ACAT2

Summary

ACAT2 (acetyl-CoA acetyltransferase 2, HGNC:94) is a protein-coding gene on chromosome 6q25.3, encoding Acetyl-CoA acetyltransferase, cytosolic (Q9BWD1). Involved in the biosynthetic pathway of cholesterol.

The product of this gene is an enzyme involved in lipid metabolism, and it encodes cytosolic acetoacetyl-CoA thiolase. This gene shows complementary overlapping with the 3-prime region of the TCP1 gene in both mouse and human. These genes are encoded on opposite strands of DNA, as well as in opposite transcriptional orientation. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 39 — RefSeq curated summary.

At a glance

• Gene–disease (curated): acetyl-CoA acetyltransferase-2 deficiency (Limited, GenCC)
• Clinical variants (ClinVar): 105 total — 13 pathogenic
• GTEx eGene: eQTL in 23 tissues, sQTL in 1 (q < 0.05)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.99 (unconstrained)
• MANE Select transcript: NM_005891
• Notable: 105 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:94
Approved symbol	ACAT2
Name	acetyl-CoA acetyltransferase 2
Location	6q25.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000120437
Ensembl biotype	protein_coding
Entrez	39

Gene structure

Transcript identifiers

Ensembl transcripts: 28 — 24 protein_coding, 2 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

MANE Select: ENST00000367048

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

ENST00000367048, ENST00000467951, ENST00000472052, ENST00000869581, ENST00000869582, ENST00000869583, ENST00000869584, ENST00000869585, ENST00000869586, ENST00000869587, ENST00000869588, ENST00000869589, ENST00000869590, ENST00000869591, ENST00000934470, ENST00000934471, ENST00000934472, ENST00000934473, ENST00000934474, ENST00000942453, ENST00001082911, ENST00001096361, ENST00001106205, ENST00001118931, ENST00001118932, ENST00001128575, ENST00001130288, ENST00001135724

RefSeq mRNA: 2 — MANE Select: NM_005891 NM_001303253, NM_005891

CCDS: CCDS5268

Canonical transcript exons

ENST00000367048 — 9 exons

Exon	Start	End
ENSE00000765642	159775170	159775313
ENSE00000765643	159776150	159776272
ENSE00001510952	159762045	159762142
ENSE00001923516	159778659	159779112
ENSE00003507618	159767005	159767186
ENSE00003528567	159768511	159768628
ENSE00003534886	159778170	159778280
ENSE00003610929	159762919	159763053
ENSE00003693368	159777302	159777456

Expression profiles

Bgee: expression breadth ubiquitous, 283 present calls, max score 98.16.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 71.2848 / max 575.3258, expressed in 1822 samples.

Highest expression (Bgee): ventricular zone, ganglionic eminence, adrenal tissue, embryo, cortical plate.

Genetic regulation across tissues (GTEx eQTL / sQTL)

ACAT2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 23 tissues and its splicing (sQTL) in 1 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 24 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Testis	eqtl	4.0e-14	+0.32	6:159733067:G:C
Cells Cultured fibroblasts	eqtl	4.4e-13	+0.19	6:159772208:C:A
Muscle Skeletal	eqtl	2.3e-10	+0.27	6:159650620:T:G
Artery Tibial	eqtl	1.7e-07	+0.27	6:159769586:A:T
Breast Mammary Tissue	eqtl	3.4e-07	+0.31	6:159799655:A:G
Adipose Visceral Omentum	eqtl	4.4e-07	+0.24	6:159780263:C:A
Skin Not Sun Exposed Suprapubic	eqtl	1.3e-06	+0.21	6:159781828:C:T
Skin Sun Exposed Lower leg	eqtl	1.1e-05	+0.20	6:159780263:C:A
Esophagus Muscularis	eqtl	1.7e-05	+0.22	6:159656890:G:C
Esophagus Gastroesophageal Junction	eqtl	3.4e-05	+0.27	6:159791236:G:A
Adipose Subcutaneous	eqtl	5.0e-05	+0.23	6:159781828:C:T
Brain Caudate basal ganglia	eqtl	1.0e-04	+0.30	6:159738471:C:T
Brain Cerebellum	eqtl	4.5e-04	+0.65	6:160650950:G:A
Small Intestine Terminal Ileum	eqtl	4.7e-04	+0.31	6:159776770:C:T
Brain Hippocampus	eqtl	6.9e-04	+0.28	6:159727968:C:G
Artery Aorta	eqtl	2.3e-03	+0.27	6:159741804:G:A
Thyroid	eqtl	2.6e-03	+0.14	6:159764345:G:A
Brain Putamen basal ganglia	eqtl	3.1e-03	+0.31	6:159769586:A:T
Spleen	eqtl	6.1e-03	+0.28	6:159762293:G:C
Brain Amygdala	eqtl	1.7e-02	+2.36	6:159648846:G:C

FANTOM5 promoters

6 alternative TSS:

Promoter ID	TPM avg	Samples expressed
70983	66.3265	1820
70985	3.3816	1043
70984	0.7673	400
70987	0.6514	159
70986	0.1410	56
204276	0.0170	10

Top tissues by expression

showing 100 of 293 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	98.16	gold quality
ganglionic eminence	UBERON:0004023	98.15	gold quality
adrenal tissue	UBERON:0018303	97.94	gold quality
embryo	UBERON:0000922	97.64	gold quality
cortical plate	UBERON:0005343	96.84	gold quality
pons	UBERON:0000988	95.36	gold quality
right lobe of liver	UBERON:0001114	95.04	gold quality
upper leg skin	UBERON:0004262	94.97	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	94.41	gold quality
liver	UBERON:0002107	94.17	gold quality
mucosa of transverse colon	UBERON:0004991	94.16	gold quality
esophagus mucosa	UBERON:0002469	93.83	gold quality
islet of Langerhans	UBERON:0000006	93.66	gold quality
spinal cord	UBERON:0002240	93.56	gold quality
prefrontal cortex	UBERON:0000451	93.52	gold quality
sperm	CL:0000019	93.05	gold quality
oocyte	CL:0000023	92.99	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	92.79	gold quality
male germ cell	CL:0000015	92.19	gold quality
right testis	UBERON:0004534	92.05	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	91.96	gold quality
rectum	UBERON:0001052	91.77	gold quality
Brodmann (1909) area 9	UBERON:0013540	91.75	gold quality
right frontal lobe	UBERON:0002810	91.64	gold quality
secondary oocyte	CL:0000655	91.60	gold quality
left testis	UBERON:0004533	91.33	gold quality
cingulate cortex	UBERON:0003027	91.08	gold quality
mammalian vulva	UBERON:0000997	91.02	gold quality
anterior cingulate cortex	UBERON:0009835	90.95	gold quality
testis	UBERON:0000473	90.66	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	90.66	gold quality
superior vestibular nucleus	UBERON:0007227	90.50	gold quality
hypothalamus	UBERON:0001898	90.13	gold quality
right adrenal gland	UBERON:0001233	89.65	gold quality
amygdala	UBERON:0001876	89.61	gold quality
transverse colon	UBERON:0001157	89.57	gold quality
neocortex	UBERON:0001950	89.53	gold quality
gingival epithelium	UBERON:0001949	89.30	gold quality
frontal cortex	UBERON:0001870	89.23	gold quality
upper arm skin	UBERON:0004263	89.17	gold quality
upper lobe of left lung	UBERON:0008952	88.91	gold quality
pigmented layer of retina	UBERON:0001782	88.85	gold quality
right adrenal gland cortex	UBERON:0035827	88.78	gold quality
upper lobe of lung	UBERON:0008948	88.74	gold quality
gingiva	UBERON:0001828	88.51	gold quality
pharyngeal mucosa	UBERON:0000355	88.37	gold quality
dorsal root ganglion	UBERON:0000044	88.33	gold quality
skin of abdomen	UBERON:0001416	88.32	gold quality
oral cavity	UBERON:0000167	88.28	gold quality
adrenal gland	UBERON:0002369	88.22	gold quality
cerebral cortex	UBERON:0000956	87.97	gold quality
mouth mucosa	UBERON:0003729	87.95	gold quality
body of stomach	UBERON:0001161	87.94	gold quality
right lung	UBERON:0002167	87.93	gold quality
cerebellar hemisphere	UBERON:0002245	87.89	gold quality
minor salivary gland	UBERON:0001830	87.87	gold quality
cerebellar cortex	UBERON:0002129	87.85	gold quality
tibial nerve	UBERON:0001323	87.73	gold quality
right hemisphere of cerebellum	UBERON:0014890	87.66	gold quality
zone of skin	UBERON:0000014	87.62	gold quality
vagina	UBERON:0000996	87.59	gold quality
left adrenal gland	UBERON:0001234	87.59	gold quality
lower esophagus mucosa	UBERON:0035834	87.56	gold quality
esophagus	UBERON:0001043	87.52	gold quality
cervix epithelium	UBERON:0004801	87.40	gold quality
substantia nigra	UBERON:0002038	87.37	gold quality
midbrain	UBERON:0001891	87.32	gold quality
skin of leg	UBERON:0001511	87.25	gold quality
right ovary	UBERON:0002118	87.25	gold quality
tonsil	UBERON:0002372	87.18	gold quality
telencephalon	UBERON:0001893	86.92	gold quality
duodenum	UBERON:0002114	86.90	gold quality
vermiform appendix	UBERON:0001154	86.89	gold quality
inferior vagus X ganglion	UBERON:0005363	86.87	gold quality
left adrenal gland cortex	UBERON:0035825	86.85	gold quality
adrenal cortex	UBERON:0001235	86.81	gold quality
small intestine Peyer’s patch	UBERON:0003454	86.79	gold quality
cerebellum	UBERON:0002037	86.69	gold quality
central nervous system	UBERON:0001017	86.67	gold quality
granulocyte	CL:0000094	86.65	gold quality
nasal cavity mucosa	UBERON:0001826	86.64	gold quality
prostate gland	UBERON:0002367	86.58	gold quality
forebrain	UBERON:0001890	86.50	gold quality
brain	UBERON:0000955	86.45	gold quality
penis	UBERON:0000989	86.44	gold quality
corpus callosum	UBERON:0002336	86.41	gold quality
lymph node	UBERON:0000029	86.38	gold quality
squamous epithelium	UBERON:0006914	86.37	gold quality
tibial artery	UBERON:0007610	86.29	gold quality
popliteal artery	UBERON:0002250	86.28	gold quality
ovary	UBERON:0000992	86.22	gold quality
saliva-secreting gland	UBERON:0001044	86.21	gold quality
ectocervix	UBERON:0012249	86.17	gold quality
epithelium of esophagus	UBERON:0001976	86.14	gold quality
left ovary	UBERON:0002119	86.09	gold quality
stomach	UBERON:0000945	86.08	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.07	gold quality
tibia	UBERON:0000979	86.03	gold quality
small intestine	UBERON:0002108	86.00	gold quality
esophagus squamous epithelium	UBERON:0006920	85.93	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-HCAD-5	yes	40.98
E-MTAB-6819	no	1774.24
E-ANND-3	no	0.00

