Novel effect of C75 on carnitine palmitoyltransferase I activity and palmitate oxidation

Biochemistry. 2006 Apr 11;45(14):4339-50. doi: 10.1021/bi052186q.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 4-Butyrolactone / analogs & derivatives*
  • 4-Butyrolactone / metabolism
  • 4-Butyrolactone / pharmacology
  • Acyl Coenzyme A / biosynthesis
  • Acyl Coenzyme A / pharmacology
  • Animals
  • Carnitine O-Palmitoyltransferase / antagonists & inhibitors
  • Carnitine O-Palmitoyltransferase / metabolism*
  • Cells, Cultured
  • Coenzyme A Ligases / metabolism
  • Epoxy Compounds / metabolism
  • Humans
  • Kinetics
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria, Liver / enzymology
  • Mitochondria, Muscle / enzymology
  • Oxidation-Reduction
  • Palmitic Acid / metabolism
  • Rats
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization


  • 4-methylene-2-octyl-5-oxofuran-3-carboxylic acid
  • Acyl Coenzyme A
  • C75-coenzyme A
  • Epoxy Compounds
  • Palmitic Acid
  • Carnitine O-Palmitoyltransferase
  • Coenzyme A Ligases
  • etomoxir
  • 4-Butyrolactone