Biosynthesis and Metabolism of Carnitine

Both hydroxylation reactions in the synthesis of carnitine from trimethyllysine are ascorbic acid-dependent, 2-oxoglutarate-linked, reactions (Section 13.3.3), and impaired synthesis of carnitine probably accounts for the muscle fatigue associated with vitamin C deficiency. 

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. 

Ccunitine is synthesized from lysine and methionine by the pathway shown in Eigure 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. Eree trimethyllysine is then relecised by proteolysis. It is not clear whether there is a specific precursor protein for Ccunitine synthesis, because trimethyllysine occurs in a number of proteins, including actin, calmodulin, cytochrome c, histones, and myosin. 

Both hydroxylation reactions in the synthesis of ceimitine from trimethyi-lysine are ascorbic acid-dependent, 2-oxoglutttrate-linked, reactions (Section 

ttnd impaired synthesis of cttmitine prohahly accounts for the muscle fatigue associated with vitamin C deficiency. 

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Pharmacology Vitamin C, a water-soluble vitamin, is an essential vitamin in man however, its exact biological functions are not fully understood. It is essential for the formation and the maintenance of intercellular ground substance and collagen, for catecholamine biosynthesis, for synthesis of carnitine and steroids, for conversion of folic acid to folinic acid and for tyrosine metabolism. 

Rebouche, C. J. 1983. Effect of dietary carnitine isomers and gamma-butyrobetaine on L-carnitine biosynthesis and metabolism in the rat. Journal of Nutrition 113 1906-13. 

A natural question is "Why has this complex pathway evolved to do something that could have been done much more directly " One possibility is that the presence of too much malonyl-CoA, the product of the P oxidation pathway of propionate metabolism (Fig. 17-3, pathways a and c), would interfere with lipid metabolism. Malonyl-CoA is formed in the cytosol during fatty acid biosynthesis and retards mitochondrial P oxidation by inhibiting carnitine palmitoyltransferase i.46 70a 75 However, a relationship to mitochondrial propionate catabolism is not clear. 

By extrapolation from the muscle weakness and fatigue seen in children with genetic defects of carnitine biosynthesis or metabolism, it has been... 

Ascorbic acid is involved in carnitine biosynthesis. Carnitine (y-amino-P-hydroxybutyric acid, trimethylbetaine) (30) is a component of heart muscle, skeletal tissue, liver and other tissues. It is involved in the transport of fatty acids into mitochondria, where they are oxidized to provide eneigy for the ceU and animal. It is synthesized in animals from lysine and methionine by two hydroxjiases, both containing ferrous iron and L-ascorbic acid. Ascorbic acid donates electrons to the enzymes involved in the metabolism of L-tyrosine, cholesterol, and histamine (128). 

Biochemical Functions. Ascorbic acid has various biochemical fimctions, involving, for example, coUagen synthesis, immune fimction, drug metabohsm, folate metabolism, cholesterol catabolism, iron metabolism, and carnitine biosynthesis. Clear-cut evidence for its biochemical role is available only with respect to coUagen biosynthesis (hydroxylation of prolin and lysine). In addition, ascorbic acid can act as a reducing agent and as an effective antioxidant. Ascorbic acid also interferes with nitrosamine formation by reacting directly with nitrites, and consequently may potentially reduce cancer risk. 

Acetyl-CoA synthetase (ACS) catalyzes the conversion of acetate to acetyl-CoA. In photosynthetic tissue, this enzyme is localized in the chloroplast (l) where it potentially provides a key source of acetyl-CoA for fatty acid, isoprenoid, and branch-chain amino acid biosynthesis. Acetyl-CoA synthetase s contribution to chloroplast acetyl-CoA is presently controversial because of the identification of alternative sources of acetyl-CoA (i. e. pyruvate dehydrogenase complex (2,3), and carnitine acyltransferase (4)), in the chloroplast. To further elucidate the role of ACS in chloroplast acetyl-CoA metabolism we have partially purified and characterized ACS from mature spinach leaves. 

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