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 127 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Liver	tissue	216.3	medium
Spinal cord	tissue	123.5
Medulla oblongata	tissue	74.9
Corpus callosum	tissue	65.3
Midbrain	tissue	63.7
Pons	tissue	58.5
Substantia nigra	tissue	52.2
Thalamus	tissue	51.3
Periaqueductal gray	tissue	46.2
Hypothalamus	tissue	41.8
Cerebral cortex	tissue	40.6	medium
Motor cortex	tissue	40.6
Prefrontal cortex	tissue	39.9
Locus coeruleus	tissue	39.2
Retrosplenial and cingulate cortex	tissue	38.8
Superior colliculi	tissue	38.4
Hippocampal formation	tissue	38.1
Somatosensory cortex	tissue	37.9
Epididymis	tissue	37.8	medium
Retrosplenial cortex	tissue	37.4
Thymus	tissue	36.7
Occipital cortex	tissue	36.1
Colon	tissue	36.0	high
Insular cortex	tissue	35.8
Tonsil	tissue	34.4	medium
Prostate	tissue	33.4	high
Entorhinal cortex	tissue	33.4
Temporal cortex	tissue	33.0
Rectum	tissue	31.7	high
Amygdala	tissue	31.7
Esophagus	tissue	30.6	medium
Septum	tissue	29.8
Vagina	tissue	29.6	low
Duodenum	tissue	29.4	high
Ventral forebrain	tissue	29.2
Testis	tissue	26.7	high
Kidney	tissue	25.2	high
Olfactory bulb	tissue	24.2
Postcentral gyrus	tissue	23.6
Lymph node	tissue	23.4	medium
Putamen	tissue	22.6
Breast	tissue	22.1	medium
Bone marrow	tissue	21.1	medium
Basal ganglia	tissue	21.0	low
Ovary	tissue	20.9	high
Adrenal gland	tissue	20.3	medium
Lung	tissue	19.1	high
Stomach 1	tissue	18.4	high
Cerebellum	tissue	18.4	medium
Small intestine	tissue	18.3
Retina	tissue	18.1
Appendix	tissue	17.4	high
Skin 1	tissue	17.1	low
Small intestine	tissue	16.8	medium
Hippocampus	tissue	16.4	medium
Smooth muscle	tissue	14.8	low
Salivary gland	tissue	14.6	medium
Choroid plexus	tissue	14.3
Nucleus accumbens	tissue	13.0
Urinary bladder	tissue	12.8	medium

Brain sub-regions (HPA Brain Atlas): detected in 202; highest nTPM — Ventral spinal cord (123.5), Dorsal spinal cord (93.5), White matter (65.3), Nucleus raphe magnus (55.1), Pontine nuclei (54.0).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting ACAT2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 42 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502
HSA-MIR-548H-5P	99.94	71.24	3488
HSA-MIR-548I	99.94	71.25	3481
HSA-MIR-548J-5P	99.94	71.14	3489
HSA-MIR-548O-5P	99.94	71.24	3488
HSA-MIR-548W	99.94	71.24	3488
HSA-MIR-548Y	99.94	71.28	3514
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-377-5P	99.70	65.28	712
HSA-MIR-6086	99.70	65.38	699
HSA-MIR-466	99.67	70.85	2863
HSA-MIR-548AV-5P	99.60	70.84	2107
HSA-MIR-548K	99.60	70.84	2107

Functional genomics

gnomAD constraint: pLI 1.91e-06, LOEUF 0.99, missense Z 0.849 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000367048 — one region, missense o/e 0.96.

