmitoylation with diminished Wnt activity. The molecular pathway is probably relevant for intestinal homeostasis, overwhelmed by other pathways in carcinogenesis. (PMID:25356045)
  • Functional variant (rs2256368:A>G) affecting ACSL5 exon 20 skipping was identified as a causal factor linked to the migraine-associated rs12355831:A>G, suggesting that the activation of long-chain fatty acids by the spliced ACSL5-Delta20 molecules is involved in migraine pathology. (PMID:27189022)
  • colorectal adenocarcinomas with low (n=41; group 1) or high (n=31; group 2) ACSL5 levels were identified. In a one-year follow-up, tumour recurrence was significantly increased in group 1. (PMID:28153554)
  • These results suggest that ACSL1, ACSL4 and ACSL5 expression is regulated by ER signaling pathways and ACSL5 is a potential novel biomarker for predicting prognosis of breast cancer patients. (PMID:28498416)
  • our study has demonstrated that ACS5 expression was increased in colorectal cancer (CRC) cells and CRC tissues and its upregulation closely correlated to poor tumor differentiation and excess muscular layer in patients with CRC (PMID:28808653)
  • rs2419621 T allele carriers are more responsive to lifestyle interventions partly due to an increase in the short ACSL5 protein isoform, increasing cellular, tissue and whole-body fatty acid utilization. (PMID:29605434)
  • downregulation of ACSL5 and Wnt2B could play an important role in the development of bronchial-alveolar structures in congenital pulmonary airway malformations (CPAMs). (PMID:30463708)
  • Our findings reveal that LOX and ACSL5 are potential prognostic markers for the prognosis of pancreatic cancer patients. (PMID:30712446)
  • Our findings indicate that the variant rs2256368:A>G can predict a growth inhibitory activity, caused by the Spl isoform of ACSL5 protein, opposed to the activity of the NSpl. Deep understanding of its functioning might have application in metabolic diseases and cancer. (PMID:31053784)
  • miR-497-5p mediates starvation-induced death in colon cancer cells by targeting acyl-CoA synthetase-5 and modulation of lipid metabolism. (PMID:32012265)
  • ONECUT2 upregulation is associated with CpG hypomethylation at promoter-proximal DNA in gastric cancer and triggers ACSL5. (PMID:32129880)
  • Roles of acyl-CoA synthetase long-chain family member 5 and colony stimulating factor 2 in inhibition of palmitic or stearic acids in lung cancer cell proliferation and metabolism. (PMID:32347412)
  • ACYL-CoA synthetase long-chain 5 polymorphism is associated with weight loss and metabolic changes in response to a partial meal-replacement hypocaloric diet.", trans “El polimorfismo de la ACYL-CoA-sintetasa de cadena larga 5 se asocia a perdida de peso y cambios metabolicos en respuesta a una dieta hipocalorica parcial de reemplazo. (PMID:32686444)
  • A multi-ethnic meta-analysis identifies novel genes, including ACSL5, associated with amyotrophic lateral sclerosis. (PMID:32968195)
  • Deficiency of acyl-CoA synthetase 5 is associated with a severe and treatable failure to thrive of neonatal onset. (PMID:33191500)
  • The gene variant rs2419621 of ACYL-CoA synthetase long-chain 5 gene is associated with weight loss and metabolic changes in response to a robotic sleeve gastrectomy in morbid obese subjects. (PMID:34859867)
  • Lysophosphatidylcholine inhibits lung cancer cell proliferation by regulating fatty acid metabolism enzyme long-chain acyl-coenzyme A synthase 5. (PMID:36639836)
  • More than just a histone deacetylase: cytoplasmic SIRT6 facilitates fatty acid oxidation through ACSL5 deacetylation. (PMID:36880305)
  • Hypoxia-responsive PPARGC1A/BAMBI/ACSL5 axis promotes progression and resistance to lenvatinib in hepatocellular carcinoma. (PMID:36932115)
  • ACSL5, a prognostic factor in acute myeloid leukemia, modulates the activity of Wnt/beta-catenin signaling by palmitoylation modification. (PMID:37131085)

Cross-species orthologs

5 orthologs

OrganismSymbolGene ID
danio_rerioacsl5ENSDARG00000075931
mus_musculusAcsl5ENSMUSG00000024981
rattus_norvegicusAcsl5ENSRNOG00000016265
drosophila_melanogasterCG3961FBGN0036821
caenorhabditis_elegansacs-13WBGENE00022037

Paralogs (12): ACSL4 (ENSG00000068366), SLC27A5 (ENSG00000083807), ACSBG1 (ENSG00000103740), SLC27A6 (ENSG00000113396), ACSL3 (ENSG00000123983), SLC27A1 (ENSG00000130304), ACSBG2 (ENSG00000130377), SLC27A2 (ENSG00000140284), SLC27A3 (ENSG00000143554), ACSL1 (ENSG00000151726), ACSL6 (ENSG00000164398), SLC27A4 (ENSG00000167114)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1919129) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 17 distinct phenotype terms.

