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J. Biol. Chem., Vol. 277, Issue 13, 11473-11480, March 29, 2002

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Structural Model of a Malonyl-CoA-binding Site of Carnitine Octanoyltransferase and Carnitine Palmitoyltransferase I
MUTATIONAL ANALYSIS OF A MALONYL-CoA AFFINITY DOMAIN^*

Montserrat Morillas^§, Paulino Gómez-Puertas^¶, Blanca Rubí, Josep Clotet^**, Joaquín Ariño, Alfonso Valencia^¶, Fausto G. Hegardt^§§, Dolors Serra, and Guillermina Asins

From the  Department of Biochemistry and Molecular Biology, School of Pharmacy, University of Barcelona, E-08028 Barcelona, Spain, the ^¶ Protein Design Group, National Center for Biotechnology, Consejo Superior de Investigaciones Científicas, Cantoblanco, E-28049 Madrid, Spain, the ^** Department of Biochemistry and Molecular Biology, International University of Catalonia, 08190 Sant Cugat, Spain, and the  Department of Biochemistry and Molecular Biology, School of Veterinary Medicine, Autonomous University of Barcelona, Bellaterra, E-08193 Barcelona, Spain

Carnitine octanoyltransferase (COT) and carnitine palmitoyltransferase (CPT) I, which facilitate the transport of medium- and long-chain fatty acids through the peroxisomal and mitochondrial membranes, are physiologically inhibited by malonyl-CoA. Using an "in silico" macromolecular docking approach, we built a model in which malonyl-CoA could be attached near the catalytic core. This disrupts the positioning of the acyl-CoA substrate in the channel in the model reported for both proteins (Morillas, M., Gómez-Puertas, P., Roca, R., Serra, D., Asins, G., Valencia, A., and Hegardt, F. G. (2001) J. Biol. Chem. 276, 45001-45008). The putative malonyl-CoA domain contained His³⁴⁰, implicated together with His¹³¹ in COT malonyl-CoA sensitivity (Morillas, M., Clotet, J., Rubí, B., Serra, D., Asins, G., Ariño, J., and Hegardt F. G. (2000) FEBS Lett. 466, 183-186). When we mutated COT His¹³¹ the IC₅₀ increased, and malonyl-CoA competed with the substrate decanoyl-CoA. Mutation of COT Ala³³², present in the domain 8 amino acids away from His³⁴⁰, decreased the malonyl-CoA sensitivity of COT. The homologous histidine and alanine residues of L-CPT I, His²⁷⁷, His⁴⁸³, and Ala⁴⁷⁸ were also mutated, which decreased malonyl-CoA sensitivity. Natural mutation of Pro⁴⁷⁹, which is also located in the malonyl-CoA predicted site, to Leu in a patient with human L-CPT I hereditary deficiency, modified malonyl-CoA sensitivity. We conclude that this malonyl-CoA domain is present in both COT and L-CPT I proteins and might be the site at which malonyl-CoA interacts with the substrate acyl-CoA. Other malonyl-CoA non-inhibitable members of the family, CPT II and carnitine acetyltransferase, do not contain this domain.

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