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P24752 (THIL_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 156. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Acetyl-CoA acetyltransferase, mitochondrial

EC=2.3.1.9
Alternative name(s):
Acetoacetyl-CoA thiolase
T2
Gene names
Name:ACAT1
Synonyms:ACAT, MAT
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length427 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Plays a major role in ketone body metabolism.

Catalytic activity

2 acetyl-CoA = CoA + acetoacetyl-CoA. Ref.9

Enzyme regulation

Activated by potassium ions, but not sodium ions. Ref.9

Subunit structure

Homotetramer. Ref.9

Subcellular location

Mitochondrion.

Post-translational modification

Succinylation at Lys-268, adjacent to a coenzyme A binding site. Desuccinylated by SIRT5 By similarity.

Involvement in disease

3-ketothiolase deficiency (3KTD) [MIM:203750]: An 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.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.11 Ref.12 Ref.13 Ref.14

Sequence similarities

Belongs to the thiolase family.

Biophysicochemical properties

Kinetic parameters:

KM=4 µM for acetoacetyl coenzyme A Ref.9

KM=20 µM for coenzyme A

KM=8 µM for 2-methylacetoacetyl coenzyme A

KM=508 µM for acetyl coenzyme A

Ontologies

Keywords
   Cellular componentMitochondrion
   Coding sequence diversityPolymorphism
   DiseaseDisease mutation
   DomainTransit peptide
   LigandMetal-binding
Potassium
   Molecular functionAcyltransferase
Transferase
   PTMAcetylation
   Technical term3D-structure
Complete proteome
Direct protein sequencing
Reference proteome
Gene Ontology (GO)
   Biological_processadipose tissue development

Inferred from electronic annotation. Source: Ensembl

brain development

Inferred from electronic annotation. Source: Ensembl

branched-chain amino acid catabolic process

Traceable author statement. Source: Reactome

cellular ketone body metabolic process

Traceable author statement. Source: Reactome

cellular lipid metabolic process

Traceable author statement. Source: Reactome

cellular nitrogen compound metabolic process

Traceable author statement. Source: Reactome

ketone body biosynthetic process

Traceable author statement. Source: Reactome

ketone body catabolic process

Traceable author statement. Source: Reactome

liver development

Inferred from electronic annotation. Source: Ensembl

metanephric proximal convoluted tubule development

Inferred from electronic annotation. Source: Ensembl

protein homooligomerization

Inferred from electronic annotation. Source: Ensembl

response to hormone

Inferred from electronic annotation. Source: Ensembl

response to organic cyclic compound

Inferred from electronic annotation. Source: Ensembl

response to starvation

Inferred from electronic annotation. Source: Ensembl

small molecule metabolic process

Traceable author statement. Source: Reactome

   Cellular_componentextracellular vesicular exosome

Inferred from direct assay PubMed 19056867PubMed 23376485. Source: UniProt

mitochondrial inner membrane

Inferred from electronic annotation. Source: Ensembl

mitochondrial matrix

Traceable author statement. Source: Reactome

mitochondrion

Inferred from direct assay. Source: HPA

   Molecular_functionacetyl-CoA C-acetyltransferase activity

Inferred from experiment. Source: Reactome

coenzyme binding

Inferred from electronic annotation. Source: Ensembl

metal ion binding

Inferred from electronic annotation. Source: UniProtKB-KW

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Transit peptide1 – 3333Mitochondrion By similarity
Chain34 – 427394Acetyl-CoA acetyltransferase, mitochondrial
PRO_0000034085

Regions

Region258 – 2603Coenzyme A binding

Sites

Active site1261Acyl-thioester intermediate Probable
Active site3851Proton acceptor Probable
Active site4131Proton acceptor Probable
Metal binding2191Potassium
Metal binding2801Potassium; via carbonyl oxygen
Metal binding2811Potassium; via carbonyl oxygen
Metal binding2831Potassium; via carbonyl oxygen
Metal binding3811Potassium; via carbonyl oxygen
Binding site2191Coenzyme A
Binding site2631Coenzyme A
Binding site2841Coenzyme A

Amino acid modifications

Modified residue661N6-acetyllysine; alternate By similarity
Modified residue661N6-succinyllysine; alternate By similarity
Modified residue781N6-succinyllysine By similarity
Modified residue1741N6-acetyllysine; alternate Ref.7
Modified residue1741N6-succinyllysine; alternate By similarity
Modified residue1811N6-acetyllysine; alternate Ref.7
Modified residue1811N6-succinyllysine; alternate By similarity
Modified residue1901N6-acetyllysine; alternate By similarity
Modified residue1901N6-succinyllysine; alternate By similarity
Modified residue2021N6-acetyllysine; alternate By similarity
Modified residue2021N6-succinyllysine; alternate By similarity
Modified residue2231N6-acetyllysine; alternate By similarity
Modified residue2231N6-succinyllysine; alternate By similarity
Modified residue2301N6-acetyllysine; alternate By similarity
Modified residue2301N6-succinyllysine; alternate By similarity
Modified residue2431N6-succinyllysine By similarity
Modified residue2511N6-acetyllysine Ref.7
Modified residue2571N6-acetyllysine By similarity
Modified residue2631N6-acetyllysine; alternate Ref.7
Modified residue2631N6-succinyllysine; alternate By similarity
Modified residue2661N6-succinyllysine By similarity
Modified residue2681N6-succinyllysine By similarity
Modified residue2731N6-acetyllysine By similarity
Modified residue3381N6-acetyllysine By similarity

Natural variations

Natural variant51A → P.
Corresponds to variant rs3741056 [ dbSNP | Ensembl ].
VAR_007496
Natural variant851Missing in 3KTD.
VAR_007497
Natural variant931N → S in 3KTD; 10% activity. Ref.14
VAR_007498
Natural variant1521G → A in 3KTD.
VAR_007499
Natural variant1581N → D in 3KTD; no activity. Ref.13
VAR_007500
Natural variant1831G → R in 3KTD; no activity. Ref.11
VAR_007501
Natural variant2971T → M in 3KTD; 10% normal activity. Ref.13
VAR_007502
Natural variant3011A → P in 3KTD; 5% normal activity. Ref.13
VAR_007503
Natural variant3121I → T in 3KTD; 10% activity. Ref.14
VAR_007504
Natural variant3331A → P in 3KTD; no activity. Ref.14
VAR_007505
Natural variant3791G → V in 3KTD.
VAR_007506
Natural variant3801A → T in 3KTD; 7% normal activity. Ref.12
VAR_007507

Experimental info

Sequence conflict3401V → M in BAA01387. Ref.2
Sequence conflict3461D → N in BAA01387. Ref.2
Sequence conflict3801A → S in BAA01387. Ref.2
Sequence conflict4121I → F in BAA01387. Ref.2

Secondary structure

........................................................................ 427
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
P24752 [UniParc].

Last modified March 1, 1992. Version 1.
Checksum: 2E81168EB39D0142

FASTA42745,200
        10         20         30         40         50         60 
MAVLAALLRS GARSRSPLLR RLVQEIRYVE RSYVSKPTLK EVVIVSATRT PIGSFLGSLS 

        70         80         90        100        110        120 
LLPATKLGSI AIQGAIEKAG IPKEEVKEAY MGNVLQGGEG QAPTRQAVLG AGLPISTPCT 

       130        140        150        160        170        180 
TINKVCASGM KAIMMASQSL MCGHQDVMVA GGMESMSNVP YVMNRGSTPY GGVKLEDLIV 

       190        200        210        220        230        240 
KDGLTDVYNK IHMGSCAENT AKKLNIARNE QDAYAINSYT RSKAAWEAGK FGNEVIPVTV 

       250        260        270        280        290        300 
TVKGQPDVVV KEDEEYKRVD FSKVPKLKTV FQKENGTVTA ANASTLNDGA AALVLMTADA 

       310        320        330        340        350        360 
AKRLNVTPLA RIVAFADAAV EPIDFPIAPV YAASMVLKDV GLKKEDIAMW EVNEAFSLVV 

       370        380        390        400        410        420 
LANIKMLEID PQKVNINGGA VSLGHPIGMS GARIVGHLTH ALKQGEYGLA SICNGGGGAS 


AMLIQKL 

« Hide

References

« Hide 'large scale' references
[1]"Molecular cloning and sequence of the complementary DNA encoding human mitochondrial acetoacetyl-coenzyme A thiolase and study of the variant enzymes in cultured fibroblasts from patients with 3-ketothiolase deficiency."
Fukao T., Yamaguchi S., Kano M., Orii T., Fujiki Y., Osumi T., Hashimoto T.
J. Clin. Invest. 86:2086-2092(1990) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]"Structure and expression of the human mitochondrial acetoacetyl-CoA thiolase-encoding gene."
Kano M., Fukao T., Yamaguchi S., Orii T., Osumi T., Hashimoto T.
Gene 109:285-290(1991) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]"Complete sequencing and characterization of 21,243 full-length human cDNAs."
Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. expand/collapse author list , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.
Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Tissue: Brain.
[4]Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. expand/collapse author list , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C.
Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]"Vectorial proteomics reveal targeting, phosphorylation and specific fragmentation of polymerase I and transcript release factor (PTRF) at the surface of caveolae in human adipocytes."
Aboulaich N., Vainonen J.P., Stralfors P., Vener A.V.
Biochem. J. 383:237-248(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: PROTEIN SEQUENCE OF 50-78 AND 312-338.
Tissue: Adipocyte.
[6]Lubec G., Chen W.-Q., Sun Y.
Submitted (DEC-2008) to UniProtKB
Cited for: PROTEIN SEQUENCE OF 50-78 AND 231-243, IDENTIFICATION BY MASS SPECTROMETRY.
Tissue: Fetal brain cortex.
[7]"Lysine acetylation targets protein complexes and co-regulates major cellular functions."
Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C., Olsen J.V., Mann M.
Science 325:834-840(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-174; LYS-181; LYS-251 AND LYS-263, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[8]"Initial characterization of the human central proteome."
Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.
BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[9]"Crystallographic and kinetic studies of human mitochondrial acetoacetyl-CoA thiolase: the importance of potassium and chloride ions for its structure and function."
Haapalainen A.M., Merilaeinen G., Pirilae P.L., Kondo N., Fukao T., Wierenga R.K.
Biochemistry 46:4305-4321(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) OF 35-427 IN COMPLEX WITH COENZYME A AND POTASSIUM, SUBUNIT, BIOPHYSICOCHEMICAL PROPERTIES, CATALYTIC ACTIVITY, ENZYME REGULATION.
[10]"Molecular basis of beta-ketothiolase deficiency: mutations and polymorphisms in the human mitochondrial acetoacetyl-coenzyme A thiolase gene."
Fukao T., Yamaguchi S., Orii T., Hashimoto T.
Hum. Mutat. 5:113-120(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW ON 3KTD VARIANTS.
[11]"Identification of three mutant alleles of the gene for mitochondrial acetoacetyl-coenzyme A thiolase. A complete analysis of two generations of a family with 3-ketothiolase deficiency."
Fukao T., Yamaguchi S., Orii T., Schutgens R.B.H., Osumi T., Hashimoto T.
J. Clin. Invest. 89:474-479(1992) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT 3KTD ARG-183.
[12]"Evidence for a structural mutation (347Ala to Thr) in a German family with 3-ketothiolase deficiency."
Fukao T., Yamaguchi S., Tomatsu S., Orii T., Frauendienst-Egger G., Schrod L., Osumi T., Hashimoto T.
Biochem. Biophys. Res. Commun. 179:124-129(1991) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT 3KTD THR-380.
[13]"Molecular, biochemical, and clinical characterization of mitochondrial acetoacetyl-coenzyme A thiolase deficiency in two further patients."
Wakazono A., Fukao T., Yamaguchi S., Hori T., Orii T., Lambert M., Mitchell G.A., Lee G.W., Hashimoto T.
Hum. Mutat. 5:34-42(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS 3KTD ASP-158; MET-297 AND PRO-301.
[14]"Characterization of N93S, I312T, and A333P missense mutations in two Japanese families with mitochondrial acetoacetyl-CoA thiolase deficiency."
Fukao T., Nakamura H., Song X.-Q., Nakamura K., Orii K.E., Kohno Y., Kano M., Yamaguchi S., Hashimoto T., Orii T., Kondo N.
Hum. Mutat. 12:245-254(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS 3KTD SER-93; THR-312 AND PRO-333.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
D90228 mRNA. Translation: BAA14278.1.
D10511 Genomic DNA. Translation: BAA01387.1.
AK312574 mRNA. Translation: BAG35468.1.
CH471065 Genomic DNA. Translation: EAW67104.1.
CCDSCCDS8339.1.
PIRJH0255.
RefSeqNP_000010.1. NM_000019.3.
UniGeneHs.232375.

3D structure databases

PDBe
RCSB-PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
2F2SX-ray2.00A/B/C/D41-427[»]
2IB7X-ray2.05A/B/C/D34-427[»]
2IB8X-ray1.85A/B/C/D34-427[»]
2IB9X-ray2.05A/B/C/D34-427[»]
2IBUX-ray1.90A/B/C/D34-427[»]
2IBWX-ray1.90A/B/C/D34-427[»]
2IBYX-ray1.85A/B/C/D34-427[»]
ProteinModelPortalP24752.
SMRP24752. Positions 35-427.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid106556. 36 interactions.
IntActP24752. 3 interactions.
MINTMINT-5000530.
STRING9606.ENSP00000265838.

Chemistry

BindingDBP24752.
DrugBankDB00795. Sulfasalazine.

PTM databases

PhosphoSiteP24752.

Polymorphism databases

DMDM135755.

2D gel databases

REPRODUCTION-2DPAGEIPI00030363.
UCD-2DPAGEP24752.

Proteomic databases

MaxQBP24752.
PaxDbP24752.
PeptideAtlasP24752.
PRIDEP24752.

Protocols and materials databases

DNASU38.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000265838; ENSP00000265838; ENSG00000075239.
GeneID38.
KEGGhsa:38.
UCSCuc001pjy.3. human.

Organism-specific databases

CTD38.
GeneCardsGC11P107992.
HGNCHGNC:93. ACAT1.
HPAHPA004428.
HPA007569.
MIM203750. phenotype.
607809. gene.
neXtProtNX_P24752.
Orphanet134. Ketoacidosis due to beta-ketothiolase deficiency.
PharmGKBPA24431.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG0183.
HOGENOMHOG000012238.
HOVERGENHBG003112.
InParanoidP24752.
KOK00626.
OMADQVAIWE.
OrthoDBEOG7JQBNG.
PhylomeDBP24752.
TreeFamTF300650.

Enzyme and pathway databases

BioCycMetaCyc:HS01167-MONOMER.
ReactomeREACT_111217. Metabolism.

Gene expression databases

ArrayExpressP24752.
BgeeP24752.
CleanExHS_ACAT1.
GenevestigatorP24752.

Family and domain databases

Gene3D3.40.47.10. 4 hits.
InterProIPR002155. Thiolase.
IPR016039. Thiolase-like.
IPR016038. Thiolase-like_subgr.
IPR020615. Thiolase_acyl_enz_int_AS.
IPR020610. Thiolase_AS.
IPR020617. Thiolase_C.
IPR020613. Thiolase_CS.
IPR020616. Thiolase_N.
[Graphical view]
PfamPF02803. Thiolase_C. 1 hit.
PF00108. Thiolase_N. 1 hit.
[Graphical view]
PIRSFPIRSF000429. Ac-CoA_Ac_transf. 1 hit.
SUPFAMSSF53901. SSF53901. 2 hits.
TIGRFAMsTIGR01930. AcCoA-C-Actrans. 1 hit.
PROSITEPS00098. THIOLASE_1. 1 hit.
PS00737. THIOLASE_2. 1 hit.
PS00099. THIOLASE_3. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

EvolutionaryTraceP24752.
GeneWikiACAT1.
GenomeRNAi38.
NextBio149.
PROP24752.
SOURCESearch...

Entry information

Entry nameTHIL_HUMAN
AccessionPrimary (citable) accession number: P24752
Secondary accession number(s): B2R6H1
Entry history
Integrated into UniProtKB/Swiss-Prot: March 1, 1992
Last sequence update: March 1, 1992
Last modified: July 9, 2014
This is version 156 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 11

Human chromosome 11: entries, gene names and cross-references to MIM