ACAT1

Summary

ACAT1 (acetyl-CoA acetyltransferase 1, HGNC:93) is a protein-coding gene on chromosome 11q22.3, encoding Acetyl-CoA acetyltransferase, mitochondrial (P24752). This is one of the enzymes that catalyzes the last step of the mitochondrial beta-oxidation pathway, an aerobic process breaking down fatty acids into acetyl-CoA.

This gene encodes a mitochondrially localized enzyme that catalyzes the reversible formation of acetoacetyl-CoA from two molecules of acetyl-CoA. Defects in this gene are associated with 3-ketothiolase deficiency, an inborn error of isoleucine catabolism characterized by urinary excretion of 2-methyl-3-hydroxybutyric acid, 2-methylacetoacetic acid, tiglylglycine, and butanone.

Source: NCBI Gene 38 — RefSeq curated summary.

At a glance

• Gene–disease (curated): beta-ketothiolase deficiency (Definitive, ClinGen)
• Clinical variants (ClinVar): 834 total — 98 pathogenic, 79 likely-pathogenic
• Phenotypes (HPO): 47
• Druggable target: yes — 5 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_000019

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:93
Approved symbol	ACAT1
Name	acetyl-CoA acetyltransferase 1
Location	11q22.3
Locus type	gene with protein product
Status	Approved
Aliases	THIL
Ensembl gene	ENSG00000075239
Ensembl biotype	protein_coding
OMIM	607809
Entrez	38

Gene structure

Transcript identifiers

Ensembl transcripts: 41 — 27 protein_coding, 5 retained_intron, 5 protein_coding_CDS_not_defined, 4 nonsense_mediated_decay

ENST00000265838, ENST00000299355, ENST00000524833, ENST00000526119, ENST00000527942, ENST00000528370, ENST00000531813, ENST00000531853, ENST00000532792, ENST00000533597, ENST00000533610, ENST00000534773, ENST00000671707, ENST00000672008, ENST00000672031, ENST00000672284, ENST00000672354, ENST00000672367, ENST00000672580, ENST00000672907, ENST00000673000, ENST00000673531, ENST00000907942, ENST00000907943, ENST00000907944, ENST00000907945, ENST00000907946, ENST00000907947, ENST00000907948, ENST00000907949, ENST00000907950, ENST00000907951, ENST00000907952, ENST00000907953, ENST00000907954, ENST00000907955, ENST00000907956, ENST00000938152, ENST00000959309, ENST00000959310, ENST00000959311

RefSeq mRNA: 13 — MANE Select: NM_000019 NM_000019, NM_001386677, NM_001386678, NM_001386679, NM_001386681, NM_001386682, NM_001386685, NM_001386686, NM_001386687, NM_001386688, NM_001386689, NM_001386690, NM_001386691

CCDS: CCDS8339, CCDS91579, CCDS91580, CCDS91581

Canonical transcript exons

ENST00000265838 — 12 exons

Exon	Start	End
ENSE00001101628	108146202	108146359
ENSE00001101634	108147270	108147603
ENSE00001101638	108143983	108144047
ENSE00001101665	108135142	108135242
ENSE00003465300	108140065	108140215
ENSE00003517302	108134221	108134316
ENSE00003521274	108131907	108131954
ENSE00003565194	108142437	108142550
ENSE00003573786	108121567	108121678
ENSE00003633614	108133820	108133937
ENSE00003642660	108138898	108139041
ENSE00003667534	108141605	108141700

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 99.58.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 62.5715 / max 2540.3619, expressed in 1819 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
116517	51.1386	1817
116518	11.3430	1710
116519	0.0734	5
116516	0.0166	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
nephron tubule	UBERON:0001231	99.58	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	99.51	gold quality
renal medulla	UBERON:0000362	99.48	gold quality
right lobe of liver	UBERON:0001114	99.45	gold quality
heart right ventricle	UBERON:0002080	99.39	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	99.27	gold quality
biceps brachii	UBERON:0001507	99.25	gold quality
diaphragm	UBERON:0001103	99.18	gold quality
hindlimb stylopod muscle	UBERON:0004252	99.16	gold quality
left ventricle myocardium	UBERON:0006566	99.14	gold quality
apex of heart	UBERON:0002098	99.11	gold quality
liver	UBERON:0002107	99.08	gold quality
deltoid	UBERON:0001476	99.07	gold quality
gastrocnemius	UBERON:0001388	98.98	gold quality
skeletal muscle tissue	UBERON:0001134	98.97	gold quality
muscle of leg	UBERON:0001383	98.95	gold quality
body of tongue	UBERON:0011876	98.92	gold quality
cardiac ventricle	UBERON:0002082	98.88	gold quality
heart left ventricle	UBERON:0002084	98.87	gold quality
triceps brachii	UBERON:0001509	98.84	gold quality
right adrenal gland cortex	UBERON:0035827	98.79	gold quality
tibialis anterior	UBERON:0001385	98.71	gold quality
right adrenal gland	UBERON:0001233	98.69	gold quality
myocardium	UBERON:0002349	98.63	gold quality
gluteal muscle	UBERON:0002000	98.62	gold quality
adrenal cortex	UBERON:0001235	98.58	gold quality
left adrenal gland cortex	UBERON:0035825	98.58	gold quality
muscle tissue	UBERON:0002385	98.57	gold quality
left adrenal gland	UBERON:0001234	98.56	gold quality
jejunal mucosa	UBERON:0000399	98.54	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-10553	yes	32.21
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

32 targeting ACAT1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-8062	99.88	68.43	995
HSA-MIR-5003-3P	99.85	69.29	2517
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-204-5P	99.79	71.62	2439
HSA-MIR-211-5P	99.79	71.65	2440
HSA-MIR-4699-3P	99.71	70.15	3142
HSA-MIR-298	99.63	67.56	1916
HSA-MIR-6832-3P	99.52	70.44	1726
HSA-MIR-6513-5P	99.43	67.81	1071
HSA-MIR-3182	99.40	68.15	2454
HSA-MIR-1276	99.36	68.18	1642
HSA-MIR-4427	99.34	70.33	1854
HSA-MIR-4311	99.31	70.47	3041
HSA-MIR-4291	99.20	68.88	2969
HSA-MIR-10399-5P	99.17	69.87	2610
HSA-MIR-6504-3P	99.17	69.31	2891
HSA-MIR-655-5P	98.74	65.93	888
HSA-MIR-198	98.70	67.32	920
HSA-MIR-4720-3P	98.50	68.88	988
HSA-MIR-7114-3P	98.42	66.53	569
HSA-MIR-1180-5P	98.16	65.32	460
HSA-MIR-376C-3P	97.63	68.88	1263
HSA-MIR-409-5P	97.31	68.07	364
HSA-MIR-6759-3P	96.94	68.31	823
HSA-MIR-4750-3P	96.65	64.38	512

Literature-anchored findings (GeneRIF, showing 4)

• sliding model in which the position-specific tethering of NURF forces a translocating ISWI ATPase to pump a DNA distortion over the histone octamer, thereby changing the translational position of the nucleosome. (PMID:15262970)
• results suggest that the ISWI-containing NURF complex functions as a co-activator of Armadillo to promote Wg-mediated transcription. (PMID:19713963)
• The current study further solidified the role of STAT and Wg in regeneration, by identifying their contribution to abnormal regenerations induced by IR. STAT92E (Drosophila STAT3/5) and Nurf-38, which encodes a member of the Nucleosome Remodeling Factor complex, oppose each other in these cells to modulate the frequency of ectopic disc growth (PMID:29028797)
• Synechococcus phage Syn5 forms infectious virions through the initial assembly of scaffolding-containing procapsids. (PMID:21177804)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	acat1	ENSDARG00000045888
mus_musculus	Acat1	ENSMUSG00000032047
rattus_norvegicus	Acat1	ENSRNOG00000007862
drosophila_melanogaster	Acat1	FBGN0029969
caenorhabditis_elegans		WBGENE00002183
caenorhabditis_elegans		WBGENE00020166

Paralogs (4): ACAA1 (ENSG00000060971), ACAT2 (ENSG00000120437), HADHB (ENSG00000138029), ACAA2 (ENSG00000167315)

Protein

Protein identifiers

Acetyl-CoA acetyltransferase, mitochondrial — P24752 (reviewed: P24752)

Alternative names: Acetoacetyl-CoA thiolase, T2

All UniProt accessions (11): P24752, A0A140VJX1, A0A5F9ZHD4, A0A5F9ZHH9, A0A5F9ZHJ0, A0A5F9ZHJ7, A0A5F9ZHL1, A0A5F9ZHL7, A0A5F9ZI66, E9PRQ6, H0YEL7

UniProt curated annotations — full annotation on UniProt →

Function. This is one of the enzymes that catalyzes the last step of the mitochondrial beta-oxidation pathway, an aerobic process breaking down fatty acids into acetyl-CoA. Using free coenzyme A/CoA, catalyzes the thiolytic cleavage of medium- to long-chain 3-oxoacyl-CoAs into acetyl-CoA and a fatty acyl-CoA shortened by two carbon atoms. The activity of the enzyme is reversible and it can also catalyze the condensation of two acetyl-CoA molecules into acetoacetyl-CoA. Thereby, it plays a major role in ketone body metabolism.

Subunit / interactions. Homotetramer.

Subcellular location. Mitochondrion.

Post-translational modifications. Succinylation at Lys-268, adjacent to a coenzyme A binding site. Desuccinylated by SIRT5.

Disease relevance. 3-ketothiolase deficiency (3KTD) [MIM:203750] An autosomal recessive inborn error of isoleucine catabolism characterized by intermittent ketoacidotic attacks associated with unconsciousness. Some patients die during an attack or are mentally retarded. Urinary excretion of 2-methyl-3-hydroxybutyric acid, 2-methylacetoacetic acid, triglylglycine, butanone is increased. It seems likely that the severity of this disease correlates better with the environmental or acquired factors than with the ACAT1 genotype. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Activated by potassium ions, but not sodium ions.

Pathway. Lipid metabolism; fatty acid beta-oxidation.