Mouse phenotype (MP)Records
decreased bone mineral density1
decreased circulating HDL cholesterol level1
abnormal lens morphology1
cornea opacity1
decreased circulating triglyceride level1
increased heart weight1
thrombocytopenia1
decreased liver weight1
increased spleen weight1
decreased circulating cholesterol level1
increased circulating bilirubin level1
decreased circulating glucose level1
decreased circulating total protein level1
abnormal enzyme/coenzyme activity1
eye hemorrhage1
decreased bone mineral content1
shortened QRS complex duration1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

OrganismUniProtIdentityMethod
Aspergillus fumigatus A1163B0XWK899.9%Diamond
Aspergillus fumigatus Af293Q4WYG299.9%Diamond
Pongo abeliiQ5R66899.7%Diamond
Arabidopsis thalianaQ9SS0091.0%Diamond
Cavia porcellusQ9JID688.7%Diamond
Penicillium brevicompactumP9WEY388.0%Diamond
Penicillium roqueforti FM164W6R1D988.0%Diamond
Coprinopsis cinerea okayama7#130A8NS2778.1%Diamond
Bacillus subtilis subsp. subtilis str. 168P2397176.7%Diamond
Humulus lupulusM4ISH167.4%Diamond
Saccharomyces cerevisiae S288CP3062461.1%Diamond
Segniliparus rugosus ATCC BAA-974E5XP7658.9%Diamond
Pseudomonas entomophila L48Q1IAK856.6%Diamond
Alternaria alternataC5NN1847.5%Diamond
Dictyostelium discoideumQ55DR645.8%Diamond
Schizosaccharomyces pombe 972h-O6013543.3%Diamond
Streptomyces niveusQ9L9F635.5%Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

SymbolTypeEntrez
LINC02935ncRNA107984158
VTI1Aprotein-coding143187
ZDHHC6protein-coding64429
MIR6715AncRNA102466189
GPAMprotein-coding57678
TECTBprotein-coding6975
MIR6715BncRNA102465427
MIR4295ncRNA100422909
TCF7L2protein-coding6934

Protein

Protein identifiers

Long-chain-fatty-acid–CoA ligase 5 — Q9ULC5 (reviewed: Q9ULC5)

Alternative names: Arachidonate–CoA ligase, Long-chain acyl-CoA synthetase 5

All UniProt accessions (4): A0A804HIN9, A0A8C8KCK5, A0A8C8L3F5, Q9ULC5

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the conversion of long-chain fatty acids to their active form acyl-CoAs for both synthesis of cellular lipids, and degradation via beta-oxidation. ACSL5 may activate fatty acids from exogenous sources for the synthesis of triacylglycerol destined for intracellular storage. Utilizes a wide range of saturated fatty acids with a preference for C16-C18 unsaturated fatty acids. It was suggested that it may also stimulate fatty acid oxidation. At the villus tip of the crypt-villus axis of the small intestine may sensitize epithelial cells to apoptosis specifically triggered by the death ligand TRAIL. May have a role in the survival of glioma cells.

Subcellular location. Mitochondrion. Endoplasmic reticulum. Mitochondrion outer membrane. Endoplasmic reticulum membrane. Cell membrane.

Disease relevance. Diarrhea 13 (DIAR13) [MIM:620357] An autosomal recessive disorder characterized by neonatal onset of recurrent vomiting and diarrhea, leading to severe failure to thrive. The disease may be caused by variants affecting the gene represented in this entry.

Miscellaneous. Localize in mitochondrion and endoplasmic reticulum. Localize in mitochondrion and endoplasmic reticulum.

