ACOT6

Summary

ACOT6 (acyl-CoA thioesterase 6, HGNC:33159) is a protein-coding gene on chromosome 14q24.3, encoding Acyl-coenzyme A thioesterase 6 (Q3I5F7). Catalyzes the hydrolysis of acyl-CoAs into free fatty acids and coenzyme A (CoASH), regulating their respective intracellular levels.

Predicted to enable fatty acyl-CoA hydrolase activity. Predicted to be involved in acyl-CoA metabolic process and fatty acid metabolic process. Located in cytosol.

Source: NCBI Gene 641372 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 32 total
• MANE Select transcript: NM_001365788

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:33159
Approved symbol	ACOT6
Name	acyl-CoA thioesterase 6
Location	14q24.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000205669
Ensembl biotype	protein_coding
OMIM	614267
Entrez	641372

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000381139, ENST00000554229, ENST00000645972

RefSeq mRNA: 3 — MANE Select: NM_001365788 NM_001037162, NM_001365788, NM_001365789

CCDS: CCDS32118, CCDS91900

Canonical transcript exons

ENST00000645972 — 3 exons

Exon	Start	End
ENSE00001487623	73619234	73619888
ENSE00003814903	73616994	73617192
ENSE00003829188	73612517	73613032

Expression profiles

Bgee: expression breadth broad, 98 present calls, max score 83.31.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.31	gold quality
right lobe of liver	UBERON:0001114	69.49	gold quality
liver	UBERON:0002107	57.34	gold quality
nucleus accumbens	UBERON:0001882	55.76	gold quality
adult mammalian kidney	UBERON:0000082	55.71	gold quality
cerebellar hemisphere	UBERON:0002245	55.34	gold quality
cerebellar cortex	UBERON:0002129	55.31	gold quality
right hemisphere of cerebellum	UBERON:0014890	54.88	gold quality
caudate nucleus	UBERON:0001873	54.63	gold quality
cerebellum	UBERON:0002037	54.29	gold quality
putamen	UBERON:0001874	52.91	gold quality
amygdala	UBERON:0001876	51.93	gold quality
kidney	UBERON:0002113	51.84	gold quality
right frontal lobe	UBERON:0002810	51.19	gold quality
hindlimb stylopod muscle	UBERON:0004252	50.81	gold quality
anterior cingulate cortex	UBERON:0009835	50.65	gold quality
apex of heart	UBERON:0002098	50.12	gold quality
right adrenal gland	UBERON:0001233	49.94	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	49.44	gold quality
right adrenal gland cortex	UBERON:0035827	49.24	gold quality
Brodmann (1909) area 9	UBERON:0013540	48.98	gold quality
cerebellar vermis	UBERON:0004720	48.63	gold quality
muscle of leg	UBERON:0001383	48.49	gold quality
brain	UBERON:0000955	48.09	gold quality
forebrain	UBERON:0001890	47.57	gold quality
gastrocnemius	UBERON:0001388	47.31	gold quality
neocortex	UBERON:0001950	47.26	gold quality
hypothalamus	UBERON:0001898	47.17	gold quality
cortex of kidney	UBERON:0001225	47.09	gold quality
primary visual cortex	UBERON:0002436	46.98	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.28

Regulation

Is transcription factor: no

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	acot20	ENSDARG00000042510
danio_rerio	acot21	ENSDARG00000042513
danio_rerio	acot22	ENSDARG00000058945
mus_musculus	Acot6	ENSMUSG00000043487
caenorhabditis_elegans	C31H5.6	WBGENE00007857
caenorhabditis_elegans		WBGENE00019404
caenorhabditis_elegans	T05E7.1	WBGENE00020258
caenorhabditis_elegans	W03D8.8	WBGENE00020989

Paralogs (4): ACOT2 (ENSG00000119673), BAAT (ENSG00000136881), ACOT4 (ENSG00000177465), ACOT1 (ENSG00000184227)

Protein

Protein identifiers

Acyl-coenzyme A thioesterase 6 — Q3I5F7 (reviewed: Q3I5F7)

All UniProt accessions (2): Q3I5F7, G3V3W6

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the hydrolysis of acyl-CoAs into free fatty acids and coenzyme A (CoASH), regulating their respective intracellular levels. Catalyzes the hydrolysis of phytanoyl-CoA and pristanoyl-CoA, two methyl-branched fatty acids derived from phytol, that enter the body via the diet.

Subcellular location. Peroxisome Cytoplasm.

Pathway. Lipid metabolism; fatty acid metabolism.

