Carnitine biosynthesis

Biochemical Functions. Ascorbic acid has various biochemical functions, involving, for example, coUagen synthesis, immune function, dmg metabohsm, folate metaboHsm, cholesterol cataboHsm, iron metaboHsm, 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 direcdy with nitrites, and consequently may potentially reduce cancer risk. 

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

Carnitine biosynthesis utilizes the essential amino acid lysine, with terminal methyl groups donated by S-adenosylmethionine. Only lysine incorporated into proteins is a substrate for the methylation reaction. In humans, the final reaction in the biosynthetic pathway, catalyzed by a cytosolic hydroxylase, occurs in liver and kidney but not in cardiac or skeletal muscle. The carnitine requirement of these tissues is met by carnitine transported to them via the plasma... 

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

Vaz FM and Wanders RJ (2002) Carnitine biosynthesis in mammals. Biochemical Journal 361, 417-29. 

Carnitine biosynthesis in humans. A lysyl residue is trimethylated by S-adenosyimethionine, with subsequent proteolytic release of trimethyllysine, the starting material. The reactions are catalyzed by (1) trimethyllysine A-hydroxylase, (2) /t-hydroxy-trimethyllysine aldolase (pyridoxal phosphate), (3) )/-trimethylaminobutyraldehyde dehydrogenase, and (4) /-butyrobetaine hydroxylase. 

In this manner, y-butyrobetaine hydroxylase catalyzes the terminal step in carnitine biosynthesis, the hydroxylation of 4-A(-trimethyl-aminobutyrate. a-Kctoglutaratc-dcpendent dioxygenases act as oxygenation catalysts only in the presence of iron ions. Formation of thermodynamically stable CO2 helps to produce a high-valent center (Scheme XI. 12) [38a]. 

In humans, carnitine is either obtained from the diet or synthesised de novo (Fig. 1). Carnitine biosynthesis in higher eukaryotes starts when protein-bound L-lysine is trimethylated by a protein-dependent methyltransferase to form e-N-trimethyllysine. Upon degradation of these proteins, free e-N-trimethyllysine becomes available and is... 

Hulse, ID. Henderson, E.M. (1980) J. Biol. Chem., 255, 1146-1151, Carnitine Biosynthesis Purification of 4-N-trimethylaminobutyraldehyde dehydrogenase from beef liver. 

Paul, H.S., Sekas, G. Adibi, S.A. (1992) Eur. J. Biochem. 203, 599-605. Carnitine biosynthesis in hepatic peroxisomes. Demonstration of y-butyrobetaine hydroxylase activity. 

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. 

Van Vlies, N., S. Ferdinandusse, M. Turkenburg, R.J. Wanders, and F.M. Vaz. 2007. PPARa-activation results in enhanced carnitine biosynthesis and OCTN2-mediated hepatic carnitine accumulation. Q jjjjjucaetBio l sicaActa 1767 1134—42. 

Dunn, W. A., Rettura, G., Seifter, E., and Englard, S., 1984, Carnitine biosynthesis from y butyrobe-taine and from exogenous protein-bound 6-N-trimethyl-L-lysine by the perfused guinea pig liver Effect of ascorbic acid deficiency on the in situ activity of y butyrobetaine hydroxylase, J. Biol. Chem. 259 10764-10770. 

HULSE, J. D., ELLIS, S. R. HENDERSON, L. M. 1978. Carnitine biosynthesis. Beta-hydroxylation of trimethyllysine by an alpha-ketoglutarate-dependent mitochondrial dioxygenase. 7 5/o/ Chem, 253, 1654-9. 

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