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Crystal Structure of Carnitine Acetyltransferase and Implications for Fatty Acid Transport¹. Gerwald Jogl and Liang Tong, Dept. of Biological Sciences, Columbia Univ., New York, NY.

Carnitine acyltransferases have crucial roles in the transport of fatty acids for ß-oxidation and they are targets for therapeutic development against diabetes and other human diseases.

Carnitine acyltransferases catalyze the exchange of acyl groups between carnitine and coenzyme A (for review see 2). These enzymes include carnitine acetyltransferase (CRAT), carnitine octanoyltransferase (COT), and carnitine palmitoyltransferase (CPT). CPT-I and CPT-II have central roles for the ß-oxidation of fatty acids in the mitochondria by facilitating their transport across the mitochondrial membrane. Inhibition of CPT-I by malonyl-CoA is a key regulatory mechanism for fatty acid oxidation.

The structure contains two domains. Surprisingly, these two domains share the same backbone fold, which is also similar to that of chlor- amphenicol acetyltransferase (CAT) and dihydrolipoyl transacetylase (E2pCD). The active site is located at the interface between the two domains. Carnitine and CoA are bound in deep channels in the enzyme, on opposite sides of the catalytic His343 residue. Carnitine is bound in a partially folded conformation. There are no negatively charged residues in the immediate vicinity of its trimethylammonium group, and our structural analysis suggests that this positive charge may be important for the catalytic activity of the enzyme. In contrast to CAT and E2pCD, the CoA molecule is bound in a fully extended conformation.

The amino acid sequences of the various carnitine acyltransferases are significantly conserved and our structural observations on CRAT should therefore be applicable to the entire family of enzymes.