DL-aminocarnitine and acetyl-DL-aminocarnitine. Potent inhibitors of carnitine acyltransferases and hepatic triglyceride catabolism.

Abstract

DL-Aminocarnitine (3-amino-4-trimethylaminobutyric acid) and acetyl-DL-aminocarnitine (3-acetamido-4-trimethylaminobutyric acid) have been synthesized and the interactions of these compounds with carnitine acetyltransferase and carnitine palmitoyltransferase investigated. As anticipated from the low group transfer potential of amides, carnitine acetyltransferase catalyzes the transfer of acetyl groups from CoASAc to aminocarnitine (Km = 3.8 mM) but does not catalyze detectable transfer from acetylaminocarnitine to CoASH. Acetyl-DL-aminocarnitine is, however, a potent competitive inhibitor of carnitine acetyltransferase (Ki = 24 microM) and is bound to carnitine acetyltransferase about 13-fold more tightly than is acetylcarnitine, with which it is isosteric. DL-Aminocarnitine and, to a lesser extent, acetyl-DL-aminocarnitine are also inhibitors of the carnitine palmitoyltransferase activity of detergent-lysed rat liver mitochondria; in the presence of 1 mM L-carnitine, 5 microM aminocarnitine inhibits palmitoyl transfer by 64%. Significant acylation of aminocarnitine by palmitoyl-CoA was not observed. Neither aminocarnitine nor acetylaminocarnitine is significantly catabolized by mice; aminocarnitine is converted to acetylaminocarnitine in vivo. Both compounds are excreted in the urine. Mice given acetylaminocarnitine catabolize [14C]acetyl-L-carnitine and [14C]palmitate to 14CO2 more slowly than do control animals. Mice given acetylaminocarnitine and then starved are found to reversibly accumulate triglycerides in their livers; mice given the inhibitor but not starved do not show this effect.