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

Isoforms (3)

UniProt IDNamesCanonical?
Q9ULC5-11, ACSL5b, ACSL5-flyes
Q9ULC5-32, ACSL5a
Q9ULC5-43, ACSL5delta20

RefSeq proteins (4): NP_001373966, NP_057318, NP_976313, NP_976314 (=MANE)

Domains & families (InterPro)

IDNameType
IPR000873AMP-dep_synth/lig_domDomain
IPR020845AMP-binding_CSConserved_site
IPR042099ANL_N_sfHomologous_superfamily
IPR045311LC-FACS_eukFamily

Pfam: PF00501

Catalyzed reactions (Rhea)

  • 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)
  • (9Z)-octadecenoate + ATP + CoA = (9Z)-octadecenoyl-CoA + AMP + diphosphate (RHEA:33607)
  • (E)-hexadec-2-enoate + ATP + CoA = (2E)-hexadecenoyl-CoA + AMP + diphosphate (RHEA:36139)
  • 11,12-epoxy-(5Z,8Z,14Z)-eicosatrienoate + ATP + CoA = 11,12-epoxy-(5Z,8Z,14Z)-eicosatrienoyl-CoA + AMP + diphosphate (RHEA:52012)
  • 14,15-epoxy-(5Z,8Z,11Z)-eicosatrienoate + ATP + CoA = 14,15-epoxy-(5Z,8Z,11Z)-eicosatrienoyl-CoA + AMP + diphosphate (RHEA:52016)
  • 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 (12 total): sequence variant 5, modified residue 2, splice variant 2, chain 1, transmembrane region 1, topological domain 1

Structure

Predicted structure (AlphaFold)

ModelpLDDTFraction very-high
AF-Q9ULC5-F190.550.69

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Ligase, Metabolic proteins, Predicted membrane proteins, Plasma proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): mitochondria; nucleoplasm

Antibody reliability (HPA): IH enhanced · IF supported

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (2)

TypePositions
Phosphoserine32
N6-acetyllysine361

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 5; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

5 pathways:

IDPathwayEvidence
R-HSA-75876Synthesis of very long-chain fatty acyl-CoAscurated
R-HSA-8978868Fatty acid metabolism—
R-HSA-75105Fatty acyl-CoA biosynthesis—
R-HSA-1430728Metabolism—
R-HSA-556833Metabolism of lipids—

MSigDB gene sets: 323 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_UP, REACTOME_SYNTHESIS_OF_VERY_LONG_CHAIN_FATTY_ACYL_COAS, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, KEGG_ADIPOCYTOKINE_SIGNALING_PATHWAY, GOBP_REGULATION_OF_ORGANIC_ACID_TRANSPORT, GOBP_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY, 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, HUMMERICH_SKIN_CANCER_PROGRESSION_DN, GOBP_POSITIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, GOBP_POSITIVE_REGULATION_OF_LIPID_TRANSPORT, CEBPB_01

GO Biological Process (6): long-chain fatty acid metabolic process (GO:0001676), positive regulation of long-chain fatty acid import across plasma membrane (GO:0010747), long-chain fatty-acyl-CoA biosynthetic process (GO:0035338), regulation of extrinsic apoptotic signaling pathway (GO:2001236), lipid metabolic process (GO:0006629), fatty acid metabolic process (GO:0006631)

GO Molecular Function (7): long-chain fatty acid-CoA ligase activity (GO:0004467), ATP binding (GO:0005524), arachidonate-CoA ligase activity (GO:0047676), oleoyl-CoA ligase activity (GO:0090434), nucleotide binding (GO:0000166), protein binding (GO:0005515), ligase activity (GO:0016874)

GO Cellular Component (6): mitochondrion (GO:0005739), mitochondrial outer membrane (GO:0005741), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

4 top-level categories:

CategoryPathways
Fatty acyl-CoA biosynthesis1
Metabolism1
Fatty acid metabolism1
Metabolism of lipids1

GO top-level categories

33 GO namespaces:

CategoryTerms
long-chain fatty acid-CoA ligase activity2
cytoplasm2
intracellular membrane-bounded organelle2
fatty acid metabolic process1
regulation of long-chain fatty acid import across plasma membrane1
long-chain fatty acid import across plasma membrane1
positive regulation of transmembrane transport1
positive regulation of long-chain fatty acid import into cell1
long-chain fatty-acyl-CoA metabolic process1
fatty-acyl-CoA biosynthetic process1
extrinsic apoptotic signaling pathway1
regulation of apoptotic signaling pathway1
primary metabolic process1
lipid metabolic process1
monocarboxylic acid metabolic process1
long-chain fatty acid metabolic process1
fatty acid-CoA ligase activity1
adenyl ribonucleotide binding1
purine ribonucleoside triphosphate binding1
anion binding1
nucleoside phosphate binding1
heterocyclic compound binding1
binding1
catalytic activity1
mitochondrial membrane1
organelle outer membrane1
endomembrane system1
organelle membrane1
nuclear outer membrane-endoplasmic reticulum membrane network1
endoplasmic reticulum subcompartment1
membrane1
cell periphery1
cellular anatomical structure1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 8 of 19 annotations. The rest are phylogenetic / computational / electronic (IEA).

