Yonetani-Theorell analysis of hepatic carnitine palmitoyltransferase-I inhibition indicates two distinct inhibitory binding sites.
Analysis of inhibitor studies indicates that carnitine palmitoyltransferase-I has two separate sites for inhibitor binding. One site is located on the cytoplasmic side of the mitochondrial outer membrane. Malonyl-CoA, the most important physiological inhibitor of carnitine palmitoyltransferase-I, binds primarily to this site, but it can also bind to another site. A second inhibitory site is located at the active site of carnitine palmitolytransferase-I. Coenzyme A, a product/inhibitor of carnitine palmitoyltransferase-I binds primarily at this site and can inhibit carnitine palmitoyltransferase-I at physiological concentrations, but can also attenuate malonyl-CoA inhibition. Analogs of malonyl-CoA and other simpler compounds containing two carbonyl groups but no coenzyme A moiety inhibit only at the cytoplasmic site, indicating that this site has an absolute requirement for two carbonyl groups but has no absolute requirement for a coenzyme A moiety. Inhibitors acting through the active site included the active-site-directed inhibitor (+)-hemipalmitoylcarnitinium. These studies support the existence of two regulatory binding sites for the control of hepatic fatty acid oxidation: (a) the active site, for regulation by the inhibitory binding of coenzyme A and acetyl-CoA, and (b) a separate regulatory malonyl-CoA-binding site that is physical separated from the active site.
Cook
G A
GA
Department of Pharmacology, College of Medicine, University of Tennessee, Memphis 38163.
Mynatt
R L
RL
Kashfi
K
K
D000818:Animals; D001665:Binding Sites; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003065:Coenzyme A / Q000378:metabolism; D006038:Glyoxylates / Q000378:metabolism / Q000494:pharmacology; D007700:Kinetics; D008316:Malonyl Coenzyme A / Q000378:metabolism / Q000494:pharmacology; D008930:Mitochondria, Liver / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley
D006038:Glyoxylates; C030921:4-hydroxyphenylglyoxylic acid; D008316:Malonyl Coenzyme A; D002334:Carnitine O-Palmitoyltransferase; D003065:Coenzyme A