Carnitine biosynthesis

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Carnitine biosynthesis is a method for the endogenous production of L-carnitine, a molecule that is essential for energy metabolism. [1] [2] [3] [4] In humans and many other animals, L-carnitine is obtained from both diet and by biosynthesis. [5] [6] The carnitine biosynthesis pathway is highly conserved among many eukaryotes and some prokaryotes. [7] [8] [9]

Contents

L-Carnitine is biosynthesized from Nε-trimethyllysine. [10] At least four enzymes are involved in the overall biosynthetic pathway. They are Nε-trimethyllysine hydroxylase, 3-hydroxy-Nε-trimethyllysine aldolase, 4-N-trimethylaminobutyraldehyde dehydrogenase and γ-butyrobetaine hydroxylase.

Nε-Trimethyllysine hydroxylase

The first enzyme of the L-carnitine biosynthetic pathway is Nε-trimethyllysine hydroxylase, an iron and 2-oxoglutarate (2OG)-dependent oxygenase that also requires ascorbate. [11] Nε-trimethyllysine hydroxylase catalyses the hydroxylation reaction of Nε-trimethyllysine to 3-hydroxy-Nε-trimethyllysine.

The current consensus theory about the origin of Nε-trimethyllysine in mammals is that mammals utilise lysosomal or proteasomal degradation of proteins containing Nε-trimethyllysine residues as starting point for carnitine biosynthesis. [12] [13] [14] An alternative theory involving endogenous non-peptidyl biosynthesis was also proposed, based on evidence gathered from a study involving feeding normal and undernourished human subjects with the amino acid lysine. [15] Although Nε-trimethyllysine biosynthetic pathway involving Nε-trimethyllysine methyltransferase has been fully characterised in fungi including Neurospora crassa , such biosynthetic pathway has never been properly characterised in mammals or humans. [16] A third theory about the origin of Nε-trimethyllysine in mammals does not involve biosynthesis at all, but involves direct dietary intake from vegetable foods.[ citation needed ] High-performance liquid chromatography (HPLC) analysis has confirmed that vegetables contain a significant amount of Nε-trimethyllysine. [17]

3-Hydroxy-Nε-trimethyllysine aldolase

The second step of L-carnitine biosynthesis requires the 3-hydroxy-Nε-trimethyllysine aldolase enzyme. 3-hydroxy-Nε-trimethyllysine aldolase is a pyridoxal phosphate dependent aldolase, and it catalyses the cleavage of 3-hydroxy-Nε-trimethyllysine into 4-N-trimethylaminobutyraldehyde and glycine.

The true identity of 3-hydroxy-Nε-trimethyllysine aldolase is elusive and the mammalian gene encoding 3-hydroxy-Nε-trimethyllysine aldolase has not been identified. 3-hydroxy-Nε-trimethyllysine aldolase activity has been demonstrated in both L-threonine aldolase and serine hydroxymethyltransferase, [18] [19] although whether this is the main catalytic activity of these enzymes remains to be established.

4-N-Trimethylaminobutyraldehyde dehydrogenase

The third enzyme of L-carnitine biosynthesis is 4-N-trimethylaminobutyraldehyde dehydrogenase. [20] 4-N-trimethylaminobutyraldehyde dehydrogenase is a NAD+ dependent enzyme. 4-N-trimethylaminobutyraldehyde dehydrogenase catalyses the dehydrogenation of 4-N-trimethylaminobutyraldehyde into gamma-butyrobetaine.

Unlike 3-hydroxy-Nε-trimethyllysine aldolase, 4-N-trimethylaminobutyraldehyde dehydrogenase has been identified and purified from many sources including rat [21] and Pseudomonas . [22] However, the human 4-N-trimethylaminobutyraldehyde dehydrogenase has so far not been identified. There is considerable sequence similarity between rat 4-N-trimethylaminobutyraldehyde dehydrogenase and human aldehyde dehydrogenase 9, [23] but the true identity of 4-N-trimethylaminobutyraldehyde dehydrogenase remains to be established.

γ-Butyrobetaine hydroxylase

The final step of L-carnitine biosynthesis is γ-butyrobetaine hydroxylase, a zinc binding enzyme. [24] [25] [26] [27] [28] [29] Like Nε-trimethyllysine hydroxylase, γ-butyrobetaine hydroxylase is a 2-oxoglutarate and iron(II)-dependent oxygenase. γ-Butyrobetaine hydroxylase catalyses the stereospecific hydroxylation of γ-butyrobetaine to L-carnitine.

γ-Butyrobetaine hydroxylase is the most studied enzyme among the four enzymes in the biosynthetic pathway. It has been purified from many sources, such as Pseudomonas , [30] rat, [31] [32] [33] cow, [34] guinea pig [35] and human. [36] Recombinant human γ-butyrobetaine hydroxylase has also been produced by Escherichia coli [27] and baculoviruses [26] systems.

Scheme describing the biosynthetic pathway of L-carnitine in humans. CarnitineBiosynthesis.png
Scheme describing the biosynthetic pathway of L-carnitine in humans.

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References

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  7. ↑ Lindstedt, G.; Lindstedt, S.; Midtvedt, T.; Tofft, M. The formation and degradation of carnitine in Pseudomonas. Biochemistry1967, 6, 1262–1270.
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  11. ↑ Vaz, F. M.; Ofman, R.; Westinga, K.; Back, J. W.; Wanders, R. J. A. Molecular and biochemical characterization of rat ε-N-trimethyllysine hydroxylase, the first enzyme of carnitine biosynthesis. J. Biol. Chem.2001, 276, 33512–33517.
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  15. ↑ Khan-Siddiqui, L.; Bamji, M. S. Lysine-carnitine conversion in normal and undernourished adult man – suggestion of a nonpeptidyl pathway. Am. J. Clin. Nutr.1983, 37, 93–98.
  16. ↑ Rebouche, C. J.; Broquist, H. P. Carnitine biosynthesis in Neurospora crassa: enzymatic conversion of lysine to ε-N-trimethyllysine. J. Bacteriol.1976, 126, 1207–1214.
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  27. 1 2 Tars, K.; Rumnieks, J.; Zeltins, A.; Kazaks, A.; Kotelovica, S.; Leonciks, A.; Saripo, J.; Viksna, A.; Kuka, J.; Liepinsh, E.; Dambrova, M. Crystal structure of human gamma-butyrobetaine hydroxylase. Biochem. Biophys. Res. Commun.2010, 298, 634–639.
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