The CPT1 enzymes convert long chain (greater than ∼C12) acyl-CoA molecules to acylcarnitine derivatives to facilitate their transport from the cytosol into the mitochondrial matrix via the carnitine/acylcarnitine carrier (CACT; SLC25A20). The acylcarnitines are converted back to acyl-CoA by CPT2 to support the fatty acid oxidation (FAO) cycle in the mitochondria. CPT1s are allosterically inhibited by malonyl-CoA.

Carnitine palmitoyltransferases (CPTs) play a key role in regulating the oxidation of long-chain fatty acids [3]. There are four CPT enzymes in humans; CPT1A, CPT1B, CPT1C, and CPT2, which vary in their tissue expression patterns and catalytic activities. Pharmacological modulation of CPTs is being explored for therapeutic potential in diseases that are associated with disordered metabolism, such as obesity, diabetes, and cancer.

The CPT1 enzymes convert long chain (greater than ∼C12) acyl-CoA molecules to acylcarnitine derivatives to facilitate their transport from the cytosol into the mitochondrial matrix via the carnitine/acylcarnitine carrier (CACT; SLC25A20). The acylcarnitines are converted back to acyl-CoA by CPT2 to support the fatty acid oxidation (FAO) cycle in the mitochondria. CPT1s are allosterically inhibited by malonyl-CoA [6].

Tissue expression: CPT1A is the only CPT1 isoform expressed in the liver and is detected in heart muscle, but is absent from skeletal muscle and adipose tissue. In contrast CPT1B is highly expressed in skeletal and heart muscle, adipose tissue and testis. CPT1C expression is restricted to the brain, and CPT2 is ubiquitously expressed.

Pathophysiology and therapeutic potential: Dysregualtion of CPT activity is associated with serious human diseases. Given their role in FAO the CPT1s are considered as tractable targets for the development of therapeutic agents for the treament of type 2 diabetes and obesity. As a consequence of the dependence of some cancer cells on FAO for energy production, inhibiting CPT1 function offers an attractive mechanism to 'starve' these cells and limit their proliferative potential.

* Key recommended reading is highlighted with an asterisk

* Ceccarelli SM, Chomienne O, Gubler M, Arduini A. (2011) Carnitine palmitoyltransferase (CPT) modulators: a medicinal chemistry perspective on 35 years of research. J Med Chem, 54 (9): 3109-52. [PMID:21504156]

1. Ceccarelli SM, Chomienne O, Gubler M, Arduini A. (2011) Carnitine palmitoyltransferase (CPT) modulators: a medicinal chemistry perspective on 35 years of research. J Med Chem, 54 (9): 3109-52. [PMID:21504156]

2. Giannessi F, Pessotto P, Tassoni E, Chiodi P, Conti R, De Angelis F, Dell'Uomo N, Catini R, Deias R, Tinti MO et al.. (2003) Discovery of a Long-Chain Carbamoyl Aminocarnitine Derivative, a Reversible Carnitine Palmitoyltransferase Inhibitor with Antiketotic and Antidiabetic Activity. Jourmal of Medicinal Chemistry, 46 (2): 303–309. DOI: 10.1021/jm020979u

3. Rodríguez-Rodríguez R, Baena M, Zagmutt S, Paraiso WK, Reguera AC, Fadó R, Casals N. (2025) International Union of Basic and Clinical Pharmacology: Fundamental Insights and Clinical Relevance Regarding the Carnitine Palmitoyltransferase Family of Enzymes. Pharm Rev, Online ahead of print. DOI: 10.1016/j.pharmr.2025.100051

4. Rufer AC, Lomize A, Benz J, Chomienne O, Thoma R, Hennig M. (2007) Carnitine palmitoyltransferase 2: analysis of membrane association and complex structure with a substrate analog. FEBS Lett, 581 (17): 3247-52. [PMID:17585909]

5. Rufer AC, Thoma R, Benz J, Stihle M, Gsell B, De Roo E, Banner DW, Mueller F, Chomienne O, Hennig M. (2006) The crystal structure of carnitine palmitoyltransferase 2 and implications for diabetes treatment. Structure, 14 (4): 713-23. [PMID:16615913]

6. Zammit VA. (1999) The malonyl-CoA-long-chain acyl-CoA axis in the maintenance of mammalian cell function. Biochem J, 343 Pt 3 (Pt 3): 505-15. [PMID:10527927]