ACAT1

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For the human acetyl-coA cholesterol acyltransferase messenger RNA, see ACAT1 mRNA.
Acetyl-CoA acetyltransferase 1
PDB 2ib8 EBI.png
PDB rendering based on 2ib8.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols ACAT1 ; ACAT; MAT; T2; THIL
External IDs OMIM607809 MGI87870 HomoloGene6 IUPHAR: 2435 ChEMBL: 2616 GeneCards: ACAT1 Gene
EC number 2.3.1.9
Orthologs
Species Human Mouse
Entrez 38 110446
Ensembl ENSG00000075239 ENSMUSG00000032047
UniProt P24752 Q8QZT1
RefSeq (mRNA) NM_000019 NM_144784
RefSeq (protein) NP_000010 NP_659033
Location (UCSC) Chr 11:
107.99 – 108.02 Mb
Chr 9:
53.58 – 53.61 Mb
PubMed search [1] [2]

Acetyl-CoA acetyltransferase, mitochondrial also known as acetoacetyl-CoA thiolase, is an enzyme that in humans is encoded by the ACAT1 (Acetyl-Coenzyme A acetyltransferase 1) gene.[1]

Acetyl-Coenzyme A acetyltransferase 1 is an acetyl-CoA C-acetyltransferase enzyme.

Structure[edit]

The gene spans approx. 27 kb and contains twelve exons interrupted by eleven introns. The region flanking the 5’ end of the gene lacks a TATA box, but contains many GC’s and also has two CAAT boxes. The gene also may have a binding site for the transcription factor, Sp1, and sequences resembling the binding sites of several other transcription factors. Additionally, there is a 101-bp DNA fragment immediately upstream from the cap site that has promoter activity.[2]

The human ACAT1 gene produces a chimeric mRNA through trans-splicing, a process in which separate transcripts from chromosomes 1 and 7 are spliced together. The chimeric mRNA transcript uses two sections to initiate translation: AUG(1397-1399) and GGC(1274-1276). Initiation of the first codon (AUG) results in the translation of a 50-kDa ACAT1, and initiation of the other (GGC) produces another enzymatically active 56-kDa isoform respectively; the 56kDa isoform is naturally present in human cells, including human monocyte-derived macrophages.[3]

The resulting transcript encodes ACAT1, which is a 45.1 kDa protein composed of 427 amino acids.[4][5] It is also is a homotetrameric protein that has nine transmembrane domains (TMDs). One active residue is a Histidine at the 460th position, which is in the 7th TMD. ACAT1 has seven free Cysteine residues, but they do not affect catalytic activity. There are two functional sections of this protein, TMD7 and TMD8; one side is involved in substrate binding and catalysis, while the other is involved in subunit interactions and binding. [6]

Function[edit]

This gene encodes a mitochondrially localized enzyme that catalyzes the reversible formation of acetoacetyl-CoA from two molecules of acetyl-CoA.[1] The ACAT1 enzyme has a few unique properties. First, it is activated by potassium ions binding near the CoA binding site and the catalytic site. This binding causes a structural change in the active site loop. Additionally, this enzyme is able to use 2-methyl-branched acetoacetyl-CoA as a substrate, making it a unique thiolase.[7] ACAT1 is regulated at both transcriptional and translational levels. ACAT1 enzyme activity is enhanced ACAT1’s expression is promoted transcriptionally by leptin,[8] angiotensin II,[9] and insulin in human monocytes/macrophages.[10] Insulin-mediated regulation also involves ERK, p38MAPK, and JNK signaling pathways.[11]

Clinical significance[edit]

Mutations of the ACAT1 gene are associated with a deficiency in the encoded protein mitochondrial acetoacetyl-CoA thiolase; this is also known as ketothiolase deficiency. Many mutations have been identified in specific populations, and large scale studies have been performed to determine the allelic and genotypic frequency for the defective gene.[12] As mitochondrial acetoacetyl-CoA thiolase is involved in beta-oxidation, a deficiency in this enzyme is marked by an increased amount of cholesterol compounds. Additionally, the isoleucine amino acid pathway is affected, such that proper metabolism of it is halted. This deficiency belongs to a more general class of disorders known as organic acidemias, in which the dysfunction of a specific step of amino acid catabolism results in the excretion of non-amino acids in the urine. This deficiency specifically presents as ketosis, acidosis, as well as hypoglycemia, but there are other clinical manifestations as well. The characteristics of organic academia disorders are vomiting, poor feeding, neurologic symptoms such as seizures and abnormal tone, and lethargy progressing to coma, which are all manifestations of toxic encephalopathy. The clinical outcome of infants with these disorders is largely determined by the time of diagnosis, with the potential outcome greatly improving if the disease is diagnosed in the first ten days of life. Ketothiolase deficiency is diagnosed by performing GC-MS and quantitative amino acid analysis in the urine; the diagnostic markers are 2-methyl-3-hydroxybutyric acid, 2-methylacetoacetic acid, and tiglylglycine. The disease is managed by trying to restore biochemical and physiologic homeostasis; common therapies include restricting diet to avoid the precursor amino acids and use of compounds to either dispose of toxic metabolites or increase enzyme activity. This disease is inherited in an autosomal recessive manner, meaning that carriers of the gene do not show symptoms of the disease. [13]

Additionally, expression of ACAT1 has been associated with manifestations of prostate cancer, in that ACAT1 is more significantly expressed in aggressive prostate cancer tissue samples when compared to its expression in benign cells.[14][15]

References[edit]

  1. ^ a b "Entrez Gene: acetyl-Coenzyme A acetyltransferase 1". 
  2. ^ Kano, M; Fukao, T; Yamaguchi, S; Orii, T; Osumi, T; Hashimoto, T (30 December 1991). "Structure and expression of the human mitochondrial acetoacetyl-CoA thiolase-encoding gene.". Gene 109 (2): 285–90. doi:10.1016/0378-1119(91)90623-j. PMID 1684944. 
  3. ^ Chen, J; Zhao, XN; Yang, L; Hu, GJ; Lu, M; Xiong, Y; Yang, XY; Chang, CC; Song, BL; Chang, TY; Li, BL (September 2008). "RNA secondary structures located in the interchromosomal region of human ACAT1 chimeric mRNA are required to produce the 56-kDa isoform.". Cell research 18 (9): 921–36. doi:10.1038/cr.2008.66. PMID 18542101. 
  4. ^ ]Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS et al. (Oct 2013). "Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research 113 (9): 1043–53. doi:10.1161/CIRCRESAHA.113.301151. PMC 4076475. PMID 23965338. 
  5. ^ P24752 "Acetyl-CoA acetyltransferase, mitochondrial". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). 
  6. ^ Guo, ZY; Chang, CC; Chang, TY (4 September 2007). "Functionality of the seventh and eighth transmembrane domains of acyl-coenzyme A:cholesterol acyltransferase 1.". Biochemistry 46 (35): 10063–71. doi:10.1021/bi7011367. PMID 17691824. 
  7. ^ Haapalainen, AM; Meriläinen, G; Pirilä, PL; Kondo, N; Fukao, T; Wierenga, RK (10 April 2007). "Crystallographic and kinetic studies of human mitochondrial acetoacetyl-CoA thiolase: the importance of potassium and chloride ions for its structure and function.". Biochemistry 46 (14): 4305–21. doi:10.1021/bi6026192. PMID 17371050. 
  8. ^ Hongo, S; Watanabe, T; Arita, S; Kanome, T; Kageyama, H; Shioda, S; Miyazaki, A (August 2009). "Leptin modulates ACAT1 expression and cholesterol efflux from human macrophages.". American journal of physiology. Endocrinology and metabolism 297 (2): E474–82. doi:10.1152/ajpendo.90369.2008. PMID 19625677. 
  9. ^ Kanome, T; Watanabe, T; Nishio, K; Takahashi, K; Hongo, S; Miyazaki, A (September 2008). "Angiotensin II upregulates acyl-CoA:cholesterol acyltransferase-1 via the angiotensin II Type 1 receptor in human monocyte-macrophages.". Hypertension research : official journal of the Japanese Society of Hypertension 31 (9): 1801–10. doi:10.1291/hypres.31.1801. PMID 18971559. 
  10. ^ Ge, J; Zhai, W; Cheng, B; He, P; Qi, B; Lu, H; Zeng, Y; Chen, X (September 2013). "Insulin induces human acyl-coenzyme A: cholesterol acyltransferase1 gene expression via MAP kinases and CCAAT/enhancer-binding protein α.". Journal of cellular biochemistry 114 (9): 2188–98. doi:10.1002/jcb.24568. PMID 23564383. 
  11. ^ Xin, C; Yan-Fu, W; Ping, H; Jing, G; Jing-Jing, W; Chun-Li, M; Wei, L; Bei, C (May 2009). "Study of the insulin signaling pathways in the regulation of ACAT1 expression in cultured macrophages.". Cell biology international 33 (5): 602–6. doi:10.1016/j.cellbi.2009.02.011. PMID 19269342. 
  12. ^ Francis, T; Wartofsky, L (1 September 1992). "Common thyroid disorders in the elderly.". Postgraduate medicine 92 (3): 225–30, 233–6. PMID 1518756. 
  13. ^ Seashore, MR; Pagon, RA; Adam, MP; Ardinger, HH; Bird, TD; Dolan, CR; Fong, CT; Smith, RJH; Stephens, K (1993). "The Organic Acidemias: An Overview". PMID 20301313. 
  14. ^ Saraon, P; Trudel, D; Kron, K; Dmitromanolakis, A; Trachtenberg, J; Bapat, B; van der Kwast, T; Jarvi, KA; Diamandis, EP (April 2014). "Evaluation and prognostic significance of ACAT1 as a marker of prostate cancer progression.". The Prostate 74 (4): 372–80. doi:10.1002/pros.22758. PMID 24311408. 
  15. ^ Saraon, P; Cretu, D; Musrap, N; Karagiannis, GS; Batruch, I; Drabovich, AP; van der Kwast, T; Mizokami, A; Morrissey, C; Jarvi, K; Diamandis, EP (June 2013). "Quantitative proteomics reveals that enzymes of the ketogenic pathway are associated with prostate cancer progression.". Molecular & cellular proteomics : MCP 12 (6): 1589–601. doi:10.1074/mcp.m112.023887. PMID 23443136. 


Further reading[edit]

This article incorporates text from the United States National Library of Medicine, which is in the public domain.