ACOT8

Summary

ACOT8 (acyl-CoA thioesterase 8, HGNC:15919) is a protein-coding gene on chromosome 20q13.12, encoding Acyl-coenzyme A thioesterase 8 (O14734). Catalyzes the hydrolysis of acyl-CoAs into free fatty acids and coenzyme A (CoASH), regulating their respective intracellular levels.

The protein encoded by this gene is a peroxisomal thioesterase that appears to be involved more in the oxidation of fatty acids rather than in their formation. The encoded protein can bind to the human immunodeficiency virus-1 protein Nef, and mediate Nef-induced down-regulation of CD4 in T-cells.

Source: NCBI Gene 10005 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 64 total — 2 pathogenic, 1 likely-pathogenic
• GTEx eGene: eQTL in 22 tissues, sQTL in 36 (q < 0.05)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.10 (unconstrained)
• MANE Select transcript: NM_005469
• Notable: 64 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15919
Approved symbol	ACOT8
Name	acyl-CoA thioesterase 8
Location	20q13.12
Locus type	gene with protein product
Status	Approved
Aliases	hACTE-III, hTE, PTE-2, NAP1
Ensembl gene	ENSG00000101473
Ensembl biotype	protein_coding
OMIM	608123
Entrez	10005

Gene structure

Transcript identifiers

Ensembl transcripts: 42 — 21 protein_coding, 17 nonsense_mediated_decay, 3 retained_intron, 1 protein_coding_CDS_not_defined

MANE Select: ENST00000217455

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 2: 4, TSL 3: 4, TSL 5: 3

ENST00000217455, ENST00000426915, ENST00000457981, ENST00000461272, ENST00000481938, ENST00000483141, ENST00000484783, ENST00000484975, ENST00000486165, ENST00000487205, ENST00000488679, ENST00000493118, ENST00000652771, ENST00000852115, ENST00000933252, ENST00000933253, ENST00000933254, ENST00000984696, ENST00000984697, ENST00000984698, ENST00000984699, ENST00000984700, ENST00000984701, ENST00001048738, ENST00001048739, ENST00001048740, ENST00001048741, ENST00001048742, ENST00001048743, ENST00001089812, ENST00001089813, ENST00001089814, ENST00001089815, ENST00001092510, ENST00001092511, ENST00001107237, ENST00001120585, ENST00001125230, ENST00001125231, ENST00001125232, ENST00001131150, ENST00001133196

RefSeq mRNA: 1 — MANE Select: NM_005469 NM_005469

CCDS: CCDS13378

Canonical transcript exons

ENST00000217455 — 6 exons

Exon	Start	End
ENSE00001817842	45841721	45841956
ENSE00001905512	45857188	45857392
ENSE00003477516	45848450	45848675
ENSE00003487486	45844263	45844420
ENSE00003492850	45855159	45855292
ENSE00003660763	45843527	45843721

Expression profiles

Bgee: expression breadth ubiquitous, 250 present calls, max score 96.23.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 26.3590 / max 162.8225, expressed in 1819 samples.

Highest expression (Bgee): mucosa of transverse colon, adrenal gland, adrenal gland cortex, prefrontal cortex, frontal lobe.

Genetic regulation across tissues (GTEx eQTL / sQTL)

ACOT8 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 22 tissues and its splicing (sQTL) in 36 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 58 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Heart Atrial Appendage	sqtl	8.1e-61	-1.12	20:45843524:C:T
Brain Caudate basal ganglia	sqtl	4.6e-44	-1.00	20:45843524:C:T
Nerve Tibial	sqtl	6.6e-44	-0.77	20:45843524:C:T
Esophagus Mucosa	sqtl	9.4e-44	-0.88	20:45843524:C:T
Testis	sqtl	1.5e-42	-1.00	20:45843524:C:T
Heart Left Ventricle	sqtl	3.5e-38	-1.10	20:45843524:C:T
Brain Cortex	sqtl	8.2e-37	-0.96	20:45843524:C:T
Brain Frontal Cortex BA9	sqtl	1.3e-36	-1.04	20:45843524:C:T
Brain Nucleus accumbens basal ganglia	sqtl	2.0e-33	-0.90	20:45843524:C:T
Skin Not Sun Exposed Suprapubic	sqtl	8.0e-32	-0.81	20:45843524:C:T
Skin Sun Exposed Lower leg	sqtl	8.0e-30	-0.69	20:45843524:C:T
Cells EBV-transformed lymphocytes	sqtl	1.5e-26	-0.94	20:45843524:C:T
Brain Anterior cingulate cortex BA24	sqtl	1.6e-25	-0.94	20:45843524:C:T
Brain Spinal cord cervical c-1	sqtl	3.5e-25	-0.97	20:45843524:C:T
Brain Putamen basal ganglia	sqtl	4.3e-24	-0.84	20:45843524:C:T
Artery Tibial	sqtl	1.2e-21	-0.61	20:45843524:C:T
Brain Substantia nigra	sqtl	2.1e-19	-0.92	20:45843524:C:T
Brain Hippocampus	sqtl	2.8e-19	-1.00	20:45843524:C:T
Lung	sqtl	6.3e-19	-0.55	20:45843524:C:T
Esophagus Muscularis	sqtl	1.3e-18	-0.62	20:45843524:C:T

