ACOT6

Acyl-CoA thioesterase 6
Identifiers
Symbols ACOT6 ; C14orf42; c14_5530
External IDs OMIM: 614267 HomoloGene: 128697 GeneCards: ACOT6 Gene
EC number 3.1.2.2
Orthologs
Species Human Mouse
Entrez 641372 n/a
Ensembl ENSG00000205669 n/a
UniProt Q3I5F7 n/a
RefSeq (mRNA) NM_001037162 n/a
RefSeq (protein) NP_001032239 n/a
Location (UCSC) Chr 14:
73.61 – 73.62 Mb		 n/a
PubMed search n/a

Acyl-CoA thioesterase 6 is a protein that in humans is encoded by the ACOT6 gene.[1] The protein, also known as C14orf42, is an enzyme with thioesterase activity.[1]

Function

The protein encoded by the ACOT1 gene is part of a family of Acyl-CoA thioesterases, which catalyze the hydrolysis of various Coenzyme A esters of various molecules to the free acid plus CoA. These enzymes have also been referred to in the literature as acyl-CoA hydrolases, acyl-CoA thioester hydrolases, and palmitoyl-CoA hydrolases. The reaction carried out by these enzymes is as follows:

CoA ester + H2O → free acid + coenzyme A

These enzymes use the same substrates as long-chain acyl-CoA synthetases, but have a unique purpose in that they generate the free acid and CoA, as opposed to long-chain acyl-CoA synthetases, which ligate fatty acids to CoA, to produce the CoA ester.[2] The role of the ACOT- family of enzymes is not well understood; however, it has been suggested that they play a crucial role in regulating the intracellular levels of CoA esters, Coenzyme A, and free fatty acids. Recent studies have shown that Acyl-CoA esters have many more functions than simply an energy source. These functions include allosteric regulation of enzymes such as acetyl-CoA carboxylase,[3] hexokinase IV,[4] and the citrate condensing enzyme. Long-chain acyl-CoAs also regulate opening of ATP-sensitive potassium channels and activation of Calcium ATPases, thereby regulating insulin secretion.[5] A number of other cellular events are also mediated via acyl-CoAs, for example signal transduction through protein kinase C, inhibition of retinoic acid-induced apoptosis, and involvement in budding and fusion of the endomembrane system.[6][7][8] Acyl-CoAs also mediate protein targeting to various membranes and regulation of G Protein α subunits, because they are substrates for protein acylation.[9] In the mitochondria, acyl-CoA esters are involved in the acylation of mitochondrial NAD+ dependent dehydrogenases; because these enzymes are responsible for amino acid catabolism, this acylation renders the whole process inactive. This mechanism may provide metabolic crosstalk and act to regulate the NADH/NAD+ ratio in order to maintain optimal mitochondrial beta oxidation of fatty acids.[10] The role of CoA esters in lipid metabolism and numerous other intracellular processes are well defined, and thus it is hypothesized that ACOT- enzymes play a role in modulating the processes these metabolites are involved in.[11]

Model organisms

Model organisms have been used in the study of ACOT6 function. A conditional knockout mouse line, called Acot6tm1a(KOMP)Wtsi[16][17] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.[18][19][20]

Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[14][21] Twenty four tests were carried out on mutant mice but no significant abnormalities were observed.[14]

References

  1. 1 2 "Acyl-CoA thioesterase 6". Retrieved 2011-12-04.
  2. ↑ Mashek DG, Bornfeldt KE, Coleman RA, Berger J, Bernlohr DA, Black P, DiRusso CC, Farber SA, Guo W, Hashimoto N, Khodiyar V, Kuypers FA, Maltais LJ, Nebert DW, Renieri A, Schaffer JE, Stahl A, Watkins PA, Vasiliou V, Yamamoto TT (Oct 2004). "Revised nomenclature for the mammalian long-chain acyl-CoA synthetase gene family". Journal of Lipid Research 45 (10): 1958–61. doi:10.1194/jlr.E400002-JLR200. PMID 15292367.
  3. ↑ Ogiwara H, Tanabe T, Nikawa J, Numa S (Aug 1978). "Inhibition of rat-liver acetyl-coenzyme-A carboxylase by palmitoyl-coenzyme A. Formation of equimolar enzyme-inhibitor complex". European Journal of Biochemistry / FEBS 89 (1): 33–41. doi:10.1111/j.1432-1033.1978.tb20893.x. PMID 29756.
  4. ↑ Srere PA (Dec 1965). "Palmityl-coenzyme A inhibition of the citrate-condensing enzyme". Biochimica et Biophysica Acta 106 (3): 445–55. doi:10.1016/0005-2760(65)90061-5. PMID 5881327.
  5. ↑ Gribble FM, Proks P, Corkey BE, Ashcroft FM (Oct 1998). "Mechanism of cloned ATP-sensitive potassium channel activation by oleoyl-CoA". The Journal of Biological Chemistry 273 (41): 26383–7. doi:10.1074/jbc.273.41.26383. PMID 9756869.
  6. ↑ Nishizuka Y (Apr 1995). "Protein kinase C and lipid signaling for sustained cellular responses". FASEB Journal 9 (7): 484–96. PMID 7737456.
  7. ↑ Glick BS, Rothman JE (Mar 1987). "Possible role for fatty acyl-coenzyme A in intracellular protein transport". Nature 326 (6110): 309–12. doi:10.1038/326309a0. PMID 3821906.
  8. ↑ Wan YJ, Cai Y, Cowan C, Magee TR (Jun 2000). "Fatty acyl-CoAs inhibit retinoic acid-induced apoptosis in Hep3B cells". Cancer Letters 154 (1): 19–27. doi:10.1016/s0304-3835(00)00341-4. PMID 10799735.
  9. ↑ Duncan JA, Gilman AG (Jun 1998). "A cytoplasmic acyl-protein thioesterase that removes palmitate from G protein alpha subunits and p21(RAS)". The Journal of Biological Chemistry 273 (25): 15830–7. doi:10.1074/jbc.273.25.15830. PMID 9624183.
  10. ↑ Berthiaume L, Deichaite I, Peseckis S, Resh MD (Mar 1994). "Regulation of enzymatic activity by active site fatty acylation. A new role for long chain fatty acid acylation of proteins". The Journal of Biological Chemistry 269 (9): 6498–505. PMID 8120000.
  11. ↑ Hunt MC, Alexson SE (Mar 2002). "The role Acyl-CoA thioesterases play in mediating intracellular lipid metabolism". Progress in Lipid Research 41 (2): 99–130. doi:10.1016/s0163-7827(01)00017-0. PMID 11755680.
  12. ↑ "Salmonella infection data for Acot6". Wellcome Trust Sanger Institute.
  13. ↑ "Citrobacter infection data for Acot6". Wellcome Trust Sanger Institute.
  14. 1 2 3 Gerdin AK (2010). "The Sanger Mouse Genetics Programme: High throughput characterisation of knockout mice". Acta Ophthalmologica 88 (S248). doi:10.1111/j.1755-3768.2010.4142.x.
  15. ↑ Mouse Resources Portal, Wellcome Trust Sanger Institute.
  16. ↑ "International Knockout Mouse Consortium".
  17. ↑ "Mouse Genome Informatics".
  18. ↑ Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A (Jun 2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature 474 (7351): 337–42. doi:10.1038/nature10163. PMC 3572410. PMID 21677750.
  19. ↑ Dolgin E (Jun 2011). "Mouse library set to be knockout". Nature 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
  20. ↑ Collins FS, Rossant J, Wurst W (Jan 2007). "A mouse for all reasons". Cell 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247.
  21. ↑ van der Weyden L, White JK, Adams DJ, Logan DW (2011). "The mouse genetics toolkit: revealing function and mechanism". Genome Biology 12 (6): 224. doi:10.1186/gb-2011-12-6-224. PMC 3218837. PMID 21722353.

Further reading

  • Hunt MC, Rautanen A, Westin MA, Svensson LT, Alexson SE (Sep 2006). "Analysis of the mouse and human acyl-CoA thioesterase (ACOT) gene clusters shows that convergent, functional evolution results in a reduced number of human peroxisomal ACOTs". FASEB Journal 20 (11): 1855–64. doi:10.1096/fj.06-6042com. PMID 16940157. 
  • Hunt MC, Yamada J, Maltais LJ, Wright MW, Podesta EJ, Alexson SE (Sep 2005). "A revised nomenclature for mammalian acyl-CoA thioesterases/hydrolases". Journal of Lipid Research 46 (9): 2029–32. doi:10.1194/jlr.E500003-JLR200. PMID 16103133. 
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