Carnitine synthesis

Ascorbic acid or vitamin C is found in fruits, especially citrus fruits, and in fresh vegetables. Man is one of the few mammals unable to manufacture vitamin C in the liver. It is essential for the formation of collagen as it is a cofactor for the conversion of proline and lysine residues to hydroxyproline and hydroxylysine. It is also a cofactor for carnitine synthesis, for the conversion of folic acid to folinic acid and for the hydroxylation of dopamine to form norepinephrine. Being a lactone with two hydroxyl groups which can be oxidized to two keto groups forming dehydroascorbic acid, ascorbic acid is also an anti-oxidant. By reducing ferric iron to the ferrous state in the stomach, ascorbic acid promotes iron absorption. 

Application of Aldehyde Reductase to the Production of Chiral Building Blocks for L-Carnitine Synthesis... 

Individuals with HMG-CoA lyase deficiency are particularly susceptible to carnitine deficiency. With restriction of red meats and dairy products, dietary carnitine intake is quite low. Carnitine is also synthesized endogenously from the modified, methylated lysine resides of various proteins free trimethyllysine is released when the protein is degraded. Since the therapy for patients with HMG-CoA lyase deficiency must minimize their endogenous protein catabolism, they also have limited availability of trimethyllysine for carnitine synthesis. 

Fatty acids are the major fuel for red muscle fibers, which are the main type involved in moderate exercise. Children who lack one or the other of the enzymes required for carnitine synthesis, and are therefore reliant on a dietary intake, have poor exercise tolerance, because they have an impaired ability to transport fatty acids into the mitochondria for /S - oxidation. Provision of supplements of carnitine to the affected children overcomes the problem. Extrapolation from this rare clinical condition has led to the use of carnitine as a so-called ergogenic aid to improve athletic performance. 

Carnitine is synthesized from lysine and methionine by the pathway shown in Figure 14.2 (Vaz and Wanders, 2002). The synthesis of carnitine involves the stepwise methylation of a protein-incorporated lysine residue at the expense of methionine to yield a trimethyllysine residue. Free trimethyllysine is then released by proteolysis. It is not clear whether there is a specific precursor protein for carnitine synthesis, because trimethyllysine occurs in a number of proteins, including actin, calmodulin, cytochrome c, histones, and myosin. 

Another topic of occasional concern is the carnitine status of people in the Middle East and India who consume cereal-based diets. Although these diets supply only about 15 mg of carnitine per day, there is little reason to believe that the rate of carnitine synthesis in these persons is inadequate to supply the body s needs. 

Trimethyl lysine hydroxylase Hydroxylation of trimethyl lysine Carnitine synthesis... 

Ascorbate increases the activity of hydroxylases needed for the conversion of p-hydroxyphenylpyruvate to homogentisate (Chapter 17), synthesis of norepinephrine from dopamine (Chapter 32), and two reactions in carnitine synthesis (Chapter 18). It is not known whether decreased activity of these enzymes contributes to the clinical characteristics of scurvy. Although ascorbic acid is needed for maximal activity of these enzymes in vivo and in vitro, most show some activity when other reducing agents are used. 

An individual with a deficiency of an enzyme in the pathway for carnitine synthesis is not eating adequate amounts of carnitine in the diet. Which of the following effects would you expect during fasting as compared with an individual with an adequate intake and synthesis of carnitine ... 

Water-soluble vitamins such as vitamin C are present in large amount in sea lettuces. The levels of vitamin C in sea lettuces average from 500 to 3000 mg/kg of dry matter. These levels of vitamin C are comparable with that of parsley, blackcurrant, and peppers. In sea lettuces, the highest level of vitamin C were found in Ulvafasciata (22 mg/100 g) (McDermid and Stuercke, 2003). Vitamin C is of interest for many reasons. First, it strengthens the immime defense system, activates the intestinal absorption of iron, as a reversible reductant and antioxidant in the aqueous fluid and tissue compartments. Further, this vitamin is specifically required for the activity of eight human enzymes involved in collagen, hormone, amino acid, and carnitine synthesis or metabolism (Jacob and Sotoudeh, 2002). 

Koch, A., B. Kbnig, G.l. Stangl, and K. Eder. 2008. PPARa mediates transcriptional upregu-lation of novel organic cation transporters-2 and -3 and enzymes involved in hepatic carnitine synthesis. Experimental Biology and Medicine (Maywood) 233 356-65. 

Several metabolic pathways (e.g. hpid metabohsm, creatine and carnitine synthesis) require methyl groups and these can be snppUed by choline or methionine. During the process of transmethylation, betaine, a tertiary amine, is formed by the oxidation of choline. Betaine can be added to the diet to act as a more direct supply of methyl groups, thus sparing choUne for its other fimctions of lecithin and acetylcholine formation, and methionine for protein synthesis. Betaine occurs in sugar beet. 

Ha, T. Y., Otsuka, M., and Arakawa, N., 1994, Ascorbate indirectly stimulates fatty acid utilization in primary cultured guinea pig hepatocytes by enhancing carnitine synthesis, J. Nutr. 124 732-737. 

L-ascorbic acid is a cofactor for hydroxylation involved in carnitine synthesis... 

Ascorbic acid s chemical structure makes it an electron donor and therefore a reducing agent. AA has thus been involved in two different biochemical functions redox/ antioxidant properties and enzymatic cofactor. AA has been demonstrated to be an electron donor for different enzymes. Among these enzymes, three are involved in collagen hydroxylation (Bates et al., 1972 Levene et al., 1972). Two are involved in carnitine synthesis (Nelson et al., 1981 Dunn et al., 1984). The remaining are respectively involved in norepinephrine synthesis (Kuo, 1979) and tyrosine synthesis (La Duand Zannoni, 1964). Deficiency in AA has thus been associated with extracellular matrix defects that are probably involved in vascular problems observed in scurvy. 

Y Cho, JE Leklem. In vivo evidence for a vitamin B-6 requirement in carnitine synthesis. J Nutr 120 258-265, 1990. 

Man and other higher animals appear to be able to synthesize their total needs within the body. But the mechanism of carnitine synthesis in humans is unknown. Very likely, carnitine is synthesized in humans from lysine and methionine—two essential amino acids which are low in plant foods. 

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