Novel Effect of C75 on Carnitine Palmitoyltransferase I Activity and Palmitate Oxidation
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- 作者：Assia Bentebibel ; David Sebastiá ; n ; Laura Herrero ; Eduardo Ló ; pez-Viñ ; as ; Dolors Serra ; Guillermina Asins ; Paulino Gó ; mez-Puertas ; and Fausto G. Hegardt
- 刊名：Biochemistry
- 出版年：2006
- 出版时间：April 11, 2006
- 年：2006
- 卷：45
- 期：14
- 页码：4339 - 4350
- 全文大小：384K
- 年卷期：v.45,no.14(April 11, 2006)
- ISSN：1520-4995
文摘
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 analoguethat antagonizes the allosteric inhibitory effect of malonyl-CoA on carnitine palmitoyltransferase I (CPTI), 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 activationproduced by C75, the CoA derivative is a potent competitive inhibitor that binds tightly but reversibly toCPT I. IC50 values for yeast-overexpressed L- or M-CPT I isoforms, as well as for purified mitochondriafrom rat liver and muscle, were within the same range as those observed for etomoxiryl-CoA, a potentinhibitor of CPT I. When a pancreatic INS(823/13), muscle L6E9, or kidney HEK293 cell line was incubateddirectly with C75, fatty acid oxidation was inhibited. This suggests that C75 could be transformed in thecell 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 inmitochondria 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 occupiesthe 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 ofits C75-CoA derivative.