ACOT9

Summary

ACOT9 (acyl-CoA thioesterase 9, HGNC:17152) is a protein-coding gene on chromosome Xp22.11, encoding Acyl-coenzyme A thioesterase 9, mitochondrial (Q9Y305). Mitochondrial acyl-CoA thioesterase.

The protein encoded by this gene is a mitochondrial acyl-CoA thioesterase of unknown function. Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 23597 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 203 total — 4 pathogenic
• Druggable target: yes
• MANE Select transcript: NM_001037171

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17152
Approved symbol	ACOT9
Name	acyl-CoA thioesterase 9
Location	Xp22.11
Locus type	gene with protein product
Status	Approved
Aliases	CGI-16, MT-ACT48, ACATE2
Ensembl gene	ENSG00000123130
Ensembl biotype	protein_coding
OMIM	300862
Entrez	23597

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 16 protein_coding, 2 retained_intron, 1 nonsense_mediated_decay

ENST00000336430, ENST00000379295, ENST00000379297, ENST00000379303, ENST00000449612, ENST00000473710, ENST00000492081, ENST00000494361, ENST00000907178, ENST00000907179, ENST00000907180, ENST00000928894, ENST00000928895, ENST00000928896, ENST00000945994, ENST00000945995, ENST00000945996, ENST00000945997, ENST00000945998

RefSeq mRNA: 3 — MANE Select: NM_001037171 NM_001033583, NM_001037171, NM_001330259

CCDS: CCDS35216, CCDS43924, CCDS83460

Canonical transcript exons

ENST00000379303 — 16 exons

Exon	Start	End
ENSE00001480458	23701055	23703982
ENSE00001480462	23734341	23734367
ENSE00001889824	23743125	23743276
ENSE00003467474	23705509	23705594
ENSE00003471540	23721881	23721984
ENSE00003472646	23707877	23707944
ENSE00003475608	23730816	23730986
ENSE00003487754	23704694	23704844
ENSE00003519302	23735919	23736016
ENSE00003525537	23713135	23713208
ENSE00003528332	23722670	23722753
ENSE00003551303	23730527	23730564
ENSE00003639271	23733172	23733217
ENSE00003653139	23706628	23706739
ENSE00003666730	23704993	23705080
ENSE00003693868	23705768	23705858

Expression profiles

Bgee: expression breadth ubiquitous, 278 present calls, max score 95.11.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 37.1610 / max 226.2766, expressed in 1818 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
198723	36.9587	1818
198722	0.1336	60
198721	0.0688	27

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	95.11	gold quality
heart left ventricle	UBERON:0002084	94.71	gold quality
calcaneal tendon	UBERON:0003701	94.71	gold quality
cardiac ventricle	UBERON:0002082	94.59	gold quality
monocyte	CL:0000576	94.43	gold quality
mononuclear cell	CL:0000842	94.20	gold quality
right atrium auricular region	UBERON:0006631	94.20	gold quality
ascending aorta	UBERON:0001496	94.10	gold quality
thoracic aorta	UBERON:0001515	94.06	gold quality
mucosa of stomach	UBERON:0001199	94.03	gold quality
leukocyte	CL:0000738	93.97	gold quality
heart right ventricle	UBERON:0002080	93.95	gold quality
right coronary artery	UBERON:0001625	93.89	gold quality
aorta	UBERON:0000947	93.83	gold quality
heart	UBERON:0000948	93.83	gold quality
upper lobe of left lung	UBERON:0008952	93.83	gold quality
apex of heart	UBERON:0002098	93.82	gold quality
lower esophagus muscularis layer	UBERON:0035833	93.79	gold quality
tibial artery	UBERON:0007610	93.78	gold quality
popliteal artery	UBERON:0002250	93.77	gold quality
lower esophagus	UBERON:0013473	93.73	gold quality
right lung	UBERON:0002167	93.59	gold quality
cardiac atrium	UBERON:0002081	93.54	gold quality
left coronary artery	UBERON:0001626	93.46	gold quality
left ventricle myocardium	UBERON:0006566	93.38	gold quality
left uterine tube	UBERON:0001303	93.25	gold quality
omental fat pad	UBERON:0010414	93.24	gold quality
peritoneum	UBERON:0002358	93.19	gold quality
descending thoracic aorta	UBERON:0002345	93.18	gold quality
upper lobe of lung	UBERON:0008948	93.17	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-8142	yes	79.53
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Cross-species orthologs

