Biosynthesis and Metabolism of Carnitine

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.

Figure 14.2. Biosynthesis of carnitine. Trimethyllysine hydroxylase, EC 1.14.11.8; aldolase, EC 4.1.2."x"; aldehyde dehydrogenase, EC 1.2.1.47; y-butyrobetaine hydroxylase, EC 1.14.11.1. Relative molecular mass (Mr): carnitine, 161.2.

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 ^mol per L in men and 28 to 75 ^mol 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 ^mol (men) or 200 to 320 ^mol (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 the kidney, whereas free carnitine and acetyl carnitine are reabsorbed until the plasma concentration exceeds the renal threshold.

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.

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