Acyl-carnitine esters

Wang J, Guo X, Xu Y, Barron L, Szoka EC Jr. Synthesis and characterization of long chain alkyl acyl carnitine esters. Potentially biodegradable cationic lipids for use in gene delivery. J Med Chem 1998 41(13) 2207-2215. 

The helper effects of DOPE and cholesterol appear to be hydrocarbon chain-specific. This is demonstrated in studies of their mixtures with a series of alkyl acyl carnitine esters (alkyl 3-acyloxy-4-trimethylammonium butyrate chloride) tested with CV-1 cell culture (monkey fibroblast) [127]. The influence of the aliphatic chain length (n - 12-18) on transfection in vitro was determined using cationic liposomes prepared from these lipids and their mixtures with the helper lipids DOPE and cholesterol (Fig. 30). Both helper lipids provided for significant transfection enhancements in an apparently chain-specific manner, with the highest effects found for short-chain lipids with diC12 0 and diC14 0 chains in 1 1 mixtures with the respective helper lipid. 

Fig. 30 Transfection activity of lipoplexes consisting of alkyl/acyl carnitine esters, alone and with helper lipid (DOPE or cholesterol), on [1-galactosidase expression in CV-1 cell culture (monkey fibroblast) cationic lipid/DNA charge ratio 4 1 [127]...

Carititine (3-hydroxy,4-AT-trimethylaminobutyric acid) has a central role in the transport of fatty acids across the mitochondrial membrane for p -oxidation. At the outer face of the outer mitochondrial membrane, carnitine acyltransferase I catalyzes the reaction shown in Figure 14.1, the transfer of fatty acids from coenzyme A (CoA) to form acyl carnitine esters that cross into the mitochondrial matrix. At the timer face of the inner mitochondrial membrane, carnitine acyltransferase II catalyzes the reverse reaction. 

The total body content of carnitine is about 100 mmol, and about 5% of this turns over daily. Plasma total carnitine is between 36 to 83 /rmol per L in men and 28 to 75 /rmol per L in women, mainly as free carnitine. Although both free carnitine and acyl carnitine esters are excreted in the urine, much is oxidized to trimethylamine and trimethylamine oxide. It is not known whether the formation of trimethylamine and trimethylamine oxide is caused by endogenous enzymes or intestinal bacterial metabolism of carnitine. 

Total urinary excretion of carnitine is between 300 to 530 /rmol (men) or 200 to 320 /rmol (women) 30% to 50% of this is free carnitine the remainder is a variety of acyl carnitine esters. Acyl carnitine esters are readily cleared in... 

Urinary excretion of acyl carnitine esters increases considerably in a variety of conditions involving organic aciduria carnitine acts to spare CoA and pantothenic acid (Section 12.2), by releasing the coenzyme from otherwise nonmetabolizable esters that would trap the coenzyme and cause functional pantothenic acid deficiency. 

PRODUCTION AND EXPORT OF ACYL-CARNITINE ESTERS BY NEONATAL RAT HEPATOCYTES... 

Other major lipid classes in the fatty acyl category include fatty add esters, such as wax monoesters and diesters and the lactones. The fatty ester class also has subclasses that include important biochemical intermediates, such as fatty acyl thioester-CoA derivatives, fatty acyl thioester-acyl carrier protein (ACP) derivatives, fatty acyl carnitines (esters of carnitine), and fatty adenylates, which are mixed anhydrides. Fatty alcohols, fatty aldehydes, and fatty amides represent further subclasses, the last sometimes showing interesting biological activities in various organisms. 

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