FANTOM5 promoters

1 alternative TSS:

Promoter ID	TPM avg	Samples expressed
187494	26.3590	1819

Top tissues by expression

showing 100 of 290 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	96.23	gold quality
right adrenal gland	UBERON:0001233	94.05	gold quality
right adrenal gland cortex	UBERON:0035827	93.93	gold quality
prefrontal cortex	UBERON:0000451	93.70	gold quality
left adrenal gland	UBERON:0001234	93.30	gold quality
left adrenal gland cortex	UBERON:0035825	93.18	gold quality
right frontal lobe	UBERON:0002810	93.05	gold quality
cingulate cortex	UBERON:0003027	92.97	gold quality
anterior cingulate cortex	UBERON:0009835	92.93	gold quality
apex of heart	UBERON:0002098	92.84	gold quality
hindlimb stylopod muscle	UBERON:0004252	92.81	gold quality
nucleus accumbens	UBERON:0001882	92.15	gold quality
adrenal cortex	UBERON:0001235	92.07	gold quality
caudate nucleus	UBERON:0001873	91.93	gold quality
granulocyte	CL:0000094	91.60	gold quality
amygdala	UBERON:0001876	91.53	gold quality
adrenal gland	UBERON:0002369	91.39	gold quality
Brodmann (1909) area 9	UBERON:0013540	91.29	gold quality
putamen	UBERON:0001874	91.28	gold quality
adrenal tissue	UBERON:0018303	91.02	gold quality
right atrium auricular region	UBERON:0006631	90.95	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	90.94	gold quality
gastrocnemius	UBERON:0001388	90.70	gold quality
body of stomach	UBERON:0001161	90.69	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	90.67	gold quality
skin of leg	UBERON:0001511	90.65	gold quality
right hemisphere of cerebellum	UBERON:0014890	90.54	gold quality
frontal cortex	UBERON:0001870	90.50	gold quality
neocortex	UBERON:0001950	90.50	gold quality
lower esophagus mucosa	UBERON:0035834	90.49	gold quality
transverse colon	UBERON:0001157	90.38	gold quality
muscle of leg	UBERON:0001383	90.28	gold quality
skin of abdomen	UBERON:0001416	90.21	gold quality
heart left ventricle	UBERON:0002084	90.18	gold quality
cerebellar hemisphere	UBERON:0002245	90.14	gold quality
cerebellar cortex	UBERON:0002129	89.98	gold quality
cardiac ventricle	UBERON:0002082	89.73	gold quality
right lobe of liver	UBERON:0001114	89.71	gold quality
adenohypophysis	UBERON:0002196	89.66	gold quality
telencephalon	UBERON:0001893	89.26	gold quality
cerebral cortex	UBERON:0000956	89.06	gold quality
forebrain	UBERON:0001890	89.01	gold quality
right ovary	UBERON:0002118	88.96	gold quality
cerebellum	UBERON:0002037	88.78	gold quality
hypothalamus	UBERON:0001898	88.72	gold quality
spinal cord	UBERON:0002240	88.69	gold quality
pituitary gland	UBERON:0000007	88.62	gold quality
small intestine Peyer’s patch	UBERON:0003454	88.55	gold quality
stromal cell of endometrium	CL:0002255	88.43	gold quality
central nervous system	UBERON:0001017	88.42	gold quality
brain	UBERON:0000955	88.41	gold quality
stomach	UBERON:0000945	88.38	gold quality
muscle layer of sigmoid colon	UBERON:0035805	88.28	gold quality
metanephros cortex	UBERON:0010533	88.26	gold quality
lower esophagus	UBERON:0013473	88.26	gold quality
lower esophagus muscularis layer	UBERON:0035833	88.25	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	88.21	gold quality
heart	UBERON:0000948	88.10	gold quality
ectocervix	UBERON:0012249	88.05	gold quality
Ammon’s horn	UBERON:0001954	87.89	gold quality
left ovary	UBERON:0002119	87.86	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.85	gold quality
nerve	UBERON:0001021	87.85	gold quality
tibial nerve	UBERON:0001323	87.85	gold quality
right testis	UBERON:0004534	87.81	gold quality
right uterine tube	UBERON:0001302	87.72	gold quality
esophagus	UBERON:0001043	87.66	gold quality
frontal pole	UBERON:0002795	87.62	gold quality
left uterine tube	UBERON:0001303	87.59	gold quality
esophagus mucosa	UBERON:0002469	87.57	gold quality
left testis	UBERON:0004533	87.57	gold quality
cardiac atrium	UBERON:0002081	87.55	gold quality
small intestine	UBERON:0002108	87.55	gold quality
zone of skin	UBERON:0000014	87.52	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.50	gold quality
colon	UBERON:0001155	87.44	gold quality
endocervix	UBERON:0000458	87.39	gold quality
right lobe of thyroid gland	UBERON:0001119	87.34	gold quality
left coronary artery	UBERON:0001626	87.29	gold quality
monocyte	CL:0000576	87.26	gold quality
large intestine	UBERON:0000059	87.19	gold quality
left lobe of thyroid gland	UBERON:0001120	87.19	gold quality
intestine	UBERON:0000160	87.09	gold quality
leukocyte	CL:0000738	87.03	gold quality
popliteal artery	UBERON:0002250	86.97	gold quality
tibial artery	UBERON:0007610	86.95	gold quality
body of uterus	UBERON:0009853	86.93	gold quality
mononuclear cell	CL:0000842	86.88	gold quality
sigmoid colon	UBERON:0001159	86.70	gold quality
right coronary artery	UBERON:0001625	86.64	gold quality
mucosa of stomach	UBERON:0001199	86.62	gold quality
aorta	UBERON:0000947	86.59	gold quality
rectum	UBERON:0001052	86.58	gold quality
coronary artery	UBERON:0001621	86.56	gold quality
temporal lobe	UBERON:0001871	86.56	gold quality
secondary oocyte	CL:0000655	86.54	gold quality
minor salivary gland	UBERON:0001830	86.49	gold quality
duodenum	UBERON:0002114	86.45	gold quality
descending thoracic aorta	UBERON:0002345	86.44	gold quality
spleen	UBERON:0002106	86.32	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.66
E-HCAD-5	no	2.28