12 orthologs

Organism	Symbol	Gene ID
danio_rerio	acot9.1	ENSDARG00000058352
danio_rerio	acot9.2	ENSDARG00000058390
mus_musculus	Acot9	ENSMUSG00000025287
mus_musculus	Acot10	ENSMUSG00000047565
rattus_norvegicus	Acot9	ENSRNOG00000003782
drosophila_melanogaster	CG13771	FBGN0031844
drosophila_melanogaster	CG1635	FBGN0039854
drosophila_melanogaster	CG1638	FBGN0039855
drosophila_melanogaster	CG1774	FBGN0039856
caenorhabditis_elegans		WBGENE00019015
caenorhabditis_elegans		WBGENE00020311
caenorhabditis_elegans		WBGENE00020674

Protein

Protein identifiers

Acyl-coenzyme A thioesterase 9, mitochondrial — Q9Y305 (reviewed: Q9Y305)

Alternative names: Acyl-CoA thioester hydrolase 9

All UniProt accessions (4): C9J7L8, Q9Y305, F8WDI2, H7C5Q2

UniProt curated annotations — full annotation on UniProt →

Function. Mitochondrial acyl-CoA thioesterase. Catalyzes the hydrolysis of acyl-CoAs into free fatty acids and coenzyme A (CoA), regulating their respective intracellular levels. Regulates both mitochondrial lipid and amino acid metabolism.

Subunit / interactions. Interacts with NYAP1, NYAP2 and MYO16.

Subcellular location. Mitochondrion. Mitochondrion matrix. Mitochondrion inner membrane.

Activity regulation. Strongly inhibited by NADH and CoA.

Pathway. Lipid metabolism; fatty acid metabolism.

Similarity. Belongs to the acyl coenzyme A hydrolase family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9Y305-1	1	yes
Q9Y305-2	2
Q9Y305-3	3
Q9Y305-4	4

RefSeq proteins (3): NP_001028755, NP_001032248, NP_001317188 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006683	Thioestr_dom	Domain
IPR029069	HotDog_dom_sf	Homologous_superfamily
IPR033120	HOTDOG_ACOT	Domain

Pfam: PF03061

Catalyzed reactions (Rhea), 9 shown:

• hexadecanoyl-CoA + H2O = hexadecanoate + CoA + H(+) (RHEA:16645)
• octanoyl-CoA + H2O = octanoate + CoA + H(+) (RHEA:30143)
• decanoyl-CoA + H2O = decanoate + CoA + H(+) (RHEA:40059)
• propanoyl-CoA + H2O = propanoate + CoA + H(+) (RHEA:40103)
• butanoyl-CoA + H2O = butanoate + CoA + H(+) (RHEA:40111)
• tetradecanoyl-CoA + H2O = tetradecanoate + CoA + H(+) (RHEA:40119)
• 4,8-dimethylnonanoyl-CoA + H2O = 4,8-dimethylnonanoate + CoA + H(+) (RHEA:40223)
• 2-methylpropanoyl-CoA + H2O = 2-methylpropanoate + CoA + H(+) (RHEA:40799)
• 3-methylbutanoyl-CoA + H2O = 3-methylbutanoate + CoA + H(+) (RHEA:66984)

UniProt features (10 total): splice variant 3, domain 2, transit peptide 1, chain 1, modified residue 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y305-F1	85.31	0.62

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 (1): 103

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-77289	Mitochondrial Fatty Acid Beta-Oxidation
R-HSA-1430728	Metabolism
R-HSA-556833	Metabolism of lipids
R-HSA-8978868	Fatty acid metabolism

