C75 activates malonyl-CoA sensitive and insensitive components of the CPT system.
Carnitine palmitoyltransferase I (CPT-I) and II (CPT-II) enzymes are components of the carnitine palmitoyltransferase shuttle system which allows entry of long-chain fatty acids into the mitochondrial matrix for subsequent oxidation. This system is tightly regulated by malonyl-CoA levels since this metabolite is a strong reversible inhibitor of the CPT-I enzyme. There are two distinct CPT-I isotypes (CPT-Ialpha and CPT-Ibeta), that exhibit different sensitivity to malonyl-CoA inhibition. Because of its ability to inhibit fatty acid synthase, C75 is able to increase malonyl-CoA intracellular levels. Paradoxically it also activates long-chain fatty acid oxidation. To identify the exact target of C75 within the CPT system, we expressed individually the different components of the system in the yeast Pichia pastoris. We show here that C75 acts on recombinant CPT-Ialpha, but also on the other CPT-I isotype (CPT-Ibeta) and the malonyl-CoA insensitive component of the CPT system, CPT-II.
Nicot
Carine
C
Department of Biochemistry and Molecular Biology, School of Pharmacy University of Barcelona, E-08028 Barcelona, Spain.
Napal
Laura
L
Relat
Joana
J
González
Silvia
S
Llebaria
Amadeu
A
Woldegiorgis
Gebre
G
Marrero
Pedro F
PF
Haro
Diego
D
D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008316:Malonyl Coenzyme A / Q000378:metabolism*; D010843:Pichia / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics; D051381:Rats; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
C406734:4-methylene-2-octyl-5-oxofuran-3-carboxylic acid; D011994:Recombinant Proteins; D008316:Malonyl Coenzyme A; D002334:Carnitine O-Palmitoyltransferase; D015107:4-Butyrolactone