Literature-anchored findings (GeneRIF, showing 6)

• Data describe the high resolution structure of human cytosolic acetoacetyl-CoA thiolase (CT), both unliganded (at 2.3 angstroms resolution) and in complex with CoA (at 1.6 angstroms resolution). (PMID:15733928)
• The increased NPC1L1 and ACAT2 mRNA levels in gallstone patients might indicate an upregulated absorption and esterification of cholesterol in the small intestine. (PMID:19071091)
• Reduced ACAT2 is associated with impaired butyrate oxidation in ulcerative colitis. (PMID:21987487)
• Results show that DLAT and ACAT2 as upstream acetyltransferases of K76 and K294 in 6PGD protein. (PMID:25042803)
• results demonstrate that the low-level expression of human ACAT2 gene with specific CpG-hypomethylated promoter is regulated by the C/EBP transcription factors in monocytic cells, and imply that the lowly expressed ACAT2 catalyzes the synthesis of certain CE/SE that are assembled into lipoproteins for the secretion (PMID:27688151)
• Circ_RPL23A acts as a miR-1233 sponge to suppress the progression of clear cell renal cell carcinoma by promoting ACAT2. (PMID:34036483)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	acat2	ENSDARG00000007127
mus_musculus	Acat2	ENSMUSG00000023832
mus_musculus	Acat3	ENSMUSG00000062480
rattus_norvegicus	Acat2l1	ENSRNOG00000013975
rattus_norvegicus	Acat2	ENSRNOG00000019189
drosophila_melanogaster	Acat2	FBGN0035203

Paralogs (4): ACAA1 (ENSG00000060971), ACAT1 (ENSG00000075239), HADHB (ENSG00000138029), ACAA2 (ENSG00000167315)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:87871) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 5 distinct phenotype terms.

Mouse phenotype (MP)	Records
increased body length	1
abnormal embryo size	1
increased circulating chloride level	1
abnormal body wall morphology	1
preweaning lethality, complete penetrance	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
Aspergillus fumigatus A1163	B0XMC1	100.0%	Diamond
Clostridioides difficile	P45362	100.0%	Diamond
Mycobacterium tuberculosis variant bovis AF2122/97	P66927	100.0%	Diamond
Mycobacterium tuberculosis CDC1551	P9WG68	100.0%	Diamond
Staphylococcus aureus subsp. aureus USA300	Q2FJQ9	100.0%	Diamond
Staphylococcus aureus subsp. aureus NCTC 8325	Q2G124	100.0%	Diamond
Aspergillus fumigatus Af293	Q4WCL5	100.0%	Diamond
Staphylococcus epidermidis RP62A	Q5HS07	100.0%	Diamond
Staphylococcus aureus subsp. aureus MSSA476	Q6GCB8	100.0%	Diamond
Staphylococcus aureus subsp. aureus N315	Q7A7L2	100.0%	Diamond
Staphylococcus epidermidis ATCC 12228	Q8CQN7	100.0%	Diamond
Staphylococcus aureus subsp. aureus MW2	Q8NY95	100.0%	Diamond
Staphylococcus aureus subsp. aureus Mu50	Q99WM3	100.0%	Diamond
Mycobacterium tuberculosis H37Rv	P9WG69	99.7%	Diamond
Staphylococcus aureus subsp. aureus COL	Q5HIU0	99.7%	Diamond
Pongo abelii	Q5RES5	99.2%	Diamond
Staphylococcus aureus subsp. aureus MRSA252	Q6GJW4	99.2%	Diamond
Candida tropicalis	P33290	99.0%	Diamond
Staphylococcus aureus RF122	Q2YVF5	98.5%	Diamond
Macaca fascicularis	Q8HXY6	97.7%	Diamond
Xenopus laevis	Q6GN02	96.4%	Diamond
Saccharomyces pastorianus CBS 1503	P10551	95.5%	Diamond
Saccharomyces cerevisiae S288C	P41338	95.5%	Diamond
Xenopus tropicalis	Q5BKN8	95.0%	Diamond
Bos taurus	Q29RZ0	90.6%	Diamond
Shinella zoogloeoides	P07097	88.0%	Diamond
Sinorhizobium meliloti 1021	P50174	88.0%	Diamond
Mycobacterium leprae TN	P46707	87.2%	Diamond
Thiocystis violacea	P45363	86.5%	Diamond
Allochromatium vinosum DSM 180	P45369	86.5%	Diamond
Pseudomonas aeruginosa PAO1	Q9I6R0	85.8%	Diamond
Mycolicibacterium smegmatis MC2 155	A0R1Y7	85.5%	Diamond
Pseudomonas putida	Q51956	84.7%	Diamond
Candida albicans SC5314	A0A1D8PH52	84.5%	Diamond
Petunia x hybrida	C8YNG6	79.0%	Diamond
Arabidopsis thaliana	Q8S4Y1	78.8%	Diamond
Paracoccus denitrificans	P54810	75.1%	Diamond
Cupriavidus necator H16	P14611	72.3%	Diamond
Chromobacterium violaceum ATCC 12472	Q9ZHI1	72.3%	Diamond
Fusarium graminearum PH-1	I1RMA2	71.6%	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
SOD2	protein-coding	6648
SNORA20	snoRNA	677806
SNORA29	snoRNA	677812
TCP1	protein-coding	6950
WTAP	protein-coding	9589
SOD2-OT1	ncRNA	100129518
MRPL18	protein-coding	29074
PNLDC1	protein-coding	154197

