Structure and function of carnitine acyltransferases

Carnitine acyltransferases catalyze the exchange or acyl groups between carnitine and coenzyme A (CoA). These enzymes include carnitine acetyltransferase (CrAT). carnitine octanoyltransferase (CrOT), and carnitine palmitoyltransferases (CPTs). CPT-I and CPT-II are crucial for the beta-oxidation of long-chain ratty acids in the mitochondria by enabling their transport across the mitochondrial membrane. The activity of CPT-I is inhibited by malonyl-CoA, a crucial regulatory mechanism for ratty acid oxidation. Mutation or dysregulation of the CPT enzymes has been linked to many serious, Eden fatal human diseases, and these enzymes are promising targets for the development of therapeutic agents against type 2 diabetes and obesity. We have determined the crystal structures or murine CrAT. alone and in complex with its substrate carnitine or CoA. The structure contains two domains. Surprisingly, these two domains share the same backbone fold. which is also similar to that or chloramphenicol acetyltransferase and dihydrolipoyl transacetylase. The active site is located at the interface between the two domains, in a tunnel that extends through the center or the enzyme. Carnitine and CoA are bound in this tunnel. on opposite sides or the catalytic His343 residue. The structural information provides a molecular basis for understanding the catalysis by carnitine acyltransferases and for designing their inhibitors. In addition, our structural information suggests that the substrate carnitine may assist the catalysis by stabilizing the oxyanion in the reaction intermediate.