CPT1 (Carnitine palmitoyltransferase I) is a mitochondrial enzyme. Specifically, CPT1 responsible for the formation of acyl carnitines by catalyzing the transfer of the acyl group of a long-chain fatty acyl-CoA from coenzyme A to l-carnitine. Furthermore, CPT1 is associated with the outer mitochondrial membrane. In short, its role in fatty acid metabolism makes CPT1 important in many metabolic disorders.
Interestingly, CPT-1 has three isoforms, there are CPT-1a, CPT-1b and CPT-1c. Thereinto, CPT-1a predominates in lipogenic tissues like liver. Moreover, The membrane topology of CPT-1a is polyhedral, with N and C ends exposed on the cytoplasmic surface. Not only that, CPT-1a has a short ring connecting the two transmembrane domains that protrudes into the mitochondrial intermembrane space.
Here, we focus on the CPT-1a inhibitor, Etomoxir.
Etomoxir is an irreversible inhibitor of CPT-1a. Notably, Etomoxir ((R)-(+)-Etomoxir) inhibits fatty acid oxidation (FAO) through CPT-1a and inhibits palmitate β-oxidation in human, rat and guinea pig. Moreover, Etomoxir binds irreversibly to the catalytic site of CPT-1 inhibiting its activity, but also upregulates fatty acid oxidation enzymes. Alternatively, Etomoxir is a PPARalpha agonist.
In vitro, Etomoxir has a moderate effect on T cell proliferation with no observable effect on memory differentiation, but a marked effect on oxidative metabolism. Nevertheless, the inhibition of oxidative metabolism in T cells is independent of its effects on fatty acid oxidation (FAO) at concentrations exceeding 5 μM. Concentrations of Etomoxir above 5 μM induce acute production of ROS with associated evidence of severe oxidative stress in proliferating T cells. In aggregate, these data indicate that Etomoxir lacks specificity for CTP-1a above 5 μM.
Taken together, Etomoxir is an irreversible inhibitor of CPT-1a. To sum up, Etomoxir is a potent compound of metabolic disease.
. O’Connor RS, et al. Sci Rep. 2018 Apr;8(1):6289. Published 2018 Apr 19.