Protein

Protein identifiers

Acetyl-CoA acetyltransferase, cytosolic — Q9BWD1 (reviewed: Q9BWD1)

Alternative names: Acetyl-CoA transferase-like protein, Cytosolic acetoacetyl-CoA thiolase

All UniProt accessions (1): Q9BWD1

UniProt curated annotations — full annotation on UniProt →

Function. Involved in the biosynthetic pathway of cholesterol.

Subunit / interactions. Homotetramer.

Subcellular location. Cytoplasm. Cytosol.

Pathway. Lipid metabolism; fatty acid metabolism.

Similarity. Belongs to the thiolase-like superfamily. Thiolase family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9BWD1-1	1	yes
Q9BWD1-2	2

RefSeq proteins (2): NP_001290182, NP_005882* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002155	Thiolase	Family
IPR016039	Thiolase-like	Homologous_superfamily
IPR020610	Thiolase_AS	Active_site
IPR020613	Thiolase_CS	Conserved_site
IPR020616	Thiolase_N	Domain
IPR020617	Thiolase_C	Domain

Pfam: PF00108, PF02803

Enzyme classification (BRENDA)

• EC 2.3.1.9 — acetyl-CoA C-acetyltransferase (BRENDA: 44 organisms, 97 substrates, 66 inhibitors, 86 Km, 27 kcat entries)

Substrate kinetics (BRENDA)

13 substrates with measured Km, best-characterized 13. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ACETOACETYL-COA	0.0038–0.18	36
COA	0.0048–0.154	23
ACETYL-COA	0.0062–1.06	20
ACETOACETYL-10-BIS-DEMETHYLPANTETHEINE 11-PIVALA	0.21	1
ACETOACETYL-S-(11-METHOXYMETHYL)PANTETHEINE	0.12	1
ACETOACETYL-S-(11-T-BUTYLDIMETHYLSILYL)PANTETHEI	0.074	1
ACETOACETYL-S-(D-PANTETHEINE) 11-PIVALATE	0.073	1
ACETOACETYL-S-HOMOPANTETHEINE 12-PIVALATE	0.25	1
ACETOACETYL-S-PANTETHEINE	0.46	1
3-KETOBUTYRYLDITHIO-COA	—	0
ACETOACETYL-10-BIS-DEMETHYLPANTETHEINE 11-PIVALO	—	0
ACETOACETYL-S-(L-PANTETHEINE) 11-PIVALATE	—	0
THIOLYTIC CLEAVAGE	—	0

Catalyzed reactions (Rhea)

• 2 acetyl-CoA = acetoacetyl-CoA + CoA (RHEA:21036)

UniProt features (53 total): helix 20, strand 12, turn 5, modified residue 4, sequence conflict 3, binding site 3, active site 2, chain 1, splice variant 1, sequence variant 1, site 1

Structure

Experimental structures (PDB)

4 structures by resolution:

PDB	Title	Method	Resolution (Å)
1WL4	Human cytosolic acetoacetyl-CoA thiolase complexed with CoA	X-RAY DIFFRACTION	1.55
9V37	crystal structure of ACAT2	X-RAY DIFFRACTION	2.17
1WL5	Human cytosolic acetoacetyl-CoA thiolase	X-RAY DIFFRACTION	2.26
9V13	Crystal structure of ACAT2 in complex with ZH-2-077	X-RAY DIFFRACTION	2.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BWD1-F1	97.28	0.98

