PMID- 14517221
OWN - NLM
STAT- MEDLINE
DCOM- 20040115
LR  - 20210206
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 278
IP  - 50
DP  - 2003 Dec 12
TI  - Functional and structural basis of carnitine palmitoyltransferase 1A deficiency.
PG  - 50428-34
AB  - Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic 
      long-chain fatty acid beta-oxidation. Human CPT1A deficiency is characterized by 
      recurrent attacks of hypoketotic hypoglycemia. We presently analyzed at both the 
      functional and structural levels five missense mutations identified in three 
      CPT1A-deficient patients, namely A275T, A414V, Y498C, G709E, and G710E. 
      Heterologous expression in Saccharomyces cerevisiae permitted to validate them as 
      disease-causing mutations. To gain further insights into their deleterious 
      effects, we localized these mutated residues into a three-dimensional structure 
      model of the human CPT1A created from the crystal structure of the mouse 
      carnitine acetyltransferase. This study demonstrated for the first time that 
      disease-causing CPT1A mutations can be divided into two categories depending on 
      whether they affect directly (functional determinant) or indirectly the active 
      site of the enzyme (structural determinant). Mutations A275T, A414V, and Y498C, 
      which exhibit decreased catalytic efficiency, clearly belong to the second class. 
      They are located more than 20 A away from the active site and mostly affect the 
      stability of the protein itself and/or of the enzyme-substrate complex. By 
      contrast, mutations G709E and G710E, which abolish CPT1A activity, belong to the 
      first category. They affect Gly residues that are essential not only for the 
      structure of the hydrophobic core in the catalytic site, but also for the 
      chain-length specificity of CPT isoforms. This study provides novel insights into 
      the functionality of CPT1A that may contribute to the design of drugs for the 
      treatment of lipid disorders.
FAU - Gobin, Stephanie
AU  - Gobin S
AD  - Departement d'Endocrinologie, Institut Cochin, INSERM U567, CNRS Unite Mixte de 
      Recherche 8104, Universite Rene Descartes, 24 Rue du Faubourg Saint-Jacques, 
      75014 Paris, France.
FAU - Thuillier, Laure
AU  - Thuillier L
FAU - Jogl, Gerwald
AU  - Jogl G
FAU - Faye, Audrey
AU  - Faye A
FAU - Tong, Liang
AU  - Tong L
FAU - Chi, Mihaiti
AU  - Chi M
FAU - Bonnefont, Jean-Paul
AU  - Bonnefont JP
FAU - Girard, Jean
AU  - Girard J
FAU - Prip-Buus, Carina
AU  - Prip-Buus C
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20030929
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Protein Isoforms)
RN  - EC 2.3.1.21 (Carnitine O-Palmitoyltransferase)
RN  - EC 3.4.21.4 (Trypsin)
SB  - IM
MH  - Amino Acid Sequence
MH  - Binding Sites
MH  - Blotting, Western
MH  - Carnitine O-Palmitoyltransferase/*deficiency/*genetics
MH  - Catalytic Domain
MH  - Crystallography, X-Ray
MH  - Dose-Response Relationship, Drug
MH  - Electrophoresis, Polyacrylamide Gel
MH  - Fibroblasts/metabolism
MH  - Humans
MH  - Inhibitory Concentration 50
MH  - Kinetics
MH  - Lipid Metabolism
MH  - Mitochondria/metabolism
MH  - Models, Genetic
MH  - Models, Molecular
MH  - Molecular Sequence Data
MH  - Mutation
MH  - Mutation, Missense
MH  - Protein Conformation
MH  - Protein Folding
MH  - Protein Isoforms
MH  - Protein Structure, Secondary
MH  - Saccharomyces cerevisiae/metabolism
MH  - Sequence Homology, Amino Acid
MH  - Subcellular Fractions/metabolism
MH  - Trypsin/chemistry
EDAT- 2003/10/01 05:00
MHDA- 2004/01/16 05:00
CRDT- 2003/10/01 05:00
PHST- 2003/10/01 05:00 [pubmed]
PHST- 2004/01/16 05:00 [medline]
PHST- 2003/10/01 05:00 [entrez]
AID - S0021-9258(20)75562-6 [pii]
AID - 10.1074/jbc.M310130200 [doi]
PST - ppublish
SO  - J Biol Chem. 2003 Dec 12;278(50):50428-34. doi: 10.1074/jbc.M310130200. Epub 2003 
      Sep 29.