PMID- 10455107
OWN - NLM
STAT- MEDLINE
DCOM- 19990930
LR  - 20190508
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 274
IP  - 35
DP  - 1999 Aug 27
TI  - MCD encodes peroxisomal and cytoplasmic forms of malonyl-CoA decarboxylase and is
      mutated in malonyl-CoA decarboxylase deficiency.
PG  - 24461-8
AB  - 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.
FAU - Sacksteder, K A
AU  - Sacksteder KA
AD  - Department of Biological Chemistry, The Johns Hopkins University School of
      Medicine, Baltimore, Maryland 21205, USA.
FAU - Morrell, J C
AU  - Morrell JC
FAU - Wanders, R J
AU  - Wanders RJ
FAU - Matalon, R
AU  - Matalon R
FAU - Gould, S J
AU  - Gould SJ
LA  - eng
GR  - DK45787/DK/NIDDK NIH HHS/United States
GR  - HD10981/HD/NICHD NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (RNA, Messenger)
RN  - 0 (Recombinant Proteins)
RN  - EC 4.1.1.- (Carboxy-Lyases)
RN  - EC 4.1.1.9 (malonyl-CoA decarboxylase)
SB  - IM
MH  - Amino Acid Sequence
MH  - Animals
MH  - Base Sequence
MH  - Carboxy-Lyases/chemistry/deficiency/*genetics
MH  - Cloning, Molecular
MH  - Cytoplasm/enzymology
MH  - Humans
MH  - Liver/enzymology
MH  - Microbodies/enzymology
MH  - Molecular Sequence Data
MH  - Muscle, Skeletal/enzymology/metabolism
MH  - Myocardium/enzymology/metabolism
MH  - Phenotype
MH  - RNA, Messenger/metabolism
MH  - Rats
MH  - Recombinant Proteins/chemistry/genetics
MH  - Sequence Alignment
EDAT- 1999/08/24 00:00
MHDA- 1999/08/24 00:01
CRDT- 1999/08/24 00:00
PHST- 1999/08/24 00:00 [pubmed]
PHST- 1999/08/24 00:01 [medline]
PHST- 1999/08/24 00:00 [entrez]
AID - 10.1074/jbc.274.35.24461 [doi]
PST - ppublish
SO  - J Biol Chem. 1999 Aug 27;274(35):24461-8. doi: 10.1074/jbc.274.35.24461.