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 79 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Superior colliculi	tissue	47.5
Pons	tissue	45.6
Thalamus	tissue	45.5
Midbrain	tissue	40.3
Medulla oblongata	tissue	36.2
Substantia nigra	tissue	36.1
Cerebral cortex	tissue	34.8	medium
Somatosensory cortex	tissue	34.8
Putamen	tissue	33.9
Cerebellum	tissue	33.9	high
Spinal cord	tissue	33.4
Occipital cortex	tissue	32.6
Hypothalamus	tissue	32.0
Locus coeruleus	tissue	30.8
Postcentral gyrus	tissue	30.6
Septum	tissue	28.9
Hippocampal formation	tissue	27.8
Basal ganglia	tissue	27.3	medium
Hippocampus	tissue	27.3	medium
Ventral forebrain	tissue	27.3
Motor cortex	tissue	27.0
Periaqueductal gray	tissue	26.4
Nucleus accumbens	tissue	26.3
Retrosplenial and cingulate cortex	tissue	25.7
Entorhinal cortex	tissue	25.4
Temporal cortex	tissue	25.2
Olfactory bulb	tissue	24.6
Retrosplenial cortex	tissue	24.4
Prefrontal cortex	tissue	24.3
Heart muscle	tissue	24.0	medium
Corpus callosum	tissue	22.6
Skeletal muscle	tissue	21.5	medium
Choroid plexus	tissue	21.0
Insular cortex	tissue	20.6
Duodenum	tissue	20.1	high
Amygdala	tissue	19.9
Small intestine	tissue	19.5	high
Bone marrow	tissue	17.2	low
Tongue	tissue	16.6
Skin 1	tissue	15.5	low
Stomach 1	tissue	15.1	high
Pituitary gland	tissue	15.0
Colon	tissue	14.7	high
Pancreas	tissue	14.7	medium
Adrenal gland	tissue	14.4	high
Parathyroid gland	tissue	14.2	high
Esophagus	tissue	13.2	medium
Kidney	tissue	12.8	high
Salivary gland	tissue	12.3	medium
Thymus	tissue	12.3
Rectum	tissue	12.1	medium
Lymph node	tissue	11.9	high
Liver	tissue	11.5	high
Epididymis	tissue	10.4	high
Retina	tissue	10.3
Thyroid gland	tissue	10.2	medium
Fallopian tube	tissue	10.2	medium
Vagina	tissue	10.1	low
Testis	tissue	9.5	high
Tonsil	tissue	9.1	high

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Dorsal spinal cord (33.4), Hippocampus, CA1 (33.0), Nucleus of the diagonal band (32.1), Perirhinal gyrus (31.5), Posterior thalamic nucleus (31.5).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SMARCA1

Functional genomics

gnomAD constraint: pLI 5.83e-10, LOEUF 1.1, missense Z 1.11 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000217455 — one region, missense o/e 0.88.