Human Protein Atlas

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

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol; nucleoplasm

Antibody reliability (HPA): IH enhanced · IF approved

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
92	acyl-thioester intermediate
383	proton donor/acceptor
353	increases nucleophilicity of active site cys

Ligand- & substrate-binding residues (3)

Position	Role
223	CoA
226	CoA
252	CoA

Post-translational modifications (4)

Type	Positions
N6-acetyllysine	235, 200, 233
N-acetylmethionine	1

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:

ID	Pathway	Evidence
R-HSA-9969896	Lanosterol biosynthesis	curated
R-HSA-191273	Cholesterol biosynthesis	—
R-HSA-1430728	Metabolism	—
R-HSA-556833	Metabolism of lipids	—
R-HSA-8957322	Metabolism of steroids	—

MSigDB gene sets: 238 (showing top): GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_UP, HORIUCHI_WTAP_TARGETS_DN, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, YANG_BREAST_CANCER_ESR1_LASER_DN, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, KEGG_VALINE_LEUCINE_AND_ISOLEUCINE_DEGRADATION, SHEPARD_BMYB_MORPHOLINO_DN, PUJANA_CHEK2_PCC_NETWORK, GOBP_PHOSPHOLIPID_BIOSYNTHETIC_PROCESS, chr6q25, DAVICIONI_RHABDOMYOSARCOMA_PAX_FOXO1_FUSION_UP

GO Biological Process (2): lipid metabolic process (GO:0006629), fatty acid metabolic process (GO:0006631)

GO Molecular Function (5): acetyl-CoA C-acetyltransferase activity (GO:0003985), protein binding (GO:0005515), transferase activity (GO:0016740), acyltransferase activity (GO:0016746), acyltransferase activity, transferring groups other than amino-acyl groups (GO:0016747)

GO Cellular Component (3): cytoplasm (GO:0005737), cytosol (GO:0005829), extracellular exosome (GO:0070062)

Reactome top-level categories

4 top-level categories:

Category	Pathways
Cholesterol biosynthesis	1
Metabolism of steroids	1
Metabolism	1
Metabolism of lipids	1

GO top-level categories

13 GO namespaces:

Category	Terms
cellular anatomical structure	2
primary metabolic process	1
lipid metabolic process	1
monocarboxylic acid metabolic process	1
acetyl-CoA C-acyltransferase activity	1
C-acetyltransferase activity	1
binding	1
catalytic activity	1
transferase activity	1
acyltransferase activity	1
intracellular anatomical structure	1
cytoplasm	1
extracellular vesicle	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 3 of 11 annotations. The rest are phylogenetic / computational / electronic (IEA).

3 experimentally-supported GO terms:

GO term	NS	Evidence
cytoplasm	CC	direct assay
extracellular exosome	CC	high-throughput assay
acetyl-CoA C-acetyltransferase activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 1,324 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ACAT2	MVD	P53602	766
ACAT2	MVK	Q03426	743
ACAT2	HMGCR	P04035	724
ACAT2	TCP1	P17987	722
ACAT2	GGPS1	O95749	676
ACAT2	HMGCS1	Q01581	672
ACAT2	FDPS	P14324	661
ACAT2	IDI2	Q9BXS1	650
ACAT2	PMVK	Q15126	646
ACAT2	IDI1	Q13907	642
ACAT2	LSS	P48449	641
ACAT2	FDFT1	P37268	635
ACAT2	SQLE	Q14534	628
ACAT2	DHCR7	Q9UBM7	598
ACAT2	HMGCS2	P54868	577

IntAct

Human interaction partners of ACAT2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

16 partners by confidence:

Partner	Interaction type	MIscore	Records
LNX1	physical association	0.560	3
WWOX	physical association	0.560	3
ZNF76	physical association	0.560	3
TERF1	physical association	0.510	2
ACAT1	physical association	0.400	1
ATG5	physical association	0.000	1
CCNA1	physical association	0.000	1
EIF1B	physical association	0.000	1
FTSJ1	physical association	0.000	1
GNAS	physical association	0.000	1
HLA-B	physical association	0.000	1
MCC	physical association	0.000	1
PRKAB1	physical association	0.000	1
TNIK	physical association	0.000	1
TRAF6	physical association	0.000	1
VDAC1	physical association	0.000	1

BioGRID (87 interactions; top human partners by supporting records): ACAT1 (Affinity Capture-MS; 2 records), MLST8 (Affinity Capture-MS; 2 records), AHCY (Co-fractionation), AKT1 (Two-hybrid), ALDH9A1 (Co-fractionation), BAG3 (Affinity Capture-MS), BAP1 (Affinity Capture-MS), CLIC1 (Affinity Capture-MS), CTBP2 (Affinity Capture-MS), DAK (Co-fractionation), DDX58 (Affinity Capture-RNA), DDX6 (Co-fractionation), ENO1 (Cross-Linking-MS (XL-MS)), FASN (Negative Genetic), FH (Co-fractionation)

