ACOT4 explained

Acyl-coenzyme A thioesterase 4 is an enzyme that in humans is encoded by the ACOT4 gene.^{[1] [2] [3]}

Function

The protein encoded by the ACOT4 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.^[4] 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,^[5] hexokinase IV,^[6] 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.^[7] 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.^{[8] [9] [10]} Acyl-CoAs also mediate protein targeting to various membranes and regulation of G Protein α subunits, because they are substrates for protein acylation.^[11] 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.^[12] 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.^[13]

Further reading

• Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H, Lin C, Li G, Holman K, Tsuda T, Mar L, Foncin JF, Bruni AC, Montesi MP, Sorbi S, Rainero I, Pinessi L, Nee L, Chumakov I, Pollen D, Brookes A, Sanseau P, Polinsky RJ, Wasco W, Da Silva HA, Haines JL, Perkicak-Vance MA, Tanzi RE, Roses AD, Fraser PE, Rommens JM, St George-Hyslop PH . Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease . Nature . 375 . 6534 . 754–60 . Jun 1995 . 7596406 . 10.1038/375754a0 . 1995Natur.375..754S . 4308372 .
• Hunt MC, Nousiainen SE, Huttunen MK, Orii KE, Svensson LT, Alexson SE . Peroxisome proliferator-induced long chain acyl-CoA thioesterases comprise a highly conserved novel multi-gene family involved in lipid metabolism . The Journal of Biological Chemistry . 274 . 48 . 34317–26 . Nov 1999 . 10567408 . 10.1074/jbc.274.48.34317 . free .
• Jones JM, Gould SJ . Identification of PTE2, a human peroxisomal long-chain acyl-CoA thioesterase . Biochemical and Biophysical Research Communications . 275 . 1 . 233–40 . Aug 2000 . 10944470 . 10.1006/bbrc.2000.3285 .
• Westin MA, Hunt MC, Alexson SE . The identification of a succinyl-CoA thioesterase suggests a novel pathway for succinate production in peroxisomes . The Journal of Biological Chemistry . 280 . 46 . 38125–32 . Nov 2005 . 16141203 . 10.1074/jbc.M508479200 . free .

Notes and References

1. Hunt MC, Yamada J, Maltais LJ, Wright MW, Podesta EJ, Alexson SE . A revised nomenclature for mammalian acyl-CoA thioesterases/hydrolases . Journal of Lipid Research . 46 . 9 . 2029–32 . Sep 2005 . 16103133 . 10.1194/jlr.E500003-JLR200 . free .
2. Hunt MC, Rautanen A, Westin MA, Svensson LT, Alexson SE . 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 . Sep 2006 . 16940157 . 10.1096/fj.06-6042com . free . 501610 .
3. Web site: Entrez Gene: ACOT4 acyl-CoA thioesterase 4.
4. 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 . Revised nomenclature for the mammalian long-chain acyl-CoA synthetase gene family . Journal of Lipid Research . 45 . 10 . 1958–61 . Oct 2004 . 15292367 . 10.1194/jlr.E400002-JLR200 . free .
5. Ogiwara H, Tanabe T, Nikawa J, Numa S . Inhibition of rat-liver acetyl-coenzyme-A carboxylase by palmitoyl-coenzyme A. Formation of equimolar enzyme-inhibitor complex . European Journal of Biochemistry . 89 . 1 . 33–41 . Aug 1978 . 29756 . 10.1111/j.1432-1033.1978.tb20893.x.
6. Srere PA . Palmityl-coenzyme A inhibition of the citrate-condensing enzyme . Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism . 106 . 3 . 445–55 . Dec 1965 . 5881327 . 10.1016/0005-2760(65)90061-5.
7. Gribble FM, Proks P, Corkey BE, Ashcroft FM . Mechanism of cloned ATP-sensitive potassium channel activation by oleoyl-CoA . The Journal of Biological Chemistry . 273 . 41 . 26383–7 . Oct 1998 . 9756869 . 10.1074/jbc.273.41.26383. free .
8. Nishizuka Y . Protein kinase C and lipid signaling for sustained cellular responses . FASEB Journal . 9 . 7 . 484–96 . Apr 1995 . 7737456 . 10.1096/fasebj.9.7.7737456. free . 31065063 .
9. Glick BS, Rothman JE . Possible role for fatty acyl-coenzyme A in intracellular protein transport . Nature . 326 . 6110 . 309–12 . Mar 1987 . 3821906 . 10.1038/326309a0 . 1987Natur.326..309G . 4306469 .
10. Wan YJ, Cai Y, Cowan C, Magee TR . Fatty acyl-CoAs inhibit retinoic acid-induced apoptosis in Hep3B cells . Cancer Letters . 154 . 1 . 19–27 . Jun 2000 . 10799735 . 10.1016/s0304-3835(00)00341-4.
11. Duncan JA, Gilman AG . 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 . 9624183 . 10.1074/jbc.273.25.15830. free .
12. Berthiaume L, Deichaite I, Peseckis S, Resh MD . 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 . 10.1016/S0021-9258(17)37399-4 . 8120000 . free .
13. Hunt MC, Alexson SE . The role Acyl-CoA thioesterases play in mediating intracellular lipid metabolism . Progress in Lipid Research . 41 . 2 . 99–130 . Mar 2002 . 11755680 . 10.1016/s0163-7827(01)00017-0.