Reviewed, UniProtKB/Swiss-Prot P24752 (THIL_HUMAN)

Names and origin

Protein names

Recommended name:
    Acetyl-CoA acetyltransferase, mitochondrial
    EC=2.3.1.9
Alternative name(s):
    Acetoacetyl-CoA thiolase
    T2

Gene names

Name:	ACAT1
Synonyms:	ACAT, MAT

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	427 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Plays a major role in ketone body metabolism.
Catalytic activity	2 acetyl-CoA = CoA + acetoacetyl-CoA. Ref.6
Enzyme regulation	Activated by potassium ions, but not sodium ions. Ref.6
Subunit structure	Homotetramer. Ref.6
Subcellular location	Mitochondrion.
Involvement in disease	Defects in ACAT1 are a cause of 3-ketothiolase deficiency (3KTD) [MIM:203750]; also known as alpha-methylacetoaceticaciduria. 3KTD is 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. Ref.8 Ref.9 Ref.10 Ref.11
Sequence similarities	Belongs to the thiolase family.
Biophysicochemical properties	Kinetic parameters: KM=4 µM for acteoacetyl coenzyme A KM=20 µM for coenzyme A KM=8 µM for 2-methylacteoacetyl coenzyme A KM=508 µM for acetyl coenzyme A

Ontologies

Keywords
Cellular component	Mitochondrion
Coding sequence diversity	Polymorphism
Disease	Disease mutation
Domain	Transit peptide
Ligand	Metal-binding Potassium
Molecular function	Acyltransferase Transferase
PTM	Acetylation
Technical term	3D-structure Complete proteome Direct protein sequencing
Gene Ontology (GO)
Biological process	metabolic process Inferred from electronic annotation. Source: InterPro
Cellular component	mitochondrial matrix Inferred from Experiment. Source: Reactome
Molecular function	acetyl-CoA C-acetyltransferase activity Ref.1 Traceable author statement. Source: ProtInc potassium ion binding Inferred from electronic annotation. Source: UniProtKB-KW protein binding Inferred from physical interaction. Source: IntAct
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
EIF1B	O60739	1	EBI-1051459,EBI-1043343

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Transit peptide

1 – 33

33

Mitochondrion By similarity

Chain

34 – 427

394

Acetyl-CoA acetyltransferase, mitochondrial

PRO_0000034085

Regions

Region

258 – 260

3

Coenzyme A binding

Sites

Active site

126

1

Acyl-thioester intermediate Probable

Active site

385

1

Proton acceptor Probable

Active site

413

1

Proton acceptor Probable

Metal binding

219

1

Potassium

Metal binding

280

1

Potassium; via carbonyl oxygen

Metal binding

281

1

Potassium; via carbonyl oxygen

Metal binding

283

1

Potassium; via carbonyl oxygen

Metal binding

381

1

Potassium; via carbonyl oxygen

Binding site

219

1

Coenzyme A

Binding site

263

1

Coenzyme A

Binding site

284

1

Coenzyme A

Amino acid modifications

Modified residue

174

1

N6-acetyllysine By similarity

Modified residue

190

1

N6-acetyllysine By similarity

Modified residue

230

1

N6-acetyllysine By similarity

Modified residue

338

1

N6-acetyllysine By similarity

Natural variations

Natural variant

5

1

A → P: dbSNP rs3741056.

VAR_007496

Natural variant

85

1

Missing in 3KTD.

VAR_007497

Natural variant

93

1

N → S in 3KTD; 10% activity. Ref.11

VAR_007498

Natural variant

152

1

G → A in 3KTD.

VAR_007499

Natural variant

158

1

N → D in 3KTD; no activity. Ref.10

VAR_007500

Natural variant

183

1

G → R in 3KTD; no activity. Ref.8

VAR_007501

Natural variant

297

1

T → M in 3KTD; 10% normal activity. Ref.10

VAR_007502

Natural variant

301

1

A → P in 3KTD; 5% normal activity. Ref.10

VAR_007503

Natural variant

312

1

I → T in 3KTD; 10% activity. Ref.11

VAR_007504

Natural variant

333

1

A → P in 3KTD; no activity. Ref.11

VAR_007505

Natural variant

379

1

G → V in 3KTD.

VAR_007506

Natural variant

380

1

A → T in 3KTD; 7% normal activity. Ref.9

VAR_007507

Experimental info

Sequence conflict

340

1

V → M in BAA01387. Ref.2

Sequence conflict

346

1

D → N in BAA01387. Ref.2

Sequence conflict

380

1

A → S in BAA01387. Ref.2

Sequence conflict

412

1

I → F in BAA01387. Ref.2

Secondary structure

1

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427

Helix Strand Turn

Details...

Beta strand

43 – 49

7

Turn

58 – 61

4

Helix

64 – 79

16

Helix

83 – 85

3

Beta strand

88 – 92

5

Helix

103 – 110

8

Beta strand

119 – 123

5

Helix

125 – 127

3

Helix

128 – 141

14

Beta strand

146 – 155

10

Helix

156 – 158

3

Beta strand

161 – 163

3

Beta strand

165 – 167

3

Beta strand

173 – 177

5

Helix

178 – 182

5

Turn

187 – 190

4

Helix

193 – 203

11

Helix

208 – 227

20

Turn

228 – 234

7

Helix

255 – 257

3

Turn

261 – 263

3

Helix

264 – 266

3

Beta strand

273 – 275

3

Beta strand

280 – 283

4

Beta strand

287 – 296

10

Helix

298 – 303

6

Beta strand

309 – 319

11

Helix

322 – 324

3

Turn

325 – 327

3

Helix

328 – 338

11

Helix

339 – 341

3

Helix

344 – 346

3

Beta strand

347 – 352

6

Helix

357 – 367

11

Helix

371 – 373

3

Helix

380 – 383

4

Turn

387 – 389

3

Helix

390 – 401

12

Beta strand

407 – 414

8

Turn

415 – 417

3

Beta strand

418 – 426

9

Sequences

	Sequence		Length	Mass (Da)
	P24752-1 [UniParc]. Last modified March 1, 1992. Version 1. Checksum: 2E81168EB39D0142	FASTA	427	45,200
	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

References

	« Hide 'large scale' referencesShow '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: 1979337] [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: 1684944] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]	"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: 15242332] [Abstract] Cited for: PROTEIN SEQUENCE OF 50-78 AND 312-338. Tissue: Adipocyte.
[4]	Lubec G., Chen W.-Q., Sun Y. Submitted (DEC-2008) to UniProtKB Cited for: PROTEIN SEQUENCE OF 50-78 AND 231-243, MASS SPECTROMETRY. Tissue: Fetal brain cortex.
[5]	Colinge J., Superti-Furga G., Bennett K.L. Submitted (OCT-2008) to UniProtKB Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
[6]	"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: 17371050] [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.
[7]	"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: 7749408] [Abstract] Cited for: REVIEW ON 3KTD VARIANTS.
[8]	"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: 1346617] [Abstract] Cited for: VARIANT 3KTD ARG-183.
[9]	"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: 1715688] [Abstract] Cited for: VARIANT 3KTD THR-380.
[10]	"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: 7728148] [Abstract] Cited for: VARIANTS 3KTD ASP-158; MET-297 AND PRO-301.
[11]	"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: 9744475] [Abstract] Cited for: VARIANTS 3KTD SER-93; THR-312 AND PRO-333.
+	Additional computationally mapped references.

Web resources

GeneReviews

Cross-references

Sequence databases

EMBLGenBankDDBJ

D90228 mRNA. Translation: BAA14278.1.
D10511 Genomic DNA. Translation: BAA01387.1.

IPI

IPI00030363.

PIR

JH0255.

RefSeq

NP_000010.1.

UniGene

Hs.232375

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2F2S	X-ray	2.00	A/B/C/D	41-427	[»]
2IB7	X-ray	2.05	A/B/C/D	35-427	[»]
2IB8	X-ray	1.85	A/B/C/D	35-427	[»]
2IB9	X-ray	2.05	A/B/C/D	35-427	[»]
2IBU	X-ray	1.90	A/B/C/D	35-427	[»]
2IBW	X-ray	1.90	A/B/C/D	35-427	[»]
2IBY	X-ray	1.85	A/B/C/D	35-427	[»]

ModBase

Search...

Protein-protein interaction databases

IntAct

P24752. 7 interactions.

PTM databases

PhosphoSite

P24752.

2-D gel databases

REPRODUCTION-2DPAGE

IPI00030363.

Proteomic databases

PeptideAtlas

P24752.

PRIDE

P24752.

Genome annotation databases

Ensembl

ENSG00000075239. Homo sapiens. [Contig view]

GeneID

38.

KEGG

hsa:38.

NMPDR

fig|9606.3.peg.6566.

UCSC

uc001pjy.1. human.

Organism-specific databases

GeneCards

GC11P107499.

H-InvDB

HIX0035960.

HGNC

HGNC:93. ACAT1.

HPA

HPA004428.
HPA007569.

MIM

203750. phenotype.
607809. gene.

Orphanet

134. Ketoacidosis due to betaketothiolase deficiency.

PharmGKB

PA24431.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

P24752.

HOVERGEN

P24752.

OMA

P24752. AYAVPKV.

Enzyme and pathway databases

BioCyc

MetaCyc:MON-11817.

BRENDA

2.3.1.9. 247.

Reactome

REACT_13. Metabolism of amino acids.
REACT_602. Metabolism of lipids and lipoproteins.

Gene expression databases

ArrayExpress

P24752.

Bgee

P24752.

CleanEx

HS_ACAT1.

GermOnline

ENSG00000075239. Homo sapiens.

Family and domain databases

InterPro

IPR002155. Thiolase.
IPR016038. Thiolase-like_subgr.
[Graphical view]

Gene3D

G3DSA:3.40.47.10. Thiolase-like_subgr. 1 hit.

PANTHER

PTHR18919. Thiolase. 1 hit.

Pfam

PF02803. Thiolase_C. 1 hit.
PF00108. Thiolase_N. 1 hit.
[Graphical view]

PIRSF

PIRSF000429. Ac-CoA_Ac_transf. 1 hit.

TIGRFAMs

TIGR01930. AcCoA-C-Actrans. 1 hit.

PROSITE

PS00098. THIOLASE_1. 1 hit.
PS00737. THIOLASE_2. 1 hit.
PS00099. THIOLASE_3. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

DrugBank

DB00795. Sulfasalazine.

NextBio

149.

SOURCE

Search...

Entry information

Entry name

THIL_HUMAN

Accession

Primary (citable) accession number: P24752

Entry history

Integrated into UniProtKB/Swiss-Prot:	March 1, 1992
Last sequence update:	March 1, 1992
Last modified:	July 7, 2009
This is version 103 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)