AWAT1 Inhibitors

AWAT1 inhibitors encompass a variety of compounds that interfere with the enzyme's ability to synthesize wax esters by targeting different aspects of fatty acid metabolism. One class of inhibitors operates by causing substrate inhibition, where excess amounts of long-chain fatty acyl-CoAs accumulate to levels that impede AWAT1's enzymatic activity. This form of inhibition is characterized by a decrease in enzyme efficiency as substrate concentrations rise beyond optimal levels. Another mechanism involves competitive inhibition, exemplified by compounds that compete with AWAT1 substrates for binding, which can inhibit the enzyme by occupying its active site. Additionally, some inhibitors target upstream processes in fatty acid metabolism: they inhibit fatty acid synthase or acyl-CoA synthetase, leading to reduced availability of fatty acyl-CoA substrates necessary for AWAT1 function. In this way, the inhibitors indirectly reduce AWAT1 activity by limiting the pool of substrates required for wax ester synthesis.

Further diminishing AWAT1's activity, other inhibitors act by disrupting the transport and utilization of fatty acyl-CoAs, which are critical substrates for the enzyme's function. For instance, compounds that inhibit carnitine palmitoyltransferase-1 block the transfer of fatty acyl-CoAs into mitochondria for β-oxidation, resulting in increased cytosolic levels of these molecules. This increase can lead to substrate inhibition of AWAT1, as the enzyme becomes overwhelmed by the excessive substrate presence. Moreover, lipase inhibitors contribute to the indirect inhibition of AWAT1 by preventing the conversion of free fatty acids into triglycerides, leading to an accumulation of free fatty acids. This accumulation can suppress the synthesis of fatty acyl-CoA, indirectly reducing AWAT1 activity. Additionally, inhibitors of acetyl-CoA carboxylase play a role in this intricate network by limiting the production of malonyl-CoA, thereby alleviating the competitive inhibition of AWAT1 and contributing to its overall inhibition.