(+)-Hemipalmitoylcarnitinium strongly inhibits carnitine palmitoyltransferase-I in intact mitochondria.
The reaction of the methyl ester of (R)-norcarnitine with 1-bromo-2-heptadecanone produces (+)-6-[(methoxycarbonyl)methyl]-2-pentadecyl-4,4-dimethylmorpholinium bromide, 3, which hydrolyzes to (+)-6-(carboxylatomethyl)-2-pentadecyl-4,4-dimethylmorpholinium (hemipalmitoylcarnitinium, HPC) upon treatment with aqueous sodium hydroxide. Single-crystal X-ray analyses have confirmed the structures of (+)-HPC and 3. (+)-HPC inhibits carnitine palmitoyltransferase (CPT-I) activity for the forward reaction (palmitoyl-CoA + carnitine-->) in intact mitochondria from rat heart and rat liver. (+)-HPC competitively (versus carnitine) inhibits CPT-I activity in both rat heart and liver mitochondria with Ki = 2.8 +/- 0.5 and 4.2 +/- 0.7 microM, respectively. As one of the strongest specific inhibitors of CPT-I, HPC is a potential therapeutic agent in myocardial ischemia and Type II diabetes.
Gandour
R D
RD
Department of Chemistry, Louisiana State University, Baton Rouge 70803-1804.
Leung
O T
OT
Greway
A T
AT
Ramsay
R R
RR
Nic a'Bháird
N
N
Fronczek
F R
FR
Bellard
B M
BM
Kumaravel
G
G
D000818:Animals; D001667:Binding, Competitive; D002331:Carnitine / Q000378:metabolism; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006321:Heart / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology; D009206:Myocardium / Q000201:enzymology; D010172:Palmitoylcarnitine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
C058207:hemipalmitoylcarnitinium; D010172:Palmitoylcarnitine; D002334:Carnitine O-Palmitoyltransferase; D002331:Carnitine