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

Isoforms (2)

UniProt ID	Names	Canonical?
P24752-1	1	yes
P24752-2	2

RefSeq proteins (13): NP_000010, NP_001373606, NP_001373607, NP_001373608, NP_001373610, NP_001373611, NP_001373614, NP_001373615, NP_001373616, NP_001373617, NP_001373618, NP_001373619, NP_001373620 (=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
IPR020615	Thiolase_acyl_enz_int_AS	Active_site
IPR020616	Thiolase_N	Domain
IPR020617	Thiolase_C	Domain

Pfam: PF00108, PF02803

Catalyzed reactions (Rhea), 2 shown:

• 2 acetyl-CoA = acetoacetyl-CoA + CoA (RHEA:21036)
• propanoyl-CoA + acetyl-CoA = 2-methyl-3-oxobutanoyl-CoA + CoA (RHEA:30719)

UniProt features (97 total): modified residue 24, helix 19, strand 15, sequence variant 12, binding site 9, turn 7, sequence conflict 4, active site 2, splice variant 2, transit peptide 1, chain 1, site 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
2IB8	X-RAY DIFFRACTION	1.85
2IBY	X-RAY DIFFRACTION	1.85
2IBU	X-RAY DIFFRACTION	1.9
2IBW	X-RAY DIFFRACTION	1.9
2F2S	X-RAY DIFFRACTION	2
2IB7	X-RAY DIFFRACTION	2.05
2IB9	X-RAY DIFFRACTION	2.05

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P24752-F1	95.08	0.91

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): 385 (increases nucleophilicity of active site cys); 126 (acyl-thioester intermediate); 413 (proton donor/acceptor)

Ligand- & substrate-binding residues (9): 283; 284; 381; 219; 219; 258–260; 263; 280; 281

Post-translational modifications (24): 66, 66, 78, 174, 174, 181, 181, 190, 190, 202, 202, 223, 223, 230, 230, 243, 251, 257, 263, 263 …

Function

Pathways and Gene Ontology

Reactome pathways

16 pathways

ID	Pathway
R-HSA-70895	Branched-chain amino acid catabolism
R-HSA-77108	Utilization of Ketone Bodies
R-HSA-77111	Synthesis of Ketone Bodies
R-HSA-9837999	Mitochondrial protein degradation
R-HSA-9854311	Maturation of TCA enzymes and regulation of TCA cycle
R-HSA-9915355	Beta-ketothiolase deficiency
R-HSA-1428517	Aerobic respiration and respiratory electron transport
R-HSA-1430728	Metabolism
R-HSA-1643685	Disease
R-HSA-392499	Metabolism of proteins
R-HSA-556833	Metabolism of lipids
R-HSA-5668914	Diseases of metabolism
R-HSA-71291	Metabolism of amino acids and derivatives
R-HSA-71403	Citric acid cycle (TCA cycle)
R-HSA-74182	Ketone body metabolism
R-HSA-9865118	Diseases of branched-chain amino acid catabolism

MSigDB gene sets: 382 (showing top): GOBP_LIPID_MODIFICATION, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, GOBP_FATTY_ACID_CATABOLIC_PROCESS, GOBP_EPITHELIUM_DEVELOPMENT, ZHAN_LATE_DIFFERENTIATION_GENES_UP, GOBP_METANEPHROS_DEVELOPMENT, GOBP_METANEPHRIC_EPITHELIUM_DEVELOPMENT, GOBP_COENZYME_A_METABOLIC_PROCESS, chr11q22, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, MCBRYAN_PUBERTAL_TGFB1_TARGETS_UP, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, TGACCTY_ERR1_Q2, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_KIDNEY_EPITHELIUM_DEVELOPMENT

GO Biological Process (16): liver development (GO:0001889), acetyl-CoA biosynthetic process (GO:0006085), L-isoleucine catabolic process (GO:0006550), fatty acid beta-oxidation (GO:0006635), response to hormone (GO:0009725), coenzyme A metabolic process (GO:0015936), coenzyme A biosynthetic process (GO:0015937), response to starvation (GO:0042594), acetyl-CoA catabolic process (GO:0046356), ketone body catabolic process (GO:0046952), adipose tissue development (GO:0060612), metanephric proximal convoluted tubule development (GO:0072229), obsolete ketone body metabolic process (GO:1902224), propionyl-CoA biosynthetic process (GO:1902860), lipid metabolic process (GO:0006629), fatty acid metabolic process (GO:0006631)

GO Molecular Function (12): acetyl-CoA C-acetyltransferase activity (GO:0003985), C-acetyltransferase activity (GO:0016453), enzyme binding (GO:0019899), potassium ion binding (GO:0030955), cholesterol O-acyltransferase activity (GO:0034736), identical protein binding (GO:0042802), coenzyme A binding (GO:0120225), acetyl-CoA C-acyltransferase activity (GO:0003988), transferase activity (GO:0016740), acyltransferase activity (GO:0016746), acyltransferase activity, transferring groups other than amino-acyl groups (GO:0016747), metal ion binding (GO:0046872)

GO Cellular Component (4): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), endoplasmic reticulum (GO:0005783), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-10 pathways:

Category	Pathways
Metabolism	3
Ketone body metabolism	2
Metabolism of amino acids and derivatives	1
Metabolism of proteins	1
Citric acid cycle (TCA cycle)	1
Diseases of branched-chain amino acid catabolism	1
Disease	1
Aerobic respiration and respiratory electron transport	1
Metabolism of lipids	1
Diseases of metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
acetyl-CoA metabolic process	2
protein binding	2
cytoplasm	2
intracellular membrane-bounded organelle	2
gland development	1
hepaticobiliary system development	1
acyl-CoA biosynthetic process	1
branched-chain amino acid catabolic process	1
L-amino acid catabolic process	1
proteinogenic amino acid catabolic process	1
fatty acid catabolic process	1
fatty acid ligase activity	1
fatty acid oxidation	1
response to endogenous stimulus	1
response to chemical	1
nucleoside phosphate metabolic process	1
sulfur compound metabolic process	1
purine-containing compound metabolic process	1
coenzyme A metabolic process	1
sulfur compound biosynthetic process	1
purine-containing compound biosynthetic process	1
nucleoside phosphate biosynthetic process	1
response to stress	1
response to nutrient levels	1
sulfur compound catabolic process	1
purine-containing compound catabolic process	1
nucleoside phosphate catabolic process	1
small molecule catabolic process	1
fatty acid derivative catabolic process	1
animal organ development	1
connective tissue development	1
proximal convoluted tubule development	1
metanephric nephron tubule development	1
metanephric proximal tubule development	1
fatty-acyl-CoA biosynthetic process	1
propionyl-CoA metabolic process	1
primary metabolic process	1
lipid metabolic process	1
monocarboxylic acid metabolic process	1
acetyl-CoA C-acyltransferase activity	1

