ACOT10 Inhibitors

Chemical inhibitors of acyl-CoA thioesterase 10 can modulate the enzyme's activity by affecting the availability of its substrates or by altering the enzyme's environment in a manner that impacts its function. Triacsin C, for instance, targets the biosynthesis pathway of acyl-CoA by inhibiting long-chain acyl-CoA synthetase. This action diminishes the pool of acyl-CoA molecules, thereby reducing the availability of substrates necessary for acyl-CoA thioesterase 10 to function effectively. Similarly, Perhexiline, Etomoxir, and Oxfenicine obstruct the carnitine palmitoyltransferase-1 (CPT-1), a key transporter of long-chain fatty acids into mitochondria for β-oxidation. These inhibitors lead to an accumulation of long-chain acyl-CoAs, which can saturate acyl-CoA thioesterase 10 to the point of substrate inhibition, impeding its catalytic activity.

Other compounds, such as Malonyl-CoA, interfere with CPT-1 and result in a disruption of the normal acyl-CoA to CoA ratio, which can inhibit acyl-CoA thioesterase 10 activity due to an imbalance in substrate concentration. Mildronate reduces the synthesis of carnitine, thus affecting the transport of fatty acids into the mitochondria and limiting the substrates available for acyl-CoA thioesterase 10, leading to an indirect inhibition of the enzyme. AICAR, by activating AMP-activated protein kinase, can increase fatty acid oxidation, depleting the substrates for acyl-CoA thioesterase 10 and hindering its function. Rimonabant and Nicotinic Acid influence metabolic pathways that lead to reduced synthesis or availability of free fatty acids and their corresponding acyl-CoA derivatives, thereby limiting the substrate for the enzyme. Guggulsterone regulates lipid metabolism, potentially decreasing the synthesis of acyl-CoA molecules and consequently inhibiting acyl-CoA thioesterase 10. Lastly, Fenofibrate and Curcumin can also modulate the activity of acyl-CoA thioesterase 10 by affecting fatty acid β-oxidation and altering lipid metabolism, respectively, which can lead to a reduced pool of acyl-CoA molecules for the enzyme to act upon.