Similarity. Belongs to the C/M/P thioester hydrolase family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q3I5F7-1	1	yes
Q3I5F7-2	2

RefSeq proteins (3): NP_001032239, NP_001352717, NP_001352718 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006862	Thio_Ohase/aa_AcTrfase	Domain
IPR014940	BAAT_C	Domain
IPR016662	Acyl-CoA_thioEstase_long-chain	Family
IPR029058	AB_hydrolase_fold	Homologous_superfamily
IPR042490	Thio_Ohase/BAAT_N	Homologous_superfamily

Pfam: PF04775, PF08840

Enzyme classification (BRENDA):

• EC 3.1.2.20 — acyl-CoA hydrolase (BRENDA: 47 organisms, 273 substrates, 173 inhibitors, 271 Km, 184 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
HEXADECANOYL-COA	—	25
PALMITOYL-COA	0.0024–33	14
MYRISTOYL-COA	0.0025–0.0228	13
3-HYDROXYPHENYLACETYL-COA	0.0037–0.9	11
OLEOYL-COA	0.0014–0.0274	10
ARACHIDONOYL-COA	0.0004–0.02	9
DODECANOYL-COA	0.0018–0.325	9
LAUROYL-COA	0.0035–0.0275	9
PALMITOLEOYL-COA	0.0014–0.058	9
2,3-DIHYDROXYBENZOYL-COA	0.0375–1.42	7
ACETYL-COA	0.0047–0.29	7
SALICYLYL-COA	0.162–0.729	7
DECANOYL-COA	0.0027–19.78	6
LINOLEOYL-COA	0.0014–0.31	6
STEAROYL-COA	0.0015–0.0279	6

Catalyzed reactions (Rhea), 2 shown:

• pristanoyl-CoA + H2O = 2,6,10,14-tetramethylpentadecanoate + CoA + H(+) (RHEA:40415)
• phytanoyl-CoA + H2O = 3,7,11,15-tetramethylhexadecanoate + CoA + H(+) (RHEA:40419)

UniProt features (7 total): active site 3, chain 1, short sequence motif 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q3I5F7-F1	95.01	0.94

Functional residue map

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

Catalytic / active sites (3): 232 (charge relay system); 326 (charge relay system); 360 (charge relay system)

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 44 (showing top): GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, chr14q24, GOBP_AMIDE_METABOLIC_PROCESS, GOBP_LIPID_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_METABOLIC_PROCESS, GOBP_PURINE_CONTAINING_COMPOUND_METABOLIC_PROCESS, GOCC_MICROBODY, GOBP_FATTY_ACID_METABOLIC_PROCESS, GOMF_ACYL_COA_HYDROLASE_ACTIVITY, GOMF_THIOLESTER_HYDROLASE_ACTIVITY

GO Biological Process (2): fatty acid metabolic process (GO:0006631), acyl-CoA metabolic process (GO:0006637)

GO Molecular Function (4): fatty acyl-CoA hydrolase activity (GO:0047617), carboxylic ester hydrolase activity (GO:0052689), hydrolase activity (GO:0016787), thiolester hydrolase activity (GO:0016790)

GO Cellular Component (3): peroxisome (GO:0005777), cytosol (GO:0005829), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
hydrolase activity, acting on ester bonds	2
cellular anatomical structure	2
lipid metabolic process	1
monocarboxylic acid metabolic process	1
nucleoside phosphate metabolic process	1
sulfur compound metabolic process	1
purine-containing compound metabolic process	1
acyl-CoA hydrolase activity	1
catalytic activity	1
microbody	1
cytoplasm	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

516 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ACOT6	ACOT8	O14734	640
ACOT6	ACOT9	Q9Y305	613
ACOT6	ACOT13	Q9NPJ3	565
ACOT6	ACOT12	Q8WYK0	552
ACOT6	ZNF789	Q5FWF6	524
ACOT6	ACOT7	O00154	490
ACOT6	ACOT11	Q8WXI4	420
ACOT6	MGLL	Q99685	412
ACOT6	POU1F1	P28069	410
ACOT6	AGO3	Q9H9G7	402
ACOT6	CHD8	Q9HCK8	395
ACOT6	TOP2B	Q02880	390
ACOT6	MAP2K7	O14733	389
ACOT6	KMT5A	Q9NQR1	389
ACOT6	THEM5	Q8N1Q8	386

IntAct

119 interactions, top by confidence:

A	B	Type	Score
ACOT6	PDZD7	psi-mi:“MI:0407”(direct interaction)	0.440
ACOT6	WHRN	psi-mi:“MI:0407”(direct interaction)	0.440
ACOT6	PTPN3	psi-mi:“MI:0407”(direct interaction)	0.440
ACOT6	MAGI3	psi-mi:“MI:0407”(direct interaction)	0.440
ACOT6	ARHGAP21	psi-mi:“MI:0407”(direct interaction)	0.440
ACOT6	MAST2	psi-mi:“MI:0407”(direct interaction)	0.440
ACOT6	PDZD2	psi-mi:“MI:0407”(direct interaction)	0.440
ACOT6	PICK1	psi-mi:“MI:0407”(direct interaction)	0.440
DLG1	ACOT6	psi-mi:“MI:0407”(direct interaction)	0.440
ACOT6	MAGI2	psi-mi:“MI:0407”(direct interaction)	0.440
ACOT6	ARHGEF12	psi-mi:“MI:0407”(direct interaction)	0.440
ACOT6	SNTB1	psi-mi:“MI:0407”(direct interaction)	0.440
APBA3	ACOT6	psi-mi:“MI:0407”(direct interaction)	0.440
ACOT6	MPP2	psi-mi:“MI:0407”(direct interaction)	0.440
ACOT6	SIPA1L2	psi-mi:“MI:0407”(direct interaction)	0.440
ACOT6	DLG4	psi-mi:“MI:0407”(direct interaction)	0.440
ACOT6	GRIP1	psi-mi:“MI:0407”(direct interaction)	0.440
ACOT6	PATJ	psi-mi:“MI:0407”(direct interaction)	0.440
ACOT6	APBA2	psi-mi:“MI:0407”(direct interaction)	0.440
ACOT6	LNX2	psi-mi:“MI:0407”(direct interaction)	0.440
ACOT6	TJP3	psi-mi:“MI:0407”(direct interaction)	0.440
ACOT6	GRIP2	psi-mi:“MI:0407”(direct interaction)	0.440
HTRA2	ACOT6	psi-mi:“MI:0407”(direct interaction)	0.440
ACOT6	HTRA1	psi-mi:“MI:0407”(direct interaction)	0.440
ACOT6	CASK	psi-mi:“MI:0407”(direct interaction)	0.440
ACOT6	PDZRN4	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (7): CRIP2 (Affinity Capture-MS), ATP6V1G2 (Affinity Capture-MS), ATP6V1G2 (Affinity Capture-MS), HARS2 (Affinity Capture-MS), KITLG (Affinity Capture-MS), DDX19B (Affinity Capture-MS), SPTB (Affinity Capture-MS)

ESM2 similar proteins: A0JMS7, A2AKK5, A5PJN5, B3MF31, O55137, O55171, O88267, P08587, P10937, P21980, P21981, P34913, P40935, P40936, P49753, P51176, P70683, Q01841, Q14032, Q32Q92, Q3I5F7, Q4V8A1, Q5BJ91, Q5FVR5, Q5R8R3, Q5XHI4, Q60963, Q63276, Q6NTR1, Q6P6V7, Q6Q2C2, Q6Q2Z6, Q6QR59, Q7TS68, Q86TX2, Q8BGG9, Q8BNE1, Q8BWN8, Q8C7R4, Q8N9L9

Diamond homologs: A2AKK5, O55137, O55171, O88267, P49753, Q14032, Q32Q92, Q3I5F7, Q5FVR5, Q63276, Q6Q2Z6, Q86TX2, Q8BGG9, Q8BWN8, Q8N9L9, Q91X34, Q9QYR7, Q9QYR9

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 79 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Assembly and cell surface presentation of NMDA receptors	8	39.8×	2e-09
Neurexins and neuroligins	9	34.8×	7e-10
Protein-protein interactions at synapses	6	31.2×	2e-06
RHOB GTPase cycle	5	15.1×	3e-04
RHOC GTPase cycle	5	14.3×	4e-04
RHOA GTPase cycle	6	8.8×	8e-04
Signaling by Rho GTPases	8	5.4×	1e-03
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	8	5.2×	1e-03

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	10	77.5×	2e-14
protein localization to synapse	5	51.1×	4e-06
receptor clustering	6	49.9×	3e-07
regulation of postsynaptic membrane neurotransmitter receptor levels	6	39.6×	1e-06
cell-cell adhesion	9	12.2×	4e-06
protein-containing complex assembly	8	12.2×	2e-05
regulation of small GTPase mediated signal transduction	5	9.6×	4e-03
protein localization to plasma membrane	5	7.2×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	30
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

98 predictions. Top by Δscore:

Variant	Effect	Δscore
14:73617190:AAGG:A	donor_loss	1.0000
14:73617193:GT:G	donor_loss	1.0000
14:73617193:G:GG	donor_gain	0.9900
14:73617194:T:G	donor_loss	0.9900
14:73619233:G:A	acceptor_loss	0.9900
14:73618602:G:GA	donor_gain	0.9800
14:73619229:A:AG	acceptor_gain	0.9800
14:73619230:A:G	acceptor_gain	0.9800
14:73619232:A:AG	acceptor_gain	0.9800
14:73619233:G:GG	acceptor_gain	0.9800
14:73619233:GGTGA:G	acceptor_gain	0.9800
14:73619233:GGT:G	acceptor_gain	0.9700
14:73619229:AACAG:A	acceptor_gain	0.9600
14:73619232:AG:A	acceptor_gain	0.9600
14:73619233:GG:G	acceptor_gain	0.9600
14:73617206:A:AG	donor_gain	0.9500
14:73619232:AGGT:A	acceptor_gain	0.9500
14:73619233:GGTG:G	acceptor_gain	0.9500
14:73617191:AG:A	donor_gain	0.9400
14:73617192:GG:G	donor_gain	0.9400
14:73617190:AAG:A	donor_gain	0.9300
14:73618360:GCCC:G	donor_gain	0.9000
14:73618618:C:T	donor_gain	0.9000
14:73619232:AGGTG:A	acceptor_gain	0.8800
14:73619230:ACAGG:A	acceptor_gain	0.8400
14:73619231:CAGGT:C	acceptor_gain	0.8200
14:73619228:CAACA:C	acceptor_gain	0.7800
14:73618601:T:TA	donor_gain	0.7700
14:73619230:ACAG:A	acceptor_gain	0.7700
14:73617189:AAAG:A	donor_gain	0.7500

AlphaMissense

2747 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:73619338:T:A	N41K	0.913
14:73619338:T:G	N41K	0.913
14:73619768:T:A	W185R	0.908
14:73619768:T:C	W185R	0.908
14:73619564:A:C	S117R	0.898
14:73619566:T:A	S117R	0.898
14:73619566:T:G	S117R	0.898
14:73619337:A:T	N41I	0.881
14:73619303:T:C	F30L	0.880
14:73619305:C:A	F30L	0.880
14:73619305:C:G	F30L	0.880
14:73619770:G:C	W185C	0.872
14:73619770:G:T	W185C	0.872
14:73619786:T:C	F191L	0.867
14:73619788:C:A	F191L	0.867
14:73619788:C:G	F191L	0.867
14:73619272:A:C	K19N	0.863
14:73619272:A:T	K19N	0.863
14:73619264:T:C	F17L	0.855
14:73619266:T:A	F17L	0.855
14:73619266:T:G	F17L	0.855
14:73619287:T:G	C24W	0.851
14:73619653:C:A	H146Q	0.838
14:73619653:C:G	H146Q	0.838
14:73619765:G:C	A184P	0.836
14:73619262:G:A	G16E	0.830
14:73619551:T:A	D112E	0.818
14:73619551:T:G	D112E	0.818
14:73619285:T:C	C24R	0.808
14:73619531:T:C	F106L	0.807

dbSNP variants (sampled 300 via entrez): RS1001054758 (14:73615505 C>T), RS1001151014 (14:73615420 AAAAC>A), RS1001156058 (14:73614427 A>G,T), RS1001163912 (14:73616179 G>A), RS1001435701 (14:73616701 T>A), RS1001874893 (14:73611351 C>T), RS1001950092 (14:73610831 C>T), RS1003899922 (14:73610393 C>G), RS1004000530 (14:73613859 C>A), RS10047916 (14:73620031 A>C,G,T), RS1004964761 (14:73611486 A>G), RS1005405481 (14:73610802 T>C), RS1005613648 (14:73614148 C>T), RS1005829781 (14:73609160 T>C), RS1005994081 (14:73612634 C>T)

Disease associations

OMIM: gene MIM:614267 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST004958_3	Major coronary event in cardiovascular disease (time to event) (darapladib treatment interaction)	2.000000e-06
GCST004961_1	Major coronary event in placebo-treated cardiovascular disease (time to event)	2.000000e-08

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0006919	cardiovascular event measurement
EFO:0008395	response to darapladib
EFO:0008344	response to placebo

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs147204125	ACOT6, HEATR4		0.00	0

CTD chemical–gene interactions

15 total (human), top 15 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, decreases methylation	2
CGP 52608	affects binding, increases reaction	1
GW 4064	affects cotreatment, decreases expression	1
6-(4-chlorophenyl)imidazo(2,1-b)(1,3)thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime	affects cotreatment, increases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	increases expression, increases response to substance	1
ortho-topolin riboside	affects cotreatment, decreases expression	1
theaflavin-3,3’-digallate	affects expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	decreases methylation, increases methylation	1
Estradiol	decreases reaction, increases expression	1
Farnesol	affects cotreatment, decreases expression	1
Malathion	decreases expression	1
Melatonin	affects cotreatment, decreases expression	1
Smoke	decreases expression	1
Oleic Acid	affects cotreatment, increases expression, decreases expression	1

Clinical trials (associated diseases)

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