Protein interactions and networks

STRING

2458 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ACAT1	HADHA	P40939	862
ACAT1	HMGCS2	P54868	853
ACAT1	HMGCS1	Q01581	845
ACAT1	NPAT	Q14207	810
ACAT1	MVD	P53602	797
ACAT1	MVK	Q03426	794
ACAT1	OXCT1	P55809	761
ACAT1	HMGCR	P04035	756
ACAT1	BDH1	Q02338	735
ACAT1	GGPS1	O95749	733
ACAT1	PMVK	Q15126	730
ACAT1	NELFB	Q8WX92	725
ACAT1	OXCT2	Q9BYC2	715
ACAT1	NELFA	Q9H3P2	704
ACAT1	FDPS	P14324	675

IntAct

97 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
VCAM1	PSMD11	psi-mi:“MI:0914”(association)	0.530
DDX21	MED19	psi-mi:“MI:2364”(proximity)	0.480
LMTK3	GPI	psi-mi:“MI:0914”(association)	0.420
ACAT2	ACAT1	psi-mi:“MI:0915”(physical association)	0.400
ACAT1	PDSS2	psi-mi:“MI:0915”(physical association)	0.400
ACAT1	VIM	psi-mi:“MI:0915”(physical association)	0.400
ACAT1	AGXT	psi-mi:“MI:0915”(physical association)	0.370
SIRT4	VWA8	psi-mi:“MI:0914”(association)	0.350
OTUB1	EPM2A	psi-mi:“MI:0914”(association)	0.350
FASTKD3	VWA8	psi-mi:“MI:0914”(association)	0.350
ANG	DDX39A	psi-mi:“MI:0914”(association)	0.350
PLEKHA7	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
DLST		psi-mi:“MI:0914”(association)	0.350
HSD17B10	HMGB1P1	psi-mi:“MI:0914”(association)	0.350
PDHA1		psi-mi:“MI:0914”(association)	0.350
SOD1	NPEPPSL1	psi-mi:“MI:0914”(association)	0.350
METTL3	TUBAL3	psi-mi:“MI:0914”(association)	0.350
SH2D3C	TMEM14DP	psi-mi:“MI:0914”(association)	0.350
ARHGAP24	LDHA	psi-mi:“MI:0914”(association)	0.350
DOCK8	IPO5	psi-mi:“MI:0914”(association)	0.350
ARHGAP44	ACAT1	psi-mi:“MI:0914”(association)	0.350
	DENND11	psi-mi:“MI:0914”(association)	0.350
	NUDT19	psi-mi:“MI:0914”(association)	0.350
PAK4	SNRPE	psi-mi:“MI:0914”(association)	0.350

BioGRID (281): ACAT1 (Affinity Capture-MS), ACAT1 (Affinity Capture-MS), ACAT1 (Affinity Capture-MS), ACAT1 (Affinity Capture-RNA), ABCB7 (Co-fractionation), ACAA2 (Co-fractionation), ACAT1 (Co-fractionation), ACAT1 (Co-fractionation), ACAT1 (Co-fractionation), ACAT1 (Co-fractionation), ACAT1 (Co-fractionation), ACAT1 (Co-fractionation), ACAT1 (Co-fractionation), ACAT1 (Co-fractionation), ACAT1 (Co-fractionation)

ESM2 similar proteins: A0A2I2F2I5, A5A6L0, A7MB35, G0SHF3, O49543, P08559, P09114, P09342, P0DKC3, P0DKC4, P14874, P17597, P24226, P24752, P26284, P27818, P27819, P29401, P29804, P33121, P35486, P40142, P49724, P50137, P52901, Q2NKZ4, Q2NL26, Q41768, Q41769, Q5NAY4, Q5R1W6, Q5R490, Q5R4C1, Q5RDE7, Q60HC7, Q6AV34, Q6B855, Q6K2E8, Q7XKQ8, Q8HXW9

Diamond homologs: A0A1D8PH52, A0KEL0, A0R1Y7, A1TZR8, A5W6G9, A6VVM8, B0XMC1, B0YA65, B5FEW7, B6EGU1, I1RMA2, I1RY81, O32177, P07097, P07871, P10551, P13437, P14611, P17764, P24752, P28790, P41338, P42765, P44873, P45359, P45363, P45369, P45855, P46707, P50174, P54810, P66927, P73825, P76461, P9WG68, P9WG69, Q04677, Q0AVM3, Q0KBP1, Q0VNZ7

SIGNOR signaling

14 interactions.

