Acetyl-CoA Synthetase Inhibitors

Chemical inhibitors of Acetyl-CoA Synthetase can target the enzyme through various inhibitory mechanisms, all of which interfere with its ability to catalyze the conversion of acetate into acetyl-CoA. Triacsin C binds directly to long-chain acyl-CoA, the substrate of Acetyl-CoA Synthetase, thereby obstructing the enzyme's activity. Similarly, N-Ethylmaleimide disrupts the enzyme's function by irreversibly modifying its cysteine residues, which are essential for catalysis. Coenzyme A, a molecule intrinsically involved in the enzymatic reaction, can also inhibit Acetyl-CoA Synthetase through a feedback inhibition mechanism wherein high levels of Coenzyme A compete with acetate for the active site. Cerulenin, though primarily known for targeting fatty acid synthase, can also bind irreversibly to the active site of Acetyl-CoA Synthetase, preventing its normal function.

The inhibitory effects extend beyond direct binding to Acetyl-CoA Synthetase. Soraphen A inhibits Acetyl-CoA carboxylase, an enzyme that acts upstream in the fatty acid biosynthesis pathway, which reduces malonyl-CoA levels and thus indirectly limits the Acetyl-CoA Synthetase substrate availability. Perhexiline reduces the mitochondrial uptake of long-chain acyl-CoA esters by inhibiting carnitine palmitoyltransferase-1, which can lead to a decrease in Acetyl-CoA Synthetase activity due to reduced substrate availability. Thiolactomycin interferes with the formation of the acyl-adenylate intermediate in Acetyl-CoA Synthetase's active site, inhibiting the enzyme's action. Malonyl-CoA, a competitive inhibitor, vies for the active site with the natural substrate, acetate. Additionally, Sodium Fluoroacetate's metabolite, fluorocitrate, can cause an accumulation of citrate through aconitase inhibition, leading to product inhibition of Acetyl-CoA Synthetase. Indirect inhibitors such as Atractyloside and Monoiodoacetate impact the enzyme's activity by decreasing the availability of ATP and by irreversibly inactivating essential thiol groups, respectively. Lastly, Hydroxycitrate hinders ATP-citrate lyase, which consequently diminishes the cytosolic acetyl-CoA concentration, indirectly affecting Acetyl-CoA Synthetase availability for catalysis.