MSigDB gene sets: 197 (showing top): GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, YANG_BREAST_CANCER_ESR1_LASER_DN, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, DARWICHE_SKIN_TUMOR_PROMOTER_UP, DARWICHE_PAPILLOMA_RISK_LOW_UP, DARWICHE_PAPILLOMA_RISK_HIGH_UP, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_LONG_CHAIN_FATTY_ACID_METABOLIC_PROCESS, DARWICHE_SQUAMOUS_CELL_CARCINOMA_UP, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, BORLAK_LIVER_CANCER_EGF_UP, GOBP_SHORT_CHAIN_FATTY_ACID_METABOLIC_PROCESS, DEURIG_T_CELL_PROLYMPHOCYTIC_LEUKEMIA_DN, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM1

GO Biological Process (5): long-chain fatty acid metabolic process (GO:0001676), acyl-CoA metabolic process (GO:0006637), short-chain fatty acid metabolic process (GO:0046459), lipid metabolic process (GO:0006629), fatty acid metabolic process (GO:0006631)

GO Molecular Function (5): acetyl-CoA hydrolase activity (GO:0003986), fatty acyl-CoA hydrolase activity (GO:0047617), carboxylic ester hydrolase activity (GO:0052689), long-chain fatty acyl-CoA hydrolase activity (GO:0052816), hydrolase activity (GO:0016787)

GO Cellular Component (4): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), mitochondrial matrix (GO:0005759), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Fatty acid metabolism	1
Metabolism	1
Metabolism of lipids	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
fatty acid metabolic process	2
acyl-CoA hydrolase activity	2
nucleoside phosphate metabolic process	1
sulfur compound metabolic process	1
purine-containing compound metabolic process	1
primary metabolic process	1
lipid metabolic process	1
monocarboxylic acid metabolic process	1
hydrolase activity, acting on ester bonds	1
fatty acyl-CoA hydrolase activity	1
catalytic activity	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
mitochondrion	1
intracellular organelle lumen	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1262 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ACOT9	ACOT8	O14734	703
ACOT9	ACOT13	Q9NPJ3	671
ACOT9	ACOT2	P49753	614
ACOT9	ACOT6	Q3I5F7	613
ACOT9	ACOT4	Q8N9L9	577
ACOT9	ACOT12	Q8WYK0	563
ACOT9	ACOT7	O00154	557
ACOT9	ACOT11	Q8WXI4	500
ACOT9	APOO	Q9BUR5	477
ACOT9	ACOT1	Q86TX2	465
ACOT9	KLHL15	Q96M94	452
ACOT9	PRDX4	Q13162	419
ACOT9	CD36	P16671	400
ACOT9	QKI	Q96PU8	392
ACOT9	ACSS3	Q9H6R3	391

IntAct

123 interactions, top by confidence:

A	B	Type	Score
ASH2L	KMT2D	psi-mi:“MI:0914”(association)	0.890
ISY1	AQR	psi-mi:“MI:0914”(association)	0.740
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
E7	RB1	psi-mi:“MI:0914”(association)	0.700
RABGGTB	PIPSL	psi-mi:“MI:0914”(association)	0.530
LAMP3	METTL15	psi-mi:“MI:0914”(association)	0.530
DNAAF8	CCDC85C	psi-mi:“MI:0914”(association)	0.530
PSG8	PEX7	psi-mi:“MI:0914”(association)	0.530
EPHA1	EXOC5	psi-mi:“MI:0914”(association)	0.530
COMMD10	VPS26C	psi-mi:“MI:0914”(association)	0.530
L3HYPDH	CCNE2	psi-mi:“MI:0914”(association)	0.530
C6	B3GLCT	psi-mi:“MI:0914”(association)	0.530
ISLR	BCKDK	psi-mi:“MI:0914”(association)	0.530
NRBP1	TBC1D4	psi-mi:“MI:0914”(association)	0.530
ABHD10	UBR5	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530

BioGRID (223): ACOT9 (Affinity Capture-MS), ACOT9 (Affinity Capture-MS), ACOT9 (Affinity Capture-MS), ACOT9 (Affinity Capture-MS), ACOT9 (Affinity Capture-MS), ACOT9 (Affinity Capture-MS), ACOT9 (Affinity Capture-MS), ACOT9 (Affinity Capture-MS), ACOT9 (Affinity Capture-MS), ACOT9 (Co-fractionation), ACOT9 (Proximity Label-MS), ACOT9 (Proximity Label-MS), ACOT9 (Proximity Label-MS), ACOT9 (Affinity Capture-MS), ACOT9 (Affinity Capture-MS)

ESM2 similar proteins: A2AIG8, A6NKP2, E9PTA2, O00764, O14734, O15315, O35331, O35719, O43502, O54783, O55229, O94759, P33124, P58137, Q3SWX2, Q3U129, Q4PS77, Q5I0K3, Q5RE34, Q5RJZ1, Q5T1C6, Q5ZM83, Q6AYT9, Q6DC64, Q6GV29, Q6NUN0, Q8BGA8, Q8CIW5, Q8IZ69, Q8K183, Q8K297, Q8N0X4, Q8R2J9, Q8R4N0, Q8TCT0, Q8VCE6, Q8VHK0, Q8VHQ9, Q8WXI4, Q91WC3

Diamond homologs: Q32MW3, Q3SWX2, Q9R0X4, Q9Y305, S4TDL2, S4TF94, O00154, P49851, Q64559, Q91V12

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 157 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
RHO GTPases activate PKNs	5	15.0×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	0
Uncertain significance	46
Likely benign	6
Benign	2

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
2579271	GRCh38/hg38 Xp22.11-21.1(chrX:23730430-32849918)x3	Pathogenic
4683034	GRCh37/hg19 Xp22.2-21.1(chrX:16586960-35065946)x3	Pathogenic
564695	GRCh37/hg19 Xp22.33-11.3(chrX:168546-43248706)x1	Pathogenic
686970	GRCh37/hg19 Xp22.12-21.1(chrX:20925922-35511818)x1	Pathogenic

SpliceAI

2063 predictions. Top by Δscore:

Variant	Effect	Δscore
X:23704744:G:C	acceptor_gain	1.0000
X:23705078:CCA:C	acceptor_gain	1.0000
X:23705079:CA:C	acceptor_gain	1.0000
X:23705079:CAC:C	acceptor_gain	1.0000
X:23705081:C:CC	acceptor_gain	1.0000
X:23705549:T:TA	donor_gain	1.0000
X:23706617:ACCAT:A	donor_gain	1.0000
X:23706618:CCATC:C	donor_gain	1.0000
X:23706621:T:TA	donor_gain	1.0000
X:23706626:A:AC	donor_gain	1.0000
X:23706627:C:CC	donor_gain	1.0000
X:23706735:GTTCA:G	acceptor_gain	1.0000
X:23706736:TTCA:T	acceptor_gain	1.0000
X:23706737:TCA:T	acceptor_gain	1.0000
X:23706738:CA:C	acceptor_gain	1.0000
X:23706738:CAC:C	acceptor_gain	1.0000
X:23706739:AC:A	acceptor_loss	1.0000
X:23706740:C:CC	acceptor_gain	1.0000
X:23706740:C:CG	acceptor_loss	1.0000
X:23706741:T:A	acceptor_loss	1.0000
X:23706746:C:CT	acceptor_gain	1.0000
X:23706747:A:T	acceptor_gain	1.0000
X:23721876:TTTA:T	donor_loss	1.0000
X:23721877:TTA:T	donor_loss	1.0000
X:23721878:TA:T	donor_loss	1.0000
X:23721879:A:AT	donor_loss	1.0000
X:23721980:CATAT:C	acceptor_gain	1.0000
X:23721981:ATAT:A	acceptor_gain	1.0000
X:23721982:TAT:T	acceptor_gain	1.0000
X:23721982:TATCT:T	acceptor_loss	1.0000

AlphaMissense

2984 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:23705038:A:C	F345L	0.999
X:23705038:A:T	F345L	0.999
X:23705039:A:G	F345S	0.999
X:23705040:A:G	F345L	0.999
X:23705568:A:C	F311L	0.999
X:23705568:A:T	F311L	0.999
X:23705570:A:G	F311L	0.999
X:23730537:G:C	D121E	0.999
X:23730537:G:T	D121E	0.999
X:23730816:C:G	R112T	0.999
X:23703955:C:G	R420P	0.998
X:23705039:A:C	F345C	0.998
X:23705566:C:T	G312D	0.998
X:23705590:C:G	R304P	0.998
X:23730538:T:A	D121V	0.998
X:23730538:T:G	D121A	0.998
X:23730541:A:G	L120P	0.998
X:23730550:A:G	L117P	0.998
X:23730559:C:T	G114D	0.998
X:23703962:C:A	G418W	0.997
X:23704800:A:C	S375R	0.997
X:23704800:A:T	S375R	0.997
X:23704802:T:G	S375R	0.997
X:23705027:A:T	V349D	0.997
X:23705563:C:T	G313D	0.997
X:23705564:C:G	G313R	0.997
X:23705586:G:C	N305K	0.997
X:23705586:G:T	N305K	0.997
X:23713153:C:G	R206P	0.997
X:23713175:C:G	A199P	0.997

dbSNP variants (sampled 300 via entrez): RS1000024758 (X:23708539 A>G), RS1000096207 (X:23710245 G>A), RS1000125044 (X:23716736 G>A), RS1000156074 (X:23716304 A>G), RS1000396176 (X:23731133 C>A), RS1000499656 (X:23714641 C>G), RS1000562697 (X:23719687 C>T), RS1000569401 (X:23721793 C>A), RS1000645888 (X:23723961 T>C), RS1000689481 (X:23707421 A>T), RS1000915857 (X:23737671 T>C), RS1001014596 (X:23745128 G>A), RS1001109593 (X:23701390 T>C), RS1001224089 (X:23729415 T>C,G), RS1001289309 (X:23737971 C>T)

Disease associations

OMIM: gene MIM:300862 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): polymicrogyria (MONDO:0000087)

Orphanet (1): Polymicrogyria (Orphanet:35981)

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST009391_1076	Metabolite levels	5.000000e-07
GCST011377_8	Shoulder impingement or rotator cuff tear	4.000000e-10

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0010529	ribose-5-phosphate measurement
EFO:0010530	ribulose-5-phosphate measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D065706	Polymicrogyria	C10.500.507.500.500; C16.131.666.507.500.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295987 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	increases expression	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
triphenyl phosphate	affects expression	1
propionaldehyde	increases methylation	1
bisphenol A	decreases expression	1
deoxynivalenol	increases expression	1
nonanal	increases methylation	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, increases expression	1
n-hexanal	increases methylation	1
tetrahydropalmatine	decreases expression	1
arsenite	affects binding, decreases reaction	1
butyraldehyde	increases methylation	1
perfluorooctanoic acid	increases expression	1
caprylic aldehyde	increases methylation	1
pentanal	increases methylation	1
heptanal	increases methylation	1
di-n-butylphosphoric acid	affects expression	1
obeticholic acid	increases expression	1
bisphenol B	increases expression	1
abrine	increases expression	1
bisphenol AF	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	decreases expression	1
Arsenic Trioxide	increases expression	1
Air Pollutants	increases abundance, decreases expression	1
Atrazine	increases expression	1
Vehicle Emissions	increases abundance, increases expression	1
Benzene	increases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Carbamazepine	affects 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
CHEMBL4118704	Binding	Binding affinity to ACOT9 in human NCI-H23 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B1IT	Abcam HeLa ACOT9 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00552045	Not specified	COMPLETED	Epilepsy Phenome/Genome Project
NCT04344626	Not specified	WITHDRAWN	Use of a Tonometer to Identify Epileptogenic Lesions During Pediatric Epilepsy Surgery