A	Effect	B	Mechanism
FGFR1	“up-regulates activity”	ACAT1	phosphorylation
ACAT1	“down-regulates activity”	IDH2	acetylation
FLT3	“up-regulates activity”	ACAT1	phosphorylation
EGFR	“up-regulates activity”	ACAT1	phosphorylation
ACAT1	“down-regulates quantity”	acetoacetyl-CoA(4-)	“chemical modification”
ACAT1	“up-regulates quantity”	acetyl-CoA(4-)	“chemical modification”
ACAT1	“down-regulates quantity”	“coenzyme A(4-)”	“chemical modification”
ACAT1	“down-regulates quantity”	acetyl-CoA(4-)	“chemical modification”
ACAT1	“up-regulates quantity”	acetoacetyl-CoA(4-)	“precursor of”
ACAT1	“up-regulates quantity”	“coenzyme A(4-)”	“precursor of”
ACAT1	“down-regulates activity”	PDHA1	acetylation
ACAT1	“down-regulates activity”	PDHA2	acetylation
ACAT1	“down-regulates activity”	PDP1	acetylation
ACAT1	“up-regulates activity”	ME1	acetylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	98
Likely pathogenic	79
Uncertain significance	169
Likely benign	320
Benign	59

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1069757	NM_000019.4(ACAT1):c.1173dup (p.Ala392fs)	Pathogenic
1073055	NM_000019.4(ACAT1):c.233del (p.Lys78fs)	Pathogenic
1076202	NM_000019.4(ACAT1):c.1100T>A (p.Leu367Ter)	Pathogenic
1076974	NC_000011.9:g.(?107992324)(107992415_?)del	Pathogenic
1172774	NM_000019.4(ACAT1):c.252del (p.Glu85fs)	Pathogenic
1172775	NM_000019.4(ACAT1):c.1117A>T (p.Lys373Ter)	Pathogenic
1332739	NM_000019.4(ACAT1):c.731-2A>G	Pathogenic
1367924	NC_000011.9:g.(?108005849)(108005989_?)del	Pathogenic
1374250	NM_000019.4(ACAT1):c.316C>T (p.Gln106Ter)	Pathogenic
1384281	NM_000019.4(ACAT1):c.846dup (p.Ala283fs)	Pathogenic
1426396	NM_000019.4(ACAT1):c.1189C>A (p.His397Asn)	Pathogenic
1449779	NM_000019.4(ACAT1):c.826+2T>C	Pathogenic
1452347	NM_000019.4(ACAT1):c.655_656insTTTTTTTTTTTTTTTTTTTTNNNNNNNNNNGATGGTCTCGATCTCCTGACCTCATGATCCACCCGCCTCGGCCTCCCAAAGTGCTGGGATTACAGGCGTGAGCCACCGCGCCCGGCCGCTATTAATTCTT (p.Tyr219delinsPhePhePhePhePhePhePheXaaXaaXaaXaaTrpSerArgSerProAspLeuMetIleHisProProArgProProLysValLeuGlyLeuGlnAlaTer)	Pathogenic
1454055	NM_000019.4(ACAT1):c.763G>T (p.Glu255Ter)	Pathogenic
1459346	NC_000011.9:g.(?108010782)(108012437_?)del	Pathogenic
147281	GRCh38/hg38 11q22.3(chr11:107479091-108222532)x1	Pathogenic
1705360	NM_000019.4(ACAT1):c.433C>T (p.Gln145Ter)	Pathogenic
193787	NM_000019.4(ACAT1):c.1006-4_1006-1delinsAAA	Pathogenic
1991943	NM_000019.4(ACAT1):c.649_652dup (p.Ser218Ter)	Pathogenic
2001273	NM_000019.4(ACAT1):c.330dup (p.Ala111fs)	Pathogenic
2003666	NM_000019.4(ACAT1):c.272del (p.Met91fs)	Pathogenic
2011809	NM_000019.4(ACAT1):c.170del (p.Gly57fs)	Pathogenic
208341	NM_000019.4(ACAT1):c.149del (p.Thr50fs)	Pathogenic
2099256	NM_000019.4(ACAT1):c.542_543del (p.Lys181fs)	Pathogenic
2101162	NM_000019.4(ACAT1):c.75_76del (p.Glu25fs)	Pathogenic
2115197	NM_000019.4(ACAT1):c.580-93_626del	Pathogenic
2117488	NM_000019.4(ACAT1):c.104C>G (p.Ser35Ter)	Pathogenic
2127596	NM_000019.4(ACAT1):c.835del (p.Thr279fs)	Pathogenic
2169323	NM_001386678.1(ACAT1):c.120+2267_120+2268del	Pathogenic
225062	NM_000019.4(ACAT1):c.757G>A (p.Asp253Asn)	Pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

2781 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:108141685:T:C	F271L	0.998
11:108141687:C:A	F271L	0.998
11:108141687:C:G	F271L	0.998
11:108142460:A:C	S284R	0.998
11:108142462:T:A	S284R	0.998
11:108142462:T:G	S284R	0.998
11:108146262:T:C	F356L	0.998
11:108146264:T:A	F356L	0.998
11:108146264:T:G	F356L	0.998
11:108146265:A:C	S357R	0.998
11:108146267:T:A	S357R	0.998
11:108146267:T:G	S357R	0.998
11:108144015:T:C	F325L	0.997
11:108144017:T:A	F325L	0.997
11:108144017:T:G	F325L	0.997
11:108147345:C:G	C413W	0.997
11:108142457:G:C	A283P	0.996
11:108144025:C:A	A328D	0.996
11:108146321:T:A	N375K	0.996
11:108146321:T:G	N375K	0.996
11:108146351:T:A	H385Q	0.996
11:108146351:T:G	H385Q	0.996
11:108138932:C:T	S157F	0.995
11:108138991:G:C	D177H	0.995
11:108141631:G:C	D253H	0.995
11:108142472:G:C	D288H	0.995
11:108146255:T:A	N353K	0.995
11:108146255:T:G	N353K	0.995
11:108146257:A:T	E354V	0.995
11:108146350:A:G	H385R	0.995