Disease & clinical

Genetic variants

Variant evidence for ACAT2: 105 ClinVar records (13 pathogenic / likely pathogenic). Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	13
Likely pathogenic	0
Uncertain significance	64
Likely benign	9
Benign	6

Top pathogenic / likely-pathogenic (13)

Showing all 13 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
666538	NM_000019.3:c.(72+1_73-1)_(344+1_345-1)del	Pathogenic	criteria provided, single submitter	1
2427078	NC_000006.11:g.(?158532398)(162868359_?)del	Pathogenic	criteria provided, single submitter	2
57020	GRCh38/hg38 6q24.1-27(chr6:141132990-169339571)x3	Pathogenic	criteria provided, single submitter	1
58453	GRCh38/hg38 6q25.2-27(chr6:154118058-170602152)x1	Pathogenic	criteria provided, single submitter	1
58455	GRCh38/hg38 6q25.3-27(chr6:159454639-170612001)x1	Pathogenic	criteria provided, single submitter	1
3148927	GRCh37/hg19 6q25.2-27(chr6:152853218-170914297)x1	Pathogenic	criteria provided, single submitter	1
3391846	GRCh37/hg19 6q24.2-27(chr6:144561123-170919482)x3	Pathogenic	criteria provided, single submitter	1
3391892	GRCh37/hg19 6q25.2-27(chr6:153777725-170919482)x1	Pathogenic	criteria provided, single submitter	1
3391893	GRCh37/hg19 6q25.3-27(chr6:158471960-170919482)x1	Pathogenic	criteria provided, single submitter	1
148306	GRCh38/hg38 6q25.2-27(chr6:154539655-170714507)x1	Pathogenic	no assertion criteria provided	1
148765	GRCh38/hg38 6q25.3-26(chr6:155378049-163133499)x1	Pathogenic	no assertion criteria provided	1
153525	GRCh38/hg38 6q25.2-27(chr6:152793402-170610394)x1	Pathogenic	no assertion criteria provided	1
394997	GRCh37/hg19 6q25.1-27(chr6:151214792-170892243)x3	Pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore ACAT2’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.

AlphaMissense

864 missense substitutions predicted likely pathogenic (of 2,571 scored), across 256 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
M160	9	0.792	0.933
M293	9	0.783	0.943
D256	8	0.950	0.981
H353	8	0.938	0.985
D144	8	0.917	0.971
F324	8	0.905	0.995
D219	8	0.899	0.971
D153	8	0.800	0.911
M122	8	0.791	0.902
D149	8	0.781	0.888
F238	7	0.916	0.980
E120	7	0.910	0.981
F198	7	0.879	0.943
N321	7	0.876	0.968
E322	7	0.870	0.963
N343	7	0.866	0.968
C383	7	0.847	0.974
D179	7	0.836	0.942
E201	7	0.826	0.912
N68	7	0.822	0.975

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
Breast Invasive Carcinoma (validation)	unfavorable	2.34e-05
Kidney Chromophobe (TCGA)	unfavorable	0.000827

Disease associations

OMIM: gene `` | disease phenotypes: MIM:614739, MIM:203750

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
acetyl-CoA acetyltransferase-2 deficiency	Limited	Autosomal recessive

ClinGen Gene-Disease Validity

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

1 validity classifications:

Disease	Classification	Inheritance
acetyl-CoA acetyltransferase-2 deficiency	No Known Disease Relationship	UD

Mondo (3): 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MONDO:0013875), beta-ketothiolase deficiency (MONDO:0008760), acetyl-CoA acetyltransferase-2 deficiency (MONDO:0013548)

Orphanet (2): MEGDEL syndrome (Orphanet:352328), Beta-ketothiolase deficiency (Orphanet:134)

MeSH disease descriptors

2 disease descriptors:

Descriptor	Name	Tree numbers
C535434	Beta ketothiolase deficiency *(supp.)*
C536005	Cytosolic acetoacetyl-CoA thiolase deficiency *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2240 (SINGLE PROTEIN)

PharmGKB: 1 entry (CPIC guideline: no)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Lanosterol biosynthesis pathway

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
K-604	Inhibition	3.89	pIC50

Binding affinities (BindingDB)

