Novel Effect of C75 on Carnitine Palmitoyltransferase I Activity and Palmitate Oxidation
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.
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Pharmacological and genetic inhibition of hypothalamic CPT1A has been reported to reduce food intake.
“Even so, in the last decade, pharmacological and genetic inhibition of hypothalamic CPT1A has been reported to reduce the food intake ([10](#B10), [110](#B110), [127](#B127)), potentially as a result of LCFA-CoA cytoplasmic accumulation.”
From Mitochondrial fatty acid oxidation in obesity (2013) · cites this paper as [10]
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- Authors
- Bentebibel, A., Sebastián, D., Herrero, L., López-Viñas, E., Serra, D., Asins, G., Gómez-Puertas, P., & Hegardt, F. G.
- Affiliations
- Consejo Superior de Investigaciones Científicas (ES)
- Department of Biochemistry and Molecular Biology, School of Pharmacy, University of Barcelona, E-08028 Barcelona, Spain, and Centro de Biologia Molecular “Severo Ochoa”, Universidad Autonoma de Madrid, Consejo Superior de Investigaciones Científicas, Cantoblanco, E-28049 Madrid, Spain
- Venue
- Biochemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2006-03-14
- Volume
- 45
- Issue
- 14
- Pages
- 4339-4350
- ISSN
- 0006-2960 (ISSN-L)
- 1520-4995
- OpenAlex
- W2102016174
- Cited by
- 58
- References
- 48
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2023: 1 · 2022: 4 · 2021: 3 · 2020: 1 · 2019: 4 · 2018: 6 · 2017: 3 · 2016: 2 · 2015: 2 · 2014: 5 · 2013: 4 · 2012: 2
- FWCI
- 1.55
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Keywords
- C75, carnitine palmitoyltransferase 1, palmitate oxidation, fatty acid oxidation, fatty acid synthase inhibitors, obesity treatment, competitive inhibition, molecular docking, liver mitochondria, muscle mitochondria
- MeSH terms
- Acyl Coenzyme A, Animals, Carnitine O-Palmitoyltransferase, Cells, Cultured, Coenzyme A Ligases, Epoxy Compounds, Humans, Kinetics, Male, Mice, Inbred C57BL, Mitochondria, Liver, Mitochondria, Muscle, Oxidation-Reduction, 4-Butyrolactone, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Palmitic Acid, Mice, Rats
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