Bentebibel 2006 Biochemistry: Difference between revisions
(Created page with "{{Publication |title=Bentebibel A, Sebastián D, Herrero L, López-Viñas E, Serra D, Asins G, Gómez-Puertas P, Hegardt FG (2006) Novel effect of C75 on carnitine palmitoylt...") |
No edit summary |
||
| Line 1: | Line 1: | ||
{{Publication | {{Publication | ||
|title=Bentebibel A, Sebastián D, | |title=Bentebibel A, Sebastián D, Herrero L, López-Viñas E, Serra D, Asins G, Gómez-Puertas P, Hegardt FG (2006) Novel effect of C75 on carnitine palmitoyltransferase I activity and palmitate oxidation. Biochemistry 45:4339-50. | ||
|info=[https://pubmed.ncbi.nlm.nih.gov/16584169/ PMID:16584169] | |info=[https://pubmed.ncbi.nlm.nih.gov/16584169/ PMID:16584169] | ||
|authors=Bentebibel A, Sebastián D, Herrero L, López-Viñas E, Serra D, Asins G, Gómez-Puertas P, Hegardt FG | |authors=Bentebibel A, Sebastián D, Herrero L, López-Viñas E, Serra D, Asins G, Gómez-Puertas P, Hegardt FG | ||
| Line 7: | Line 7: | ||
|abstract=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. | |abstract=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. | ||
}} | }} | ||
== Cited by == | |||
{{Template:Cited by Silva 2021 MitoFit Etomoxir}} | |||
{{Labeling | {{Labeling | ||
|additional=MitoFit 2021 Etomoxir | |additional=MitoFit 2021 Etomoxir | ||
}} | }} | ||
Latest revision as of 10:18, 6 July 2021
| Bentebibel A, Sebastián D, Herrero L, López-Viñas E, Serra D, Asins G, Gómez-Puertas P, Hegardt FG (2006) Novel effect of C75 on carnitine palmitoyltransferase I activity and palmitate oxidation. Biochemistry 45:4339-50. |
Bentebibel A, Sebastián D, Herrero L, López-Viñas E, Serra D, Asins G, Gómez-Puertas P, Hegardt FG (2006) Biochemistry
Abstract: 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.
Cited by
- Silva et al (2021) Off-target effect of etomoxir on mitochondrial Complex I. MitoFit Preprints 2021. (in preparation)
Labels:
MitoFit 2021 Etomoxir