6 measured of 7 human assays (8 total across all organisms); most potent 6 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(2S)-4-[1-(cyclopropylmethyl)pyrazol-3-yl]-2-[2-fluoro-4-(4,4,4-trifluorobutoxy)phenyl]-5-(5-oxo-1H-tetrazol-4-yl)-2-(trifluoromethyl)-1,3-dihydropyridin-6-one	IC50	5 nM	US-11479538: Tetrazolone-substituted dihydropyridinone MGAT2 inhibitors
CHEMBL5573112	IC50	22 nM
CHEMBL2094750	IC50	22 nM
CHEMBL5583807	IC50	25 nM
CHEMBL5569869	IC50	171 nM
CHEMBL5569963	IC50	269 nM

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
7.66	IC50	22	nM	CHEMBL5573112
7.66	IC50	22	nM	CHEMBL2094750
7.60	IC50	25	nM	CHEMBL5583807
6.77	IC50	171	nM	CHEMBL5569869
6.57	IC50	269	nM	CHEMBL5569963

PubChem BioAssay actives

5 with measured affinity, of 8 total; 5 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
N-[(2-chlorophenyl)methyl]spiro[1,4-dihydroquinoxaline-3,4’-piperidine]-2-imine	2106965: Inhibition of Acetyl-CoA acetyltransferase (unknown origin)	ic50	0.0220	uM
N-[(3-chlorophenyl)methyl]spiro[1,4-dihydroquinoxaline-3,4’-piperidine]-2-imine	2106965: Inhibition of Acetyl-CoA acetyltransferase (unknown origin)	ic50	0.0220	uM
N-[(2-methylphenyl)methyl]spiro[1,4-dihydroquinoxaline-3,4’-piperidine]-2-imine	2106965: Inhibition of Acetyl-CoA acetyltransferase (unknown origin)	ic50	0.0250	uM
N-[(2-chlorophenyl)methyl]-4’-methylspiro[1,4-dihydroquinoxaline-3,1’-cyclohexane]-2-imine	2106965: Inhibition of Acetyl-CoA acetyltransferase (unknown origin)	ic50	0.1710	uM
N-[(4-methylphenyl)methyl]spiro[1,4-dihydroquinoxaline-3,1’-cyclohexane]-2-imine	2106965: Inhibition of Acetyl-CoA acetyltransferase (unknown origin)	ic50	0.2690	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
perfluorooctane sulfonic acid	affects cotreatment, decreases expression	7
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases expression	7
Cyclosporine	decreases expression, increases expression	6
bisphenol A	decreases expression, affects expression, affects cotreatment, increases methylation	5
sodium arsenite	affects methylation, decreases expression, increases abundance, increases expression	5
Benzo(a)pyrene	affects methylation, decreases expression	5
perfluorooctanoic acid	affects cotreatment, decreases expression	2
cupric chloride	decreases expression	2
cyproconazole	decreases expression, increases expression	2
perfluoro-n-nonanoic acid	decreases expression, affects cotreatment	2
bisphenol S	increases expression	2
Acetaminophen	decreases expression	2
Cisplatin	affects expression, affects cotreatment, increases expression	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
Tretinoin	decreases expression, increases expression	2
Cadmium Chloride	increases abundance, increases expression	2
Particulate Matter	decreases expression, increases abundance, decreases reaction, increases expression	2
GSK-J4	decreases expression	1
afuresertib	increases expression	1
bisphenol F	increases expression	1
lly-283	decreases expression	1
dicrotophos	decreases expression	1
beauvericin	affects cotreatment, decreases expression	1
lasiocarpine	decreases expression	1
methyleugenol	decreases expression	1
uranyl acetate	affects expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, decreases expression	1
isoquercitrin	affects cotreatment, increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
periodate-oxidized adenosine	affects expression	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5368896	Binding	Inhibition of recombinant human ACAT2	Discovery of 12 (BMS-986172) as a Highly Potent MGAT2 Inhibitor that Achieved Targeted Efficacious Exposures at a Low Human Dose for the Treatment of Metabolic Disorders. — *J Med Chem*

Cellosaurus cell lines

6 cell lines: 6 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E1PG	HAP1 ACAT2 (-) 1	Cancer cell line	Male
CVCL_E1PH	HAP1 ACAT2 (-) 2	Cancer cell line	Male
CVCL_E1PI	HAP1 ACAT2 (-) 3	Cancer cell line	Male
CVCL_E1PJ	HAP1 ACAT2 (-) 4	Cancer cell line	Male
CVCL_UQ02	Abcam Jurkat ACAT2 KO	Cancer cell line	Male
CVCL_WQ86	Abcam K-562 ACAT2 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

3 trials:

NCT	Phase	Status	Title
NCT03655223	Not specified	ACTIVE_NOT_RECRUITING	Early Check: Expanded Screening in Newborns
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT05910151	Not specified	UNKNOWN	Selective Screening of Children for Hereditary Metabolic Diseases by Tandem Mass Spectrometry in Kazakhstan

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for ACAT2 across ~30M SureChEMBL compounds — explore on Sugi Predict.