• DOI:10.1021/BI052186Q
• Corpus ID: 33830351

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

@article{Bentebibel2006NovelEO,
  title={Novel effect of C75 on carnitine palmitoyltransferase I activity and palmitate oxidation.},
  author={Assia Bentebibel and David Sebasti{\'a}n and Laura Herrero and Eduardo L{\'o}pez-Vi{\~n}as and Dolors Serra and Guillermina Asins and Paulino G{\'o}mez-Puertas and Fausto G. Hegardt},
  journal={Biochemistry},
  year={2006},
  volume={45 14},
  pages={
          4339-50
        }
}

• Assia Bentebibel, David Sebastián, +5 authors F. Hegardt
• Published 14 March 2006
• Biology, Chemistry
• Biochemistry

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.