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J Biol Chem, Vol. 274, Issue 35, 24461-24468, August 27, 1999

MCD Encodes Peroxisomal and Cytoplasmic Forms of Malonyl-CoA Decarboxylase and Is Mutated in Malonyl-CoA Decarboxylase Deficiency

Katherine A. Sacksteder, James C. Morrell, Ronald J. A. Wanders, Reuben Matalon^§, and Stephen J. Gould

From the  Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, ^§ Children's Hospital, University of Texas Medical Branch, Galveston, Texas 77555, and Department of Clinical Biochemistry and Pediatrics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

Malonyl-CoA decarboxylase (MCD) catalyzes the proton-consuming conversion of malonyl-CoA to acetyl-CoA and CO₂. Although defects in MCD activity are associated with malonyl-CoA decarboxylase deficiency, a lethal disorder characterized by cardiomyopathy and developmental delay, the metabolic role of this enzyme in mammals is unknown. A computer-based search for novel peroxisomal proteins led to the identification of a candidate gene for human MCD, which encodes a protein with a canonical type-1 peroxisomal targeting signal of serine-lysine-leucine_COOH. We observed that recombinant MCD protein has high intrinsic malonyl-CoA decarboxylase activity and that a malonyl-CoA decarboxylase-deficient patient has a severe mutation in the MCD gene (c.947-948delTT), confirming that this gene encodes human MCD. Subcellular fractionation experiments revealed that MCD resides in both the cytoplasm and peroxisomes. Cytoplasmic MCD is positioned to play a role in the regulation of cytoplasmic malonyl-CoA abundance and, thus, of mitochondrial fatty acid uptake and oxidation. This hypothesis is supported by the fact that malonyl-CoA decarboxylase-deficient patients display a number of phenotypes that are reminiscent of mitochondrial fatty acid oxidation disorders. Additional support for this hypothesis comes from our observation that MCD mRNA is most abundant in cardiac and skeletal muscles, tissues in which cytoplasmic malonyl-CoA is a potent inhibitor of mitochondrial fatty acid oxidation and which derive significant amounts of energy from fatty acid oxidation. As for the role of peroxisomal MCD, we propose that this enzyme may be involved in degrading intraperoxisomal malonyl-CoA, which is generated by the peroxisomal -oxidation of odd chain-length dicarboxylic fatty acids.

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Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.

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