8 experimentally-supported GO terms:

GO termNSEvidence
long-chain fatty acid metabolic processBPdirect assay
regulation of extrinsic apoptotic signaling pathwayBPdirect assay
endoplasmic reticulumCCdirect assay
membraneCChigh-throughput assay
mitochondrionCCdirect assay
plasma membraneCCdirect assay
long-chain fatty acid-CoA ligase activityMFdirect assay
oleoyl-CoA ligase activityMFdirect assay

Protein interactions and networks

STRING

showing 15 of 1,752 interactions by confidence (×1000):

Protein AProtein BPartner UniProtScore
ACSL5ACSS1Q9NUB1877
ACSL5AASDHQ4L235867
ACSL5ACSS2Q9NR19848
ACSL5DGAT1O75907815
ACSL5SLC27A1Q6PCB7704
ACSL5SLC27A2O14975697
ACSL5ABCD1P33897658
ACSL5CD36P16671636
ACSL5ABCD3P28288630
ACSL5ACADMP11310617
ACSL5SCARB2Q14108609
ACSL5SCARB1Q8WTV0592
ACSL5FASNP49327583
ACSL5ABL2P42684558
ACSL5THOC5Q13769554

IntAct

Human interaction partners of ACSL5 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

12 partners by confidence:

PartnerInteraction typeMIscoreRecords
RETREG3physical association0.5605
AQP6physical association0.5603
EBAG9physical association0.5603
PEX12physical association0.5603
SELIphysical association0.5603
SLC10A1physical association0.5603
SLC10A6physical association0.5603
SLC16A7physical association0.5603
SLC35C2physical association0.5603
SLC7A14physical association0.5603
TMEM14Bphysical association0.5603
CREB3physical association0.3701

BioGRID (42 interactions; top human partners by supporting records): USP29 (Affinity Capture-Western; 4 records), ACAA1 (FRET), AQP6 (Two-hybrid), CAV2 (Affinity Capture-MS), COQ9 (Affinity Capture-MS), CREB3 (Two-hybrid), EBAG9 (Two-hybrid), ELK1 (Affinity Capture-MS), EPT1 (Two-hybrid), FAM134C (Two-hybrid), FAM136A (Affinity Capture-MS), FBXO7 (Biochemical Activity), KIF11 (Affinity Capture-MS), PAK1 (Affinity Capture-MS), PARP2 (Proximity Label-MS)

SIGNOR signaling

2 signaling interactions:

AEffectBMechanism
ACSL5“up-regulates quantity”“long-chain fatty acyl-CoA(4-)”“chemical modification”
ACSL5“down-regulates quantity”“long-chain fatty acid anion”“chemical modification”

Disease & clinical

Genetic variants

Variant evidence for ACSL5: 121 ClinVar records (2 pathogenic / likely pathogenic); 9 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

ClassificationCount (floor)
Pathogenic2
Likely pathogenic0
Uncertain significance85
Likely benign10
Benign4

Top pathogenic / likely-pathogenic (2)

Showing all 2 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant IDHGVSClassificationReviewSubmitters
1527599GRCh37/hg19 10q24.32-25.3(chr10:104030479-115410590)x1Pathogeniccriteria provided, single submitter1
2500167NM_203379.2(ACSL5):c.1358C>A (p.Thr453Lys)Pathogenicno assertion criteria provided1

Per-variant reference — Sugi Variant

Explore ACSL5’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 38 predictions of 1,762):

Position(s)EffectΔscoreSites
10:112374270donor_loss1.0000
10:112409505–112409506acceptor_loss1.00006
10:112410444acceptor_gain1.0000
10:112410460acceptor_gain1.0000
10:112413171–112413172acceptor_loss1.00006
10:112413303donor_gain1.0000
10:112413308–112413309donor_loss1.00005
10:112421591–112421592acceptor_loss1.00006
10:112421666–112421667donor_loss1.00005
10:112422323–112422324acceptor_loss1.00006

HPA cancer prognostics

RNA cancer specificity: Cancer enhanced (Rectum Adenocarcinoma)

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

1 prognostic cancer types:

CancerPrognosticp-value
Pancreatic Adenocarcinoma (TCGA)unfavorable0.000584

Disease associations

OMIM: gene MIM:605677 | disease phenotypes: MIM:620357

GenCC curated gene-disease

1 curated gene-disease records:

DiseaseClassificationInheritanceRecords
diarrhea 13LimitedUnknown2

Mondo (1): diarrhea 13 (MONDO:0957253)

HPO phenotypes

9 phenotypes (HPO-id order):

HPOTerm
HP:0000007Autosomal recessive inheritance
HP:0001397Hepatic steatosis
HP:0001508Failure to thrive
HP:0001988Recurrent hypoglycemia
HP:0002013Vomiting
HP:0002910Elevated circulating hepatic transaminase concentration
HP:0003073Hypoalbuminemia
HP:0003623Neonatal onset
HP:0005208Secretory diarrhea

GWAS associations

9 associations:

StudyTraitp-value
GCST90002395_578Mean platelet volume6e-26
GCST004599_9Mean platelet volume1e-24
GCST90002395_577Mean platelet volume3e-18
GCST90002380_83Basophil percentage of white cells7e-12
GCST004599_10Mean platelet volume1e-11
GCST90002395_576Mean platelet volume2e-11
GCST010857_1Amyotrophic lateral sclerosis8e-11
GCST90002402_175Platelet count3e-10
GCST008949_1High chromosomal aberration frequency (chromosome type) in genotoxic compound exposure3e-6

EFO canonical traits (from GWAS)

3 canonical traits:

EFO IDTrait name
EFO:0009861chromosome-type aberration frequency
EFO:0007992basophil percentage of leukocytes
EFO:0004309platelet count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4105818 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 12,907 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

3 molecules by phase:

MoleculeNamePhasePatents
CHEMBL3301622GILTERITINIB42,542
CHEMBL491473CEDIRANIB39,464
CHEMBL1088752LOSMAPIMOD3901

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

2 measured of 4 human assays (184 total across all organisms); most potent 2 below. Values come from heterogeneous assays and are not directly comparable.

LigandMeasureValue
CHEMBL4761388IC5069000 nM
CHEMBL4776019IC50114000 nM

ChEMBL bioactivities

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

pChemblTypeValueUnitMolecule
8.10Kd8nMCEDIRANIB
6.68Kd208nMGILTERITINIB
5.77Kd1690nMLOSMAPIMOD

PubChem BioAssay actives

3 with measured affinity, of 181 total; 3 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

CompoundAssayTypeValueUnit
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline1424897: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.kd0.0080uM
Gilteritinib1424897: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.kd0.2080uM
6-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-N-(2,2-dimethylpropyl)pyridine-3-carboxamide1424897: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.kd1.6900uM

CTD chemical–gene interactions

67 total (human), top 30 by PubMed support.

ChemicalActions (top 5)PubMed papers
(+)-JQ1 compounddecreases expression5
Acetaminophenincreases expression, decreases expression4
Benzo(a)pyreneaffects expression, affects methylation, decreases expression4
Tetrachlorodibenzodioxindecreases expression, increases expression, affects expression4
Cyclosporinedecreases expression, increases expression3
GW 7647affects cotreatment, increases expression2
Estradiolaffects cotreatment, decreases expression2
Smokedecreases expression2
Tobacco Smoke Pollutiondecreases expression2
Valproic Aciddecreases expression, increases expression2
Palmitic Acidaffects response to substance, affects abundance, decreases expression, increases expression2
aristolochic acid Iincreases expression1
afuresertibincreases expression1
3,19-(2-bromobenzylidene)andrographolidedecreases expression, decreases response to substance1
bisphenol Fincreases expression1
sotorasibaffects cotreatment, increases expression1
methylmercuric chlorideincreases expression1
methyleugenoldecreases expression1
triphenyl phosphateaffects expression1
pirinixic acidincreases activity, increases expression, affects binding1
bisphenol Adecreases expression1
deoxynivalenoldecreases expression1
ascorbate-2-phosphateincreases expression, affects binding, affects cotreatment1
beta-lapachoneincreases expression1
mono-(2-ethylhexyl)phthalateincreases expression1
sodium arseniteincreases expression1
3,4,5,3’,4’-pentachlorobiphenylincreases expression1
ochratoxin Adecreases expression1
potassium chromate(VI)decreases expression1
nickel sulfatedecreases expression1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay IDTypeDescriptionSource paper
CHEMBL3991610BindingKinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by maThe target landscape of clinical kinase drugs. — *Science*

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for ACSL5 across ~30M SureChEMBL compounds — explore on Sugi Predict.