title: Hemipalmitoylcarnitinium, a strong competitive inhibitor of purified hepatic carnitine palmitoyltransferase.
abstract: We have synthesized (2S,6R:2R,6S)-6-carboxymethyl-2-hydroxy-2-pentadecyl-4,4-dimethylmorp holinium bromide (hemipalmitoylcarnitinium, HPC) which is a conformationally restricted analog inhibitor of carnitine palmitoyltransferase (CPT; EC 2.3.1.21). rac-HPC inhibits catalytic activity in purified rat liver CPT. In the forward reaction, HPC competes with both (R)-carnitine (Ki(app) = 5.1 +/- 0.7 microM) and palmitoyl-CoA (Ki(app) = 21.5 +/- 4.9 microM). In the reverse reaction, inhibition by HPC is competitive with palmitoyl-(R)-carnitine (Ki(app) = 1.6 +/- 0.6 microM), but inhibition is uncompetitive with CoA. The forward reaction is also competitively inhibited by its product, palmitoyl-(R)-carnitine, Ki(app)'s 14.2 +/- 2.1 microM relative to (R)-carnitine and 8.7 +/- 2.6 microM relative to palmitoyl-CoA. rac-HPC is the most potent synthetic reversible inhibitor of purified CPT. HPC fails to inhibit carnitine acetyltransferase (CAT; EC 2.3.1.7). Palmitoylcholine also inhibits CPT in the forward reaction, competing with (R)-carnitine (Ki(app) = 18.6 +/- 4.5 microM) and with palmitoyl CoA (Ki(app) = 10.4 +/- 2.5 microM). Choline is not an effective CPT inhibitor. We have shown [R.D. Gandour et al. (1986) Biochem. Biophys. Res. Commun. 138, 735-741] that hemiacetylcarnitinium inhibits CAT but not CPT. The combined data demonstrate further differences between the carnitine recognition sites in CPT and CAT.
authors.affiliation: Department of Chemistry, Louisiana State University, Baton Rouge 70803-1804.
authors.forename: R D
authors.initials: RD
authors.lastname: Gandour
authors.forename: W J
authors.initials: WJ
authors.lastname: Colucci
authors.forename: T C
authors.initials: TC
authors.lastname: Stelly
authors.forename: P S
authors.initials: PS
authors.lastname: Brady
authors.forename: L J
authors.initials: LJ
authors.lastname: Brady
mesh_terms: D000217:Acyltransferases / Q000037:antagonists & inhibitors*; D000818:Animals; D001667:Binding, Competitive; D002331:Carnitine / Q000031:analogs & derivatives* / Q000378:metabolism; D002332:Carnitine O-Acetyltransferase / Q000037:antagonists & inhibitors; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors*; D002794:Choline / Q000031:analogs & derivatives / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000201:enzymology* / Q000378:metabolism; D010171:Palmitoyl Coenzyme A / Q000378:metabolism; D010172:Palmitoylcarnitine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats
chemical_list: C058207:hemipalmitoylcarnitinium; C032703:palmitoylcholine; D010171:Palmitoyl Coenzyme A; D010172:Palmitoylcarnitine; D000217:Acyltransferases; D002334:Carnitine O-Palmitoyltransferase; D002332:Carnitine O-Acetyltransferase; D002794:Choline; D002331:Carnitine