Literature-anchored findings (GeneRIF, showing 5)

• ACOT4 and ACOT8 are responsible for the termination of beta-oxidation of dicarboxylic acids of medium-chain length with the concomitant release of the corresponding free acids (PMID:16141203)
• SREBP2 modulates brain palmitoyl-coa hydrolase gene transcription. (PMID:16335799)
• An isoform of long-chain acyl-CoA hydrolase may be responsible for the nafamostat hydrolysis in human liver cytosol. (PMID:17624024)
• Acyl-CoA thioesterase 8 is a specific protein related to nodal metastasis and prognosis of lung adenocarcinoma. (PMID:23540296)
• In summary, lipolytic enzyme ACOT8 is frequently upregulated in HCC clinical specimens. More importantly, ACOT8 silencing leads to inhibition of cell growth in HCC in vitro. (PMID:24788990)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	acot8	ENSDARG00000014138
mus_musculus	Acot8	ENSMUSG00000017307
rattus_norvegicus	Acot8	ENSRNOG00000015187
caenorhabditis_elegans	Y87G2A.2	WBGENE00013594
caenorhabditis_elegans		WBGENE00015887
caenorhabditis_elegans		WBGENE00015889
caenorhabditis_elegans		WBGENE00016511
caenorhabditis_elegans		WBGENE00017048
caenorhabditis_elegans		WBGENE00017781

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:2158201) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 1 distinct phenotype terms.

Mouse phenotype (MP)	Records
increased body length	1

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.

Organism	UniProt	Identity	Method
Escherichia coli K-12	P0AGG2	100.0%	Diamond
Escherichia coli O157:H7	P0AGG3	100.0%	Diamond
Arabidopsis thaliana	F4HU51	68.9%	Diamond
Haemophilus influenzae Rd KW20	P44498	52.3%	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).

Symbol	Type	Entrez
DNTTIP1	protein-coding	116092
WFDC3	protein-coding	140686
TNNC2	protein-coding	7125
SNX21	protein-coding	90203
UBE2C	protein-coding	11065
ZSWIM3	protein-coding	140831
ZSWIM1	protein-coding	90204
SPATA25	protein-coding	128497
NEURL2	protein-coding	140825
PLTP	protein-coding	5360
CTSA	protein-coding	5476

Protein

Protein identifiers

Acyl-coenzyme A thioesterase 8 — O14734 (reviewed: O14734)

Alternative names: Choloyl-coenzyme A thioesterase, HIV-Nef-associated acyl-CoA thioesterase, Peroxisomal acyl-CoA thioesterase 2, Peroxisomal acyl-coenzyme A thioester hydrolase 1, Peroxisomal long-chain acyl-CoA thioesterase 1, Thioesterase II

All UniProt accessions (9): A0A494C0N6, E9PIS4, E9PJN0, E9PRD4, O14734, F6VBM3, H0Y698, H7C5A7, Q9BR14

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. Displays no strong substrate specificity with respect to the carboxylic acid moiety of Acyl-CoAs. Hydrolyzes medium length (C2 to C20) straight-chain, saturated and unsaturated acyl-CoAS but is inactive towards substrates with longer aliphatic chains. Moreover, it catalyzes the hydrolysis of CoA esters of bile acids, such as choloyl-CoA and chenodeoxycholoyl-CoA and competes with bile acid CoA:amino acid N-acyltransferase (BAAT). Is also able to hydrolyze CoA esters of dicarboxylic acids. It is involved in the metabolic regulation of peroxisome proliferation. (Microbial infection) May mediate Nef-induced down-regulation of CD4 cell-surface expression.

Subunit / interactions. Homodimer. (Microbial infection) Interacts with human immunodeficiency virus (HIV-1) Nef (via middle region); this interaction enhances ACOT8 Acyl-CoA thioesterase activity and occurs in a Nef myristoylation-independent manner. According to a second report, the interaction with HIV-1 Nef occurs in a Nef myristoylation-independent manner but does not enhance ACOT8 Acyl-CoA thioesterase activity.

Subcellular location. Peroxisome matrix.

Tissue specificity. Detected in a T-cell line (at protein level). Ubiquitous.

Activity regulation. Inhibited by CoASH (IC(50)=10-15 uM). Also inhibited by cysteine-reactive agents.

Induction. Regulated by peroxisome proliferator (such as Clofibrate), via the peroxisome proliferator-activated receptors (PPARs).

Pathway. Lipid metabolism; fatty acid metabolism.

