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PMID:10455107

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Citation

Sacksteder, KA, Morrell, JC, Wanders, RJ, Matalon, R and Gould, SJ (1999) MCD encodes peroxisomal and cytoplasmic forms of malonyl-CoA decarboxylase and is mutated in malonyl-CoA decarboxylase deficiency. J. Biol. Chem. 274:24461-8

Abstract

Malonyl-CoA decarboxylase (MCD) catalyzes the proton-consuming conversion of malonyl-CoA to acetyl-CoA and CO(2). 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 beta-oxidation of odd chain-length dicarboxylic fatty acids.

Links

PubMed

Keywords

Amino Acid Sequence; Animals; Base Sequence; Carboxy-Lyases/chemistry; Carboxy-Lyases/deficiency; Carboxy-Lyases/genetics; Cloning, Molecular; Cytoplasm/enzymology; Humans; Liver/enzymology; Microbodies/enzymology; Molecular Sequence Data; Muscle, Skeletal/enzymology; Muscle, Skeletal/metabolism; Myocardium/enzymology; Myocardium/metabolism; Phenotype; RNA, Messenger/metabolism; Rats; Recombinant Proteins/chemistry; Recombinant Proteins/genetics; Sequence Alignment

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:DCMC

located_in

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:DCMC

located_in

GO:0005777: peroxisome

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

ANSAN:DCMC

enables

GO:0050080: malonyl-CoA decarboxylase activity

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:O95822

F

Seeded From UniProt

complete

RAT:DCMC

located_in

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

RAT:DCMC

located_in

GO:0005777: peroxisome

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:DCMC

part_of

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:DCMC

part_of

GO:0005777: peroxisome

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:DCMC

involved_in

GO:0006085: acetyl-CoA biosynthetic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:DCMC

enables

GO:0050080: malonyl-CoA decarboxylase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:DCMC

involved_in

GO:2001294: malonyl-CoA catabolic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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