Carnitine biosynthesis

Carnitine biosynthesis is a method for the endogenous production of L-carnitine, a molecule that is essential for energy metabolism. In humans and many other animals, L-carnitine is obtained from both diet and by biosynthesis. The carnitine biosynthesis pathway is highly conserved among many eukaryotes and some prokaryotes. Carnitine biosynthesis is a method for the endogenous production of L-carnitine, a molecule that is essential for energy metabolism. In humans and many other animals, L-carnitine is obtained from both diet and by biosynthesis. The carnitine biosynthesis pathway is highly conserved among many eukaryotes and some prokaryotes. L-Carnitine is biosynthesized from Nε-trimethyllysine. 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. 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. 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. 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. 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. 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. High-performance liquid chromatography (HPLC) analysis has confirmed that vegetables contains a significant amount of Nε-trimethyllysine. 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, although whether this is the main catalytic activity of these enzymes remains to be established. The third enzyme of L-carnitine biosynthesis is 4-N-trimethylaminobutyraldehyde dehydrogenase. 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 and Pseudomonas. 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, but the true identity of 4-N-trimethylaminobutyraldehyde dehydrogenase remains to be established. The final step of L-carnitine biosynthesis is γ-butyrobetaine hydroxylase, a zinc binding enzyme. 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.