dbSNP variants (sampled 300 via entrez): RS1000037414 (11:108141181 T>C), RS1000107805 (11:108128498 G>A), RS1000114382 (11:108147778 AGTAAATTACG>A), RS1000193806 (11:108131623 A>T), RS1000218725 (11:108117747 T>C), RS1000682871 (11:108138521 C>G,T), RS1000728955 (11:108124483 G>A,C), RS1000752309 (11:108144840 A>C), RS1000831375 (11:108131808 G>C), RS1000834832 (11:108121733 C>T), RS1000931495 (11:108127811 C>T), RS1001016275 (11:108115707 A>G), RS1001143826 (11:108145136 T>C), RS1001161373 (11:108125858 G>A), RS1001435815 (11:108119836 G>C)

Disease associations

OMIM: gene MIM:607809 | disease phenotypes: MIM:203750, MIM:208900

GenCC curated gene-disease

Disease	Classification	Inheritance
beta-ketothiolase deficiency	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
beta-ketothiolase deficiency	Definitive	AR

Mondo (3): beta-ketothiolase deficiency (MONDO:0008760), ataxia telangiectasia (MONDO:0008840), primary ovarian failure (MONDO:0005387)

Orphanet (3): Beta-ketothiolase deficiency (Orphanet:134), Ataxia-telangiectasia (Orphanet:100), NON RARE IN EUROPE: Primary ovarian failure (Orphanet:619)

HPO phenotypes

47 total (30 of 47 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000713	Agitation
HP:0000741	Apathy
HP:0000822	Hypertension
HP:0000969	Edema
HP:0000980	Pallor
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001256	Mild intellectual disability
HP:0001257	Spasticity
HP:0001259	Coma
HP:0001262	Excessive daytime somnolence
HP:0001265	Hyporeflexia
HP:0001270	Motor delay
HP:0001824	Weight loss
HP:0001894	Thrombocytosis
HP:0001941	Acidosis
HP:0001942	Metabolic acidosis
HP:0001943	Hypoglycemia
HP:0001944	Dehydration
HP:0001945	Fever
HP:0001974	Increased total leukocyte count
HP:0001987	Hyperammonemia
HP:0001993	Ketoacidosis
HP:0002013	Vomiting
HP:0002014	Diarrhea
HP:0002039	Anorexia
HP:0002149	Hyperuricemia

GWAS associations

0 associations (top):

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D001260	Ataxia Telangiectasia	C10.228.140.252.190.530.060; C10.562.100; C10.597.350.090.500.530.060; C14.907.823.213; C16.320.080; C16.320.798.250; C18.452.284.060; C20.673.795.250
D016649	Primary Ovarian Insufficiency	C12.050.351.500.056.630.750; C12.100.250.056.630.750; C19.391.630.750
C535434	Beta ketothiolase deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2616 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

5 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 85,307 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1670	MITOTANE	4	83,856
CHEMBL1908306	EFLUCIMIBE	2	272
CHEMBL2105855	ELDACIMIBE	2	278
CHEMBL274185	LECIMIBIDE	2	823
CHEMBL46423	NEVANIMIBE	2	78

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Lanosterol biosynthesis pathway

Most potent curated ligand interactions (13 total), top 13:

Ligand	Action	Affinity	Parameter
compound 16 [PMID: 16242323]	Inhibition	8.27	pIC50
compound 15b [PMID: 16242323]	Inhibition	8.08	pIC50
SM-32504	Inhibition	7.96	pIC50
compound 15a [PMID: 16242323]	Inhibition	7.85	pIC50
SMP-797	Inhibition	7.68	pIC50
compound 22d [PMID: 16242323]	Inhibition	7.37	pIC50
compound 22c [PMID: 16242323]	Inhibition	7.21	pIC50
compound 18a [PMID: 16242323]	Inhibition	6.42	pIC50
compound 26b [PMID: 16242323]	Inhibition	6.37	pIC50
K-604	Inhibition	6.35	pIC50
compound 26a [PMID: 16242323]	Inhibition	6.34	pIC50
compound 26c [PMID: 16242323]	Inhibition	6.27	pIC50
compound 18b [PMID: 16242323]	Inhibition	6.17	pIC50

ChEMBL bioactivities

14 potent at pChembl≥5 of 16 total, top 14 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.52	IC50	30	nM	ELDACIMIBE
7.51	IC50	31	nM	CHEMBL573970
7.36	IC50	44	nM	CHEMBL33780
7.35	IC50	45	nM	CHEMBL5203276
7.23	IC50	59	nM	EFLUCIMIBE
7.01	IC50	97	nM	CHEMBL47095
6.95	IC50	113	nM	CHEMBL5542126
6.95	IC50	112	nM	CL-976
6.74	IC50	183	nM	NEVANIMIBE
6.62	IC50	239	nM	LECIMIBIDE
6.27	Kd	533	nM	CHEMBL5653589
6.27	ED50	533	nM	CHEMBL5653589
5.89	IC50	1300	nM	MITOTANE
5.60	IC50	2500	nM	CHEMBL5204128

PubChem BioAssay actives

13 with measured affinity, of 32 total; 13 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
5-[(3,5-ditert-butyl-4-hydroxyanilino)-[[4-(2,2-dimethylpropyl)phenyl]methyl-hexylamino]methylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione	2075676: Inhibition of ACAT1 (unknown origin)	ic50	0.0300	uM
1-[4-amino-2,6-di(propan-2-yl)phenyl]-3-[1-butyl-4-[3-(3-hydroxypropoxy)phenyl]-2-oxo-1,8-naphthyridin-3-yl]urea	2075676: Inhibition of ACAT1 (unknown origin)	ic50	0.0310	uM
1-[5-[(4,5-diphenyl-1H-imidazol-2-yl)sulfanyl]pentyl]-3,5-dimethylpyrazole	2075676: Inhibition of ACAT1 (unknown origin)	ic50	0.0440	uM
2-[3-[5-[[5-(3,4-difluoroanilino)-1,3,4-oxadiazole-2-carbonyl]amino]-2-pyridinyl]-3-azaspiro[5.5]undecan-9-yl]acetic acid	1889802: Inhibition of human ACAT1 in HepG2 cells assessed as inhibition of triglyceride synthesis incubated for 1 hrs followed by 13C-addition of 13C-oleic acid pre-complexed with fatty acid free BSA for 6 hrs by LC/MS/MS analysis	ic50	0.0450	uM
(2S)-2-dodecylsulfanyl-N-(4-hydroxy-2,3,5-trimethylphenyl)-2-phenylacetamide	2075676: Inhibition of ACAT1 (unknown origin)	ic50	0.0590	uM
1-butyl-3-[2-[3-(5-ethyl-4-phenylimidazol-1-yl)propoxy]-6-methylphenyl]urea	2075676: Inhibition of ACAT1 (unknown origin)	ic50	0.0970	uM
2,2-dimethyl-N-(2,4,6-trimethoxyphenyl)dodecanamide	2075676: Inhibition of ACAT1 (unknown origin)	ic50	0.1120	uM
N-butyl-3-[(4-decoxybenzoyl)amino]-4-methylsulfanylbenzamide	2075676: Inhibition of ACAT1 (unknown origin)	ic50	0.1130	uM
1-[[1-[4-(dimethylamino)phenyl]cyclopentyl]methyl]-3-[2,6-di(propan-2-yl)phenyl]urea	2075676: Inhibition of ACAT1 (unknown origin)	ic50	0.1830	uM
3-(2,4-difluorophenyl)-1-[5-[(4,5-diphenyl-1H-imidazol-2-yl)sulfanyl]pentyl]-1-heptylurea	2075676: Inhibition of ACAT1 (unknown origin)	ic50	0.2390	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147781: Binding affinity to human ACAT1 incubated for 45 mins by Kinobead based pull down assay	kd	0.5330	uM
Mitotane	2075676: Inhibition of ACAT1 (unknown origin)	ic50	1.3000	uM
7-[5-[[5-(3,4-difluoroanilino)-1,3,4-oxadiazole-2-carbonyl]amino]-2-pyridinyl]-7-azaspiro[3.5]nonane-2-carboxylic acid	1889802: Inhibition of human ACAT1 in HepG2 cells assessed as inhibition of triglyceride synthesis incubated for 1 hrs followed by 13C-addition of 13C-oleic acid pre-complexed with fatty acid free BSA for 6 hrs by LC/MS/MS analysis	ic50	2.5000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, increases expression	3
bisphenol F	increases expression, affects cotreatment, decreases expression	2
bisphenol A	decreases expression, increases expression	2
Acetaminophen	decreases expression	2
Cyclosporine	decreases expression	2
Cadmium Chloride	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
dicrotophos	decreases expression	1
7-ketocholesterol	decreases expression, affects cotreatment	1
lasiocarpine	decreases expression	1
chlortoluron	decreases expression	1
potassium perchlorate	increases expression	1
titanium dioxide	decreases expression	1
arsenite	increases reaction, affects binding	1
sodium arsenite	decreases expression	1
perfluorooctanoic acid	increases expression	1
guanosine 5’-O-(2-thiodiphosphate)	decreases reaction, increases expression	1
periodate-oxidized adenosine	affects expression	1
cryptotanshinone	decreases expression	1
isobutyl alcohol	affects cotreatment, decreases expression, increases abundance	1
sarpogrelate	decreases reaction, increases expression	1
di-n-butylphosphoric acid	affects expression	1
rottlerin	increases expression, decreases reaction	1
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one	decreases reaction, increases expression	1
platycodin D	decreases activity	1
AG 1879	decreases reaction, 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, increases expression	1
nutlin 3	affects cotreatment, increases secretion	1
bisphenol B	increases expression	1

ChEMBL screening assays

12 unique, capped per target: 12 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3224752	Binding	Inhibition of ACAT1 (unknown origin)	Discovery and optimization of efficacious neutral 4-amino-6-biphenyl-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5-one diacylglycerol acyl transferase-1 (DGAT1) inhibitors — Medchemcomm

Cellosaurus cell lines

4 cell lines: 2 finite cell line, 1 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B0YQ	Abcam SW480 ACAT1 KO	Cancer cell line	Male
CVCL_B3VK	WG0138	Finite cell line	Female
CVCL_B3VL	WG0026	Finite cell line	Male
CVCL_D8YK	Ubigene HEK293 ACAT1 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01052623	PHASE4	UNKNOWN	Status of Growth Hormone/ Insulin-like Growth Factor-1 (GH/IGF-1) Axis and Growth Failure in Ataxia Telangiectasia (AT)
NCT02733679	PHASE4	COMPLETED	Response of Individuals With Ataxia-Telangiectasia to Metformin and Pioglitazone
NCT00417066	PHASE4	COMPLETED	Flexible GnRH Antagonist vs Flare up GnRH Agonist Protocol in Poor Responders
NCT00732693	PHASE4	COMPLETED	Evaluation of Physiologic and Standard Sex Steroid Replacement Regimens in Women With Premature Ovarian Failure
NCT00837616	PHASE4	COMPLETED	Estrogen Dosing in Turner Syndrome: Pharmacology and Metabolism
NCT01853501	PHASE4	UNKNOWN	Effects of ADSC Therapy in Women With POF
NCT02783937	PHASE4	COMPLETED	Filgrastim for Premature Ovarian Insufficiency
NCT03535480	PHASE4	UNKNOWN	Autologous Bone Marrow Stem Cell Ovarian Transplantation to Restore Ovarian Function in Premature Ovarian Failure
NCT00656409	PHASE3	COMPLETED	Conjugate Pneumococcal Vaccine in Ataxia Telangiectasia (AT)
NCT03563053	PHASE3	TERMINATED	Extension Treatment Using EryDex System in Patients With AT Who Participated in the ATTeST-IEDAT-02-2015 Study
NCT06193200	PHASE3	COMPLETED	Evaluate the Neurological Effects of EryDex on Subjects With A-T
NCT06664853	PHASE3	TERMINATED	Open-Label Extension of EryDex Study IEDAT-04-2022
NCT06673056	PHASE3	ACTIVE_NOT_RECRUITING	A Pivotal Study of N-Acetyl-L-Leucine on Ataxia-Telangiectasia (A-T)
NCT00140998	PHASE3	COMPLETED	Estrogen Treatment (Oral vs. Patches) in Turner Syndrome
NCT03759678	PHASE2	TERMINATED	N-Acetyl-L-Leucine for Ataxia-Telangiectasia (A-T)
NCT03962114	PHASE2	COMPLETED	Effects of Vitamin B3 in Patients With Ataxia Telangiectasia
NCT04513002	PHASE2	COMPLETED	Ataxia-telangiectasia: Treating Mitochondrial Dysfunction With a Novel Form of Anaplerosis
NCT04870866	PHASE2	ACTIVE_NOT_RECRUITING	NAD Supplementation to Prevent Progressive Neurological Disease in Ataxia Telangiectasia
NCT04887311	PHASE2	UNKNOWN	MBM-01 (Tempol) for the Treatment of Ataxia Telangiectasia
NCT00001951	PHASE2	COMPLETED	Hormone Replacement in Young Women With Premature Ovarian Failure
NCT00370019	PHASE2	WITHDRAWN	Effects of an Estrogen Replacement Therapy Skin Patch on Ovulation in Women With Premature Ovarian Failure
NCT00429494	PHASE2	COMPLETED	GnRH Analogue for Ovarian Function Preservation in Hematopoietic Stem Cell Transplantation Patients
NCT03816852	PHASE2	SUSPENDED	The Safety and Efficiency Study of Mesenchymal Stem Cell (19#iSCLife®-POI) in Premature Ovarian Insufficiency
NCT04536467	PHASE2	UNKNOWN	Prevention of Chemotherapy-Induced Ovarian Failure With Goserelin in Premenopausal Lymphoma Patients
NCT06117982	PHASE2	COMPLETED	The Impact of Granulocyte Colony Stimulating Factor on Premature Ovarian Insufficiency
NCT05531890	PHASE1	UNKNOWN	Comparative Bioavailability of Betamethasone Oral Solution Metered Spray (GTX-102) in Healthy Subjects
NCT02912104	PHASE1	COMPLETED	A Therapeutic Trial of Human Amniotic Epithelial Cells Transplantation for Primary Ovarian Failure
NCT03178695	PHASE1	COMPLETED	Inovium Ovarian Rejuvenation Trials
NCT04815213	PHASE1	ACTIVE_NOT_RECRUITING	The Use of Expandeded Mesenchymal Stromal Cells (MSC) in Premature Ovarian Failure (POF) in Adult Humans
NCT05138367	PHASE1	COMPLETED	Effects of UCA-PSCs in Women With POF
NCT06132542	PHASE1	UNKNOWN	Autologous ADMSC Transplantation in Patients With POI
NCT03655223	Not specified	ENROLLING_BY_INVITATION	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
NCT07215416	PHASE1/PHASE2	RECRUITING	Safety and Efficacy of Mutation-targeted Precision Genetic Therapy for Ataxia-Telangiectasia (A-T)
NCT00640003	EARLY_PHASE1	COMPLETED	Baclofen Treatment of Ataxia Telangiectasia
NCT00187057	Not specified	COMPLETED	Study for Treatment of Cancer in Children With Ataxia-telangiectasia
NCT00951886	Not specified	UNKNOWN	The Validity of Forced Expiratory Maneuvers in Ataxia Telangiectasia Studied Longitudinally
NCT01075438	Not specified	UNKNOWN	Immunogenicity of Pneumococcal Vaccines in Ataxia-telangiectasia Patients
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford