ACOT9 Inhibitors

Chemical inhibitors of ACOT9 can function by impeding the availability of substrates or cofactors necessary for the enzyme's activity. Triacsin C, for example, targets long-chain acyl-CoA synthetases, enzymes that play a pivotal role in providing acyl-CoA substrates for ACOT9. By inhibiting these synthetases, Triacsin C effectively reduces the concentration of acyl-CoA, thereby impeding the activity of ACOT9. Similarly, compounds such as Perhexiline and Etomoxir exert their inhibitory effects by targeting carnitine palmitoyltransferase-1 (CPT1), an enzyme critical in the transport of fatty acids into mitochondria for beta-oxidation. The inhibition of CPT1 results in lowered levels of acyl-carnitine, which in turn restricts the substrate pool available for ACOT9, thereby diminishing its enzymatic activity. Atglistatin, targeting adipose triglyceride lipase, leads to an accumulation of triglycerides that can reduce the levels of free fatty acids, crucial substrates for ACOT9, thus indirectly inhibiting its function.

Further down the metabolic pathway, Oligomycin impacts ACOT9 by inhibiting ATP synthase and thus reducing ATP levels, which are necessary for the formation of CoA esters that ACOT9 acts upon. GSK2194069 and C75, both inhibitors of fatty acid synthase, can decrease the synthesis of fatty acids, leading to a reduced substrate availability for ACOT9's enzymatic action. Cerulenin follows a similar route by also targeting fatty acid synthase, whereas TOFA inhibits acetyl-CoA carboxylase, thereby decreasing malonyl-CoA levels and indirectly affecting ACOT9's substrate pool. Thiazolidinediones, like Pioglitazone, activate PPARγ, which promotes fatty acid storage, thus decreasing the amount of free fatty acids that ACOT9 could potentially utilize. Sulfo-N-succinimidyl oleate irreversibly inhibits fatty acid transport protein, which is responsible for the uptake of fatty acids into cells, consequently decreasing the substrate availability for ACOT9. Lastly, A-769662 activates AMP-activated protein kinase, an enzyme that enhances fatty acid oxidation, which can lead to a decrease in the fatty acid substrates required for ACOT9 activity, functionally inhibiting the enzyme.