ABSTRACT
L(−)-Carnitine, a name derived from the Latin carnis (flesh), is a hygroscopic and extremely water-soluble compound ubiquitous in nature. The history of L(−)-carnitine research has extended over this century (Table 1). L(−)-Carnitine was first isolated from meat extracts in 1905 (1), and soon after, its chemical formula (C7H15NO3) was proposed. In spite of many studies on the biological effects of L(−)-carnitine, its function remained unclear for half a century. Because of the vitamin-like properties of L(−)-carnitine in the mealworm Tenebrio molitor, the name vitamin BT was created (3), but soon after it was found that microorganisms and higher animals are also able to synthesize L(−)-carnitine by themselves (7,8,17). Hence, the assumption upon which L(–)-carnitine was included among the vitamins failed. Further investigations demonstrated a function for L(−)- carnitine in the β-oxidation of fatty acids (18). It was shown that this quaternary ammonium compound is essential for the transport of long-chain fatty acids through the inner mitochondrial membrane of mammals. In 1962 the configuration of the physiological enantiomer was determined (9) and in 1997 confirmed as L(−)- or R(−)-3hydroxy-4-N,N,N-trimethylaminobutyrate (19). The discov-
1905 Isolation of carnitine from muscle (1)
1927 Elucidation of structure of carnitine (2)
1952 Carnitine was shown to be a vitamin (BT) for mealworm (Tenebrio molitor) (3,4)
1955 Discovery of reversible enzymatic acetylation of carnitine by the carnitine acetyltransferase in liver (5): Acetyl-CoA+L(−)-carnitine→acetyl-L(−)-carnitine+CoA L(−)-Carnitine was shown to stimulate long-chain fatty acid oxidation in liver homogenates (6)
1961 Evidence of γ-butyrobetaine as precursor of L(−)-carnitine (7,8)
1962 Determination of configuration of the physiological enantiomer L(−)-carnitine (9)
Fatty acid esters of carnitine were shown to be intermediates in fatty acid oxidation; discovery of carnitine palmitoyltransferase (CPT), which catalyzes the reaction: Palmitoyl-CoA+L(−)-carnitine→palmitoyl-L(−)-carnitine + CoA and the postulate of its role in fatty acid oxidation (10-13)
1966 Evidence of localization of CPT (inner mitochondrial membrane) and acylCoA synthetase (outer mitochondrial membrane) (14,15)
1970 Detection of formation of branched chain acylcarnitines (16)
1971 Role of lysine in carnitine biosynthesis in Neurospora crassa was elucidated (17)
1973 Inborn errors in carnitine metabolism were found (20,21)
1975 Report on the existence of the carnitine carrier, the carnitine acylcarnitine translocase (22,23)
1977 Evidence of malonyl-CoA as inhibitor of CPT I (24)
1981 Purification of γ-butyrobetaine hydroxylase, the last enzyme in the biosynthetic pathway of L(−)-carnitine (25)
1987 CPT I was shown to be localized in the outer membrane of the mitochondria (26)
Cloning and sequencing of genes of carnitine acyltransferases (28-32)
1995 Evidence for the function of L(−)-carnitine in the transfer of acyl groups from the peroxisomes to the mitochondria (33)
ery that L(−)-carnitine is ultimately derived from the essential amino acid lysine (17,27) and the description of human carnitine deficiency syndromes of apparent genetic origin (20), were the impetus for extensive investigation into its metabolism, function, and applications. These studies led not only to a series of clinical applications of L(−)- carnitine but also to the idea of its use as a nutraceutical.
