Acyl-CoA thioesterase

S. E. H. Alexson, R. Mentlein, C. Wernstedt, U. Hellmann, Isolation and Characterization of Microsomal Acyl-CoA Thioesterase - A Member of the Liver Microsomal Carboxylesterase Multi-Gene Family , Eur. J. Biochem. 1993, 214, 719-727. 

After comparing the protein profiles of myocardial mitochondria between a chronic restraint stress group and a control group, 11 protein spots were found to change, of which seven were identified. Five of these proteins, carnitine palmitoyltransferase 2, mitochondrial acyl-CoA thioesterase 1, isocitrate dehydrogenase 3 (NAD ) alpha, fumarate hydratase 1, and pyruvate dehydrogenase beta, were foimd to decrease in abimdance following chronic restraint stress with fimctional roles in the Krebs cycle and lipid metabolism in mitochondria. The other two proteins, creatine kinase and prohibitin, increased after chronic restraint stress (liu et ak, 2004). 

Acyl-CoA thioesterase enzymes (EC 3.1.2.-), although their catalytic activity simply entails the hydrolysis of CoA and ACP thioesters to release the fatty acids and other carboxylic acids bound to them (Equation (19)), have wide and varied physiological functions that includes the regulation of fatty acid metabolism and playing a central role in the biosynthesis of polyketide and nonribosomal peptide-based metabolites (especially the macrocyclic versions) and the degradation of aromatic compounds. These enzymes are thoroughly discussed in several recent reviews as well as the relevant chapters of this series that include fatty acids, polyketides, and nonribosomal peptide biosynthesis ° ° (see Chapters 1.05,1.02, and 5.19) therefore, only a brief overview of the structural and mechanistic diversity of acyl-CoA and acyl-ACP thioesterases is provided in this section. 

Recently, the structure of a putative third type of thioesterase from M. tuberculosis was determined.This enzyme, shown to be a long-chain fatty acyl-CoA thioesterase (FcoT), has a hotdog fold similar to type II thioesterases, but does not have a carboxylate in its active site that can act as a nucleophile or general base during catalysis. Instead, it has been suggested that hydroxide ions are formed in the active site which subsequently attack the thioester this mechanism is similar to the one described for the hydrolytic antibody D2.3, which have a similar active site architecture to that of FcoT. This difference in mechanism suggests that FcoT in fact represents a third type of thioesterase. 

Hunt, M.C., and Alexson, SU.H. (2002). The Role Acyl-CoA Thioesterases Play in Mediating Intracellular Lipid Metabolism, Prog. Lipid Res. 47,99-130. 

CLONING AND REGULATION OF PEROXISOME PROLIFERATOR-INDUCED ACYL-CoA THIOESTERASES FROM MOUSE LIVER... 

Cloiiiiig and Regidatkm of Perosisome Proliferator-lnduced Acyl-CoA Thioesterases from Mouse liver 197... 

Regulation of Acyl-CoA Thioesterases by the Peroxisome Proliferator Clofibrate... 

Cloning and Regulation of Peroxisome Proliferator-Induced Acyl-CoA Thioesterases from Mouse Liver 199... 

It is now well established that the acyl-CoA thioesterase activity in rat and mouse liver is strongly induced by peroxisome proliferators. The induced activity is due to induction of several enzymes belonging to two gene families, type I and type II thioesterases, each of which contains several members of structurally related enzymes. The t3q>e I thioesterases are loealized to e5Tosol, mitoehondria and peroxisomes, " whieh... 

Svensson, L.T., Wilcke, M. Alexson, S.E.H. (1995) Eur. J. Biochem. 230, 813-820. Pferoxisome proliferators differentially regulate long-chain acyl-CoA thioesterases in rat hver. 

Lindquist, P.J.G., Svensson, L.T. Alexson, S.E.H. (1998) Enn J. Biochem. 251, 631-640. Molecular cloning of the peroxisome proliferator-induced 46-kDa cytosolic acyl-CoA thioesterase from mouse and rat liver. 

Svensson, L.T., Engberg, S.T., Aoyama, T., Usuda, N., Alexson, SPLL T. H (1998) Biochem. J. 329, 601-608. Molecular cloning and characterization of a mitochondrial peroxisome proliferator-induced acyl-CoA thioesterase from rat liver. 

As can be seen from Table 1, the specific activity of long chain acyl CoA synthetase is significantly depressed in the Novikoff hepatoma and host liver when compared with normal liver. These results agree with those of Weinhouse et al. (1973) that made it clear that the activity of the fatty acid activating enzyme is very low in poorly differentiated hepatomas. There is no doubt that the growing tumor exerts a profound effect on the enzyme system of the host liver. On the other hand, no significant differences were observed in the activity of long chain acyl CoA thioesterase from the tissues under study. 

The specificity of the acyl-ACP thioesterase to acyl-ACP substrates with different acyl chains was evaluated. The purified STE has a high preference for 18 0-ACP (Fig.4). To eliminate the possibility that STE is a acyl-CoA thioesterase, 18 0-CoA was dso tested as substrate, and no reaction was observed. These data confirmed that the highly purified STE prefers 18 0-ACP as its substrate. 

It was also demonstrated that the binding of acyl-CoA to the membrane allowed its metabolism (4) which in turn allowed a further binding. This was established in the case of a mammalian microsomal acyl-CoA thioesterase (ACTE) (4). The free fatty acids (FFA) formed in the membrane upon acyl-CoA hydrolysis were partly released from the membrane, and the FFA partition coefficient (from membrane to water) increased as a function of time, on the other hand, the partition of the total aliphatic chains remained constant irrespective of their form (acyl-CoAs or FFA), explaining an increased binding of acyl-CoAs to the membranes (4). 

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