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

RefSeq proteins (1): NP_005460* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003703	Acyl_CoA_thio	Family
IPR029069	HotDog_dom_sf	Homologous_superfamily
IPR042171	Acyl-CoA_hotdog	Homologous_superfamily
IPR049449	TesB_ACOT8-like_N	Domain
IPR049450	ACOT8-like_C	Domain

Pfam: PF13622, PF20789

Enzyme classification (BRENDA)

• EC 3.1.2.2 — palmitoyl-CoA hydrolase (BRENDA: 40 organisms, 184 substrates, 159 inhibitors, 142 Km, 46 kcat entries)
• EC 3.1.2.20 — acyl-CoA hydrolase (BRENDA: 47 organisms, 273 substrates, 173 inhibitors, 271 Km, 184 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
HEXADECANOYL-COA	—	26
HEXADECANOYL-COA	—	25
PALMITOYL-COA	0.0024–33	14
MYRISTOYL-COA	0.0025–0.0228	13
DODECANOYL-COA	0.0018–0.325	12
3-HYDROXYPHENYLACETYL-COA	0.0037–0.9	11
LAUROYL-COA	0.0385–0.185	10
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
OLEOYL-COA	0.0014–0.0088	8
TETRADECANOYL-COA	0.0016–0.024	8
2,3-DIHYDROXYBENZOYL-COA	0.0375–1.42	7

Catalyzed reactions (Rhea)

• succinyl-CoA + H2O = succinate + CoA + H(+) (RHEA:11516)
• choloyl-CoA + H2O = cholate + CoA + H(+) (RHEA:14541)
• acetoacetyl-CoA + H2O = acetoacetate + CoA + H(+) (RHEA:15673)
• (3S)-3-hydroxy-3-methylglutaryl-CoA + H2O = 3-hydroxy-3-methylglutarate + CoA + H(+) (RHEA:16305)
• hexadecanoyl-CoA + H2O = hexadecanoate + CoA + H(+) (RHEA:16645)
• acetyl-CoA + H2O = acetate + CoA + H(+) (RHEA:20289)
• dodecanoyl-CoA + H2O = dodecanoate + CoA + H(+) (RHEA:30135)
• octadecanoyl-CoA + H2O = octadecanoate + CoA + H(+) (RHEA:30139)
• octanoyl-CoA + H2O = octanoate + CoA + H(+) (RHEA:30143)
• chenodeoxycholoyl-CoA + H2O = chenodeoxycholate + CoA + H(+) (RHEA:31511)
• decanoyl-CoA + H2O = decanoate + CoA + H(+) (RHEA:40059)
• propanoyl-CoA + H2O = propanoate + CoA + H(+) (RHEA:40103)

UniProt features (9 total): active site 3, sequence conflict 2, chain 1, region of interest 1, short sequence motif 1, mutagenesis site 1

Structure

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O14734-F1	88.58	0.70

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Hydrolases, Metabolic proteins, Predicted intracellular proteins, Plasma proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): vesicles; mitochondria

Antibody reliability (HPA): IH approved · 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.

Catalytic / active sites (3)

Position	Role
232	charge relay system
254	charge relay system
304	charge relay system

Mutagenesis-validated functional residues (1)

Position	Phenotype
78	reduces acyl-coa thioesterase activity and peroxisome proliferation.

Function

Pathways and Gene Ontology

Reactome pathways

4 curated (TAS) of 14; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

14 pathways:

ID	Pathway	Evidence
R-HSA-389887	Beta-oxidation of pristanoyl-CoA	curated
R-HSA-390247	Beta-oxidation of very long chain fatty acids	curated
R-HSA-193368	Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol	curated
R-HSA-2046106	alpha-linolenic acid (ALA) metabolism	curated
R-HSA-194068	Bile acid and bile salt metabolism	—
R-HSA-8978868	Fatty acid metabolism	—
R-HSA-1430728	Metabolism	—
R-HSA-556833	Metabolism of lipids	—
R-HSA-8957322	Metabolism of steroids	—
R-HSA-390918	Peroxisomal lipid metabolism	—
R-HSA-9033241	Peroxisomal protein import	electronic
R-HSA-9609507	Protein localization	—
R-HSA-192105	Synthesis of bile acids and bile salts	—
R-HSA-2046104	alpha-linolenic (omega3) and linoleic (omega6) acid metabolism	—

MSigDB gene sets: 199 (showing top): GOBP_LIPID_MODIFICATION, GOBP_FATTY_ACID_CATABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_LONG_CHAIN_FATTY_ACID_METABOLIC_PROCESS, TGACCTY_ERR1_Q2, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GGGTGGRR_PAX4_03, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_DICARBOXYLIC_ACID_METABOLIC_PROCESS, COUP_01, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_BILE_ACID_BIOSYNTHETIC_PROCESS, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, GOBP_REGULATION_OF_GLYCOPROTEIN_METABOLIC_PROCESS

GO Biological Process (12): fatty acid biosynthetic process (GO:0006633), acyl-CoA metabolic process (GO:0006637), bile acid biosynthetic process (GO:0006699), fatty acid catabolic process (GO:0009062), negative regulation of glycoprotein biosynthetic process (GO:0010561), peroxisome fission (GO:0016559), fatty acid beta-oxidation using acyl-CoA oxidase (GO:0033540), alpha-linolenic acid metabolic process (GO:0036109), dicarboxylic acid catabolic process (GO:0043649), lipid metabolic process (GO:0006629), fatty acid metabolic process (GO:0006631), peroxisome organization (GO:0007031)

GO Molecular Function (12): acetyl-CoA hydrolase activity (GO:0003986), succinyl-CoA hydrolase activity (GO:0004778), acyl-CoA hydrolase activity (GO:0016289), choloyl-CoA hydrolase activity (GO:0033882), acetoacetyl-CoA hydrolase activity (GO:0047603), fatty acyl-CoA hydrolase activity (GO:0047617), hydroxymethylglutaryl-CoA hydrolase activity (GO:0047994), carboxylic ester hydrolase activity (GO:0052689), medium-chain fatty acyl-CoA hydrolase activity (GO:0052815), long-chain fatty acyl-CoA hydrolase activity (GO:0052816), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (3): peroxisomal matrix (GO:0005782), cytosol (GO:0005829), peroxisome (GO:0005777)

Reactome top-level categories

9 top-level categories:

Category	Pathways
Peroxisomal lipid metabolism	2
Fatty acid metabolism	2
Metabolism of lipids	2
Synthesis of bile acids and bile salts	1
alpha-linolenic (omega3) and linoleic (omega6) acid metabolism	1
Protein localization	1
Bile acid and bile salt metabolism	1
Metabolism of steroids	1
Metabolism	1

GO top-level categories

37 GO namespaces:

Category	Terms
acyl-CoA hydrolase activity	6
fatty acid metabolic process	2
monocarboxylic acid biosynthetic process	2
fatty acyl-CoA hydrolase activity	2
lipid biosynthetic process	1
nucleoside phosphate metabolic process	1
sulfur compound metabolic process	1
purine-containing compound metabolic process	1
bile acid metabolic process	1
lipid catabolic process	1
monocarboxylic acid catabolic process	1
glycoprotein biosynthetic process	1
negative regulation of macromolecule biosynthetic process	1
regulation of glycoprotein biosynthetic process	1
negative regulation of glycoprotein metabolic process	1
peroxisome organization	1
organelle fission	1
fatty acid beta-oxidation	1
long-chain fatty acid metabolic process	1
unsaturated fatty acid metabolic process	1
olefinic compound metabolic process	1
dicarboxylic acid metabolic process	1
carboxylic acid catabolic process	1
primary metabolic process	1
lipid metabolic process	1
monocarboxylic acid metabolic process	1
organelle organization	1
thiolester hydrolase activity	1
deacylase activity	1
hydrolase activity, acting on ester bonds	1
binding	1
catalytic activity	1
peroxisome	1
microbody lumen	1
cytoplasm	1
cellular anatomical structure	1
microbody	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 8 of 27 annotations. The rest are phylogenetic / computational / electronic (IEA).

8 experimentally-supported GO terms:

GO term	NS	Evidence
acyl-CoA metabolic process	BP	direct assay
dicarboxylic acid catabolic process	BP	direct assay
negative regulation of glycoprotein biosynthetic process	BP	direct assay
peroxisome fission	BP	direct assay
peroxisomal matrix	CC	direct assay
fatty acyl-CoA hydrolase activity	MF	direct assay
long-chain fatty acyl-CoA hydrolase activity	MF	direct assay
medium-chain fatty acyl-CoA hydrolase activity	MF	direct assay

Protein interactions and networks

STRING

showing 16 of 1,130 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ACOT8	ACOT2	P49753	951
ACOT8	ACOT1	Q86TX2	949
ACOT8	ACOT4	Q8N9L9	700
ACOT8	PPARA	Q07869	672
ACOT8	ACOT9	Q9Y305	667
ACOT8	ACOT13	Q9NPJ3	665
ACOT8	ACOT12	Q8WYK0	599
ACOT8	ACOT7	O00154	584
ACOT8	ACOT6	Q3I5F7	570
ACOT8	SPATA25	Q9BR10	552
ACOT8	ACOT11	Q8WXI4	549
ACOT8	ACAD8	Q9UKU7	505
ACOT8	SLC27A5	Q9Y2P5	504
ACOT8	NEURL2	Q9BR09	500
ACOT8	EHHADH	Q08426	486
ACOT8	ACOX1	Q15067	486

IntAct

Human interaction partners of ACOT8 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

showing 30 of 31 partners by confidence:

Partner	Interaction type	MIscore	Records
PTPN3	association	0.590	2
MAST1	direct interaction	0.590	1
REL	physical association	0.560	6
P4HA3	physical association	0.560	3
PEX5	physical association	0.560	3
COA7	physical association	0.560	1
PML	association	0.530	2
SCRIB	direct interaction	0.440	2
APBA1	direct interaction	0.440	1
APBA3	direct interaction	0.440	1
ARHGEF12	direct interaction	0.440	1
DLG3	direct interaction	0.440	1
ERBIN	direct interaction	0.440	1
GORASP2	direct interaction	0.440	1
MAST2	direct interaction	0.440	1
NHERF2	direct interaction	0.440	1
PDZD7	direct interaction	0.440	1
PDZK1	direct interaction	0.440	1
RHPN1	direct interaction	0.440	1
SHANK1	direct interaction	0.440	1
SNTG2	direct interaction	0.440	1
SNX27	direct interaction	0.440	1
TIAM2	direct interaction	0.440	1
WHRN	direct interaction	0.440	1
CFTR	physical association	0.370	3
CDC26	association	0.350	2
ICP0	association	0.350	1
IGHA1	association	0.350	1
SNX21	association	0.350	1
US3	association	0.350	1

BioGRID (94 interactions; top human partners by supporting records): PEX5 (Two-hybrid; 5 records), KLHL23 (Affinity Capture-MS; 3 records), PML (Affinity Capture-MS; 3 records), IGHA1 (Affinity Capture-MS; 2 records), PTPN3 (Affinity Capture-MS; 2 records), REL (Two-hybrid; 2 records), ACOT1 (FRET), AGO2 (Affinity Capture-RNA), AGPS (Proximity Label-MS), ANPEP (Proximity Label-MS), BRCA1 (Affinity Capture-MS), BRD1 (Affinity Capture-MS), BRD8 (Affinity Capture-MS), C9orf72 (Affinity Capture-MS), CAT (Proximity Label-MS)

SIGNOR signaling

4 signaling interactions:

A	Effect	B	Mechanism
ACOT8	“up-regulates quantity”	“coenzyme A(4-)”	“chemical modification”
ACOT8	“down-regulates quantity”	succinyl-CoA(5-)	“chemical modification”
ACOT8	“up-regulates quantity”	glutarate(2-)	“chemical modification”
ACOT8	“down-regulates quantity”	glutaryl-CoA(5-)	“chemical modification”

Disease & clinical

Genetic variants

Variant evidence for ACOT8: 64 ClinVar records (3 pathogenic / likely pathogenic). Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	1
Uncertain significance	43
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (3)

Showing all 3 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
2425559	NC_000020.10:g.(?42223339)(44638757_?)del	Pathogenic	criteria provided, single submitter	1
3248279	NC_000020.10:g.(?42223339)(45362473_?)del	Pathogenic	criteria provided, single submitter	1
813269	Single allele	Likely pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore ACOT8’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; 37 predictions of 510):

Position(s)	Effect	Δscore	Sites
20:45844421–45844422	acceptor_loss	1.0000	6
20:45848448–45848449	donor_loss	1.0000	3
20:45844261–45844262	donor_loss	0.9900	5
20:45844427	acceptor_gain	0.9900
20:45848449	donor_loss	0.9900	2
20:45848676–45848677	acceptor_loss	0.9900	6
20:45855293–45855294	acceptor_loss	0.9900	6
20:45857186–45857187	donor_loss	0.9900	6
20:45844261	donor_loss	0.9800
20:45848680	acceptor_gain	0.9800

AlphaMissense

764 missense substitutions predicted likely pathogenic (of 2,080 scored), across 192 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
D232	8	0.990	0.998
F84	8	0.973	0.997
H257	8	0.972	0.989
D256	8	0.970	0.983
H81	8	0.949	0.987
F128	8	0.946	0.996
D268	8	0.926	0.976
F261	8	0.912	0.992
H262	8	0.900	0.990
H78	8	0.880	0.959
F265	8	0.870	0.974
F235	8	0.807	0.955
F122	8	0.789	0.966
F55	7	0.989	0.997
W208	7	0.979	0.995
W292	7	0.978	0.989
W270	7	0.972	0.993
F42	7	0.969	0.988
W260	7	0.968	0.994
E305	7	0.952	0.984

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

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

2 prognostic cancer types:

Cancer	Prognostic	p-value
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	4.45e-05
Liver Hepatocellular Carcinoma (validation)	unfavorable	7.03e-05

Disease associations

OMIM: gene MIM:608123 | disease phenotypes: MIM:614868, MIM:102700

GenCC curated gene-disease

Mondo (2): combined immunodeficiency due to STK4 deficiency (MONDO:0013934), severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency (MONDO:0007064)

Orphanet (2): Combined immunodeficiency due to STK4 deficiency (Orphanet:314689), Severe combined immunodeficiency due to adenosine deaminase deficiency (Orphanet:277)

MeSH disease descriptors

1 disease descriptors:

Descriptor	Name	Tree numbers
C531816	Severe combined immunodeficiency due to adenosine deaminase deficiency *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Cadmium Chloride	decreases expression	2
lasiocarpine	decreases expression	1
triphenyl phosphate	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	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, decreases expression	1
bisphenol S	decreases methylation	1
Resveratrol	affects cotreatment, increases expression	1
Orlistat	decreases expression	1
Air Pollutants	affects expression, increases abundance	1
Amiodarone	increases expression	1
Atrazine	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Diuron	decreases expression	1
Doxorubicin	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Ozone	affects expression, increases abundance	1
Plant Extracts	affects cotreatment, increases expression	1
Smoke	decreases expression	1
Paclitaxel	decreases expression	1
Antirheumatic Agents	decreases expression	1
Oleic Acid	affects cotreatment, decreases expression	1
Copper Sulfate	increases expression	1
Lactic Acid	decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_F6I2	EDITGENE ACOT8 Knockout HeLa Cell Line	Cancer cell line	Female

Clinical trials (associated diseases)

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

19 trials:

NCT	Phase	Status	Title
NCT01420627	Phase 3	COMPLETED	EZN-2279 in Patients With ADA-SCID
NCT00008450	Phase 1	COMPLETED	Total-Body Irradiation Followed By Cyclosporine and Mycophenolate Mofetil in Treating Patients With Severe Combined Immunodeficiency Undergoing Donor Bone Marrow Transplant
NCT02022696	Phase 1	COMPLETED	Treatment of SCID Due to ADA Deficiency With Autologous Transplantation of Cord Blood or Hematopoietic CD 34+ Cells After Addition of a Normal Human ADA cDNA by the EFS-ADA Lentiviral Vector
NCT04140539	Phase 2/3	WITHDRAWN	A Clinical Study to Enable Process Validation of Commercial Grade OTL-101
NCT01279720	Phase 1/2	COMPLETED	Gene Therapy ADA Deficiency
NCT01380990	Phase 1/2	COMPLETED	Lentiviral (LV) Gene Therapy for Adenosine Deaminase (ADA) Deficiency
NCT01852071	Phase 1/2	COMPLETED	Autologous CD34+ Hematopoietic Stem Cells Transduced ex Vivo With Elongation Factor 1 Alpha Shortened (EFS) Lentiviral Vector Encoding for the Human ADA Gene
NCT02999984	Phase 1/2	COMPLETED	Efficacy and Safety of the Cryopreserved Formulation of OTL-101 in Subjects With ADA-SCID
NCT03765632	Phase 1/2	COMPLETED	Efficacy and Safety of the Cryopreserved Formulation of OTL-101 in Subjects With ADA-SCID
NCT01182857	Not specified	WITHDRAWN	Quality of Life and Neuropsychiatric Sequelae in Patients Treated With Gene Therapy for ADA-SCID and in Their Parents
NCT01186913	Not specified	ENROLLING_BY_INVITATION	Natural History Study of SCID Disorders
NCT01346150	Not specified	UNKNOWN	Patients Treated for SCID (1968-Present)
NCT03232203	Not specified	COMPLETED	Evaluating the Effectiveness of STRIMVELIS Risk Minimization Measures (RMMs)
NCT03655223	Not specified	ACTIVE_NOT_RECRUITING	Early Check: Expanded Screening in Newborns
NCT04049084	Not specified	ENROLLING_BY_INVITATION	An Observational LTFU Study for Patients Previously Treated With Autologous ex Vivo Gene Therapy for ADA-SCID
NCT04959890	Not specified	UNKNOWN	Methodology Study of Retroviral Insertion Site Analysis in Strimvelis Gene Therapy
NCT05300334	Not specified	UNKNOWN	Investigation of ADA Enzyme Deficiency
NCT05300347	Not specified	UNKNOWN	Observational Study Evaluating the Prevalence of Enzyme Deficiency in Pulmonology Clinics (ADA)
NCT05300373	Not specified	UNKNOWN	Evaluation of Adenosine Deaminase (ADA) Enzyme Deficiency in Patients With Lymphopenia and/or Elevated Immunoglobulin E