ACOT6

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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[edit | edit source]

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[edit | edit source]

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[edit | edit source]

  1. 1.0 1.1 "Acyl-CoA thioesterase 6". Retrieved 2011-12-04. 
  2. "Revised nomenclature for the mammalian long-chain acyl-CoA synthetase gene family". Journal of Lipid Research 45 (10): 1958–61. Oct 2004. doi:10.1194/jlr.E400002-JLR200. PMID 15292367. 
  3. "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. Aug 1978. doi:10.1111/j.1432-1033.1978.tb20893.x. PMID 29756. 
  4. "Palmityl-coenzyme A inhibition of the citrate-condensing enzyme". Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism 106 (3): 445–55. Dec 1965. doi:10.1016/0005-2760(65)90061-5. PMID 5881327. 
  5. "Mechanism of cloned ATP-sensitive potassium channel activation by oleoyl-CoA". The Journal of Biological Chemistry 273 (41): 26383–7. Oct 1998. doi:10.1074/jbc.273.41.26383. PMID 9756869. 
  6. "Protein kinase C and lipid signaling for sustained cellular responses". FASEB Journal 9 (7): 484–96. Apr 1995. doi:10.1096/fasebj.9.7.7737456. PMID 7737456. 
  7. "Possible role for fatty acyl-coenzyme A in intracellular protein transport". Nature 326 (6110): 309–12. Mar 1987. Bibcode 1987Natur.326..309G. doi:10.1038/326309a0. PMID 3821906. 
  8. "Fatty acyl-CoAs inhibit retinoic acid-induced apoptosis in Hep3B cells". Cancer Letters 154 (1): 19–27. Jun 2000. doi:10.1016/s0304-3835(00)00341-4. PMID 10799735. 
  9. "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. Jun 1998. doi:10.1074/jbc.273.25.15830. PMID 9624183. 
  10. "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. Mar 1994. PMID 8120000. 
  11. "The role Acyl-CoA thioesterases play in mediating intracellular lipid metabolism". Progress in Lipid Research 41 (2): 99–130. Mar 2002. 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. 14.0 14.1 14.2 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. "A conditional knockout resource for the genome-wide study of mouse gene function". Nature 474 (7351): 337–42. Jun 2011. doi:10.1038/nature10163. PMC 3572410. PMID 21677750. //www.ncbi.nlm.nih.gov/pmc/articles/PMC3572410/. 
  19. "Mouse library set to be knockout". Nature 474 (7351): 262–3. Jun 2011. doi:10.1038/474262a. PMID 21677718. 
  20. "A mouse for all reasons". Cell 128 (1): 9–13. Jan 2007. doi:10.1016/j.cell.2006.12.018. PMID 17218247. 
  21. "The mouse genetics toolkit: revealing function and mechanism". Genome Biology 12 (6): 224. 2011. doi:10.1186/gb-2011-12-6-224. PMC 3218837. PMID 21722353. //www.ncbi.nlm.nih.gov/pmc/articles/PMC3218837/. 

External links[edit | edit source]

Further reading[edit | edit source]