Linked Life Data

16584169

Source:http://linkedlifedata.com/resource/pubmed/id/16584169

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
14
pubmed:dateCreated
2006-4-4
pubmed:abstractText
C75 is a potential drug for the treatment of obesity. It was first identified as a competitive, irreversible inhibitor of fatty acid synthase (FAS). It has also been described as a malonyl-CoA analogue that antagonizes the allosteric inhibitory effect of malonyl-CoA on carnitine palmitoyltransferase I (CPT I), the main regulatory enzyme involved in fatty acid oxidation. On the basis of MALDI-TOF analysis, we now provide evidence that C75 can be transformed to its C75-CoA derivative. Unlike the activation produced by C75, the CoA derivative is a potent competitive inhibitor that binds tightly but reversibly to CPT I. IC50 values for yeast-overexpressed L- or M-CPT I isoforms, as well as for purified mitochondria from rat liver and muscle, were within the same range as those observed for etomoxiryl-CoA, a potent inhibitor of CPT I. When a pancreatic INS(823/13), muscle L6E9, or kidney HEK293 cell line was incubated directly with C75, fatty acid oxidation was inhibited. This suggests that C75 could be transformed in the cell to its C75-CoA derivative, inhibiting CPT I activity and consequently fatty acid oxidation. In vivo, a single intraperitoneal injection of C75 in mice produced short-term inhibition of CPT I activity in mitochondria from the liver, soleus, and pancreas, indicating that C75 could be transformed to its C75-CoA derivative in these tissues. Finally, in silico molecular docking studies showed that C75-CoA occupies the same pocket in CPT I as palmitoyl-CoA, suggesting an inhibiting mechanism based on mutual exclusion. Overall, our results describe a novel role for C75 in CPT I activity, highlighting the inhibitory effect of its C75-CoA derivative.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Apr
pubmed:issn
0006-2960
pubmed:author
pubmed:issnType
Print
pubmed:day
11
pubmed:volume
45
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
4339-50
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed-meshheading:16584169-4-Butyrolactone, pubmed-meshheading:16584169-Acyl Coenzyme A, pubmed-meshheading:16584169-Animals, pubmed-meshheading:16584169-Carnitine O-Palmitoyltransferase, pubmed-meshheading:16584169-Cells, Cultured, pubmed-meshheading:16584169-Coenzyme A Ligases, pubmed-meshheading:16584169-Epoxy Compounds, pubmed-meshheading:16584169-Humans, pubmed-meshheading:16584169-Kinetics, pubmed-meshheading:16584169-Male, pubmed-meshheading:16584169-Mice, pubmed-meshheading:16584169-Mice, Inbred C57BL, pubmed-meshheading:16584169-Mitochondria, Liver, pubmed-meshheading:16584169-Mitochondria, Muscle, pubmed-meshheading:16584169-Oxidation-Reduction, pubmed-meshheading:16584169-Palmitic Acid, pubmed-meshheading:16584169-Rats, pubmed-meshheading:16584169-Spectrometry, Mass, Matrix-Assisted Laser...
pubmed:year
2006
pubmed:articleTitle
Novel effect of C75 on carnitine palmitoyltransferase I activity and palmitate oxidation.
pubmed:affiliation
Department of Biochemistry and Molecular Biology, School of Pharmacy, University of Barcelona, E-08028 Barcelona, Spain.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't