ACOT3 Inhibitors

Chemical inhibitors of acyl-CoA thioesterase 3 utilize a variety of mechanisms to reduce the protein's activity. Triacsin C directly targets the biosynthesis pathway of acyl-CoA by inhibiting long-chain acyl-CoA synthetase, leading to a reduced availability of the acyl-CoA substrate necessary for the enzymatic function of acyl-CoA thioesterase 3. Similarly, AICAR activates AMP-activated protein kinase, which in turn enhances fatty acid oxidation, resulting in the depletion of acyl-CoA substrates and a consequent decrease in acyl-CoA thioesterase 3 activity. Nicotinic Acid acts upstream by inhibiting lipolysis, which is the breakdown of lipids into free fatty acids, subsequently leading to lower production of acyl-CoA molecules. In this way, Nicotinic Acid indirectly limits the substrate availability for acyl-CoA thioesterase 3.

Perhexiline, Etomoxir, Oxfenicine, and Malonyl-CoA share a common mechanism of inhibiting carnitine palmitoyltransferase-1 (CPT-1), an enzyme critical for transporting acyl-CoAs into mitochondria for β-oxidation. This inhibition leads to an accumulation of acyl-CoAs within the cytosol. The resultant high levels of acyl-CoAs can saturate acyl-CoA thioesterase 3 and impede its function due to substrate inhibition. On the other hand, Mildronate inhibits gamma-butyrobetaine hydroxylase, which reduces carnitine synthesis, thereby decreasing the transport of acyl-CoA into the mitochondria and indirectly reducing the activity of acyl-CoA thioesterase 3 by limiting its substrate. Guggulsterone affects lipid metabolism, which can lead to a decrease in acyl-CoA synthesis and a consequent reduction in acyl-CoA thioesterase 3 activity by decreasing substrate availability. Fenofibrate activates peroxisome proliferator-activated receptor alpha, which regulates fatty acid oxidation, thereby potentially leading to a reduction in acyl-CoA levels and an indirect inhibition of acyl-CoA thioesterase 3. Curcumin influences various metabolic pathways that can result in altered acyl-CoA levels, again affecting the activity of acyl-CoA thioesterase 3. These diverse compounds, through their distinct actions, all contribute to the modulation of acyl-CoA thioesterase 3 activity by affecting the levels of its substrates.