Biosynthesis and Metabolism of Carnitine

Carnitine is a quaternary ammonium compound involved in the metabolism of most mammals, plants and some bacteria.To support energy metabolism, carnitine transports long-chain fatty acids to the mitochondria to be oxidized for energy production and participates in the removal of metabolites from cells. Given its critical metabolic role,carnitine is concentrated in tissues such as skeletal and cardiac muscle,which metabolize fatty acids into energy sources.In general, individuals,including strict vegetarians,synthesize adequate levels of L-carnitine in their bodies.Carnitine exists as one of two stereoisomers (two enantiomers D-carnitine (S-(+)-) and L-carnitine (R-(−)-)).Both are biologically active,but only L-carnitine occurs naturally in animals,while D-carnitine is toxic because it inhibits the activity of L-carnitine. At room temperature,pure carnitine is a white powder,which is a water-soluble zwitterion with low toxicity.Derived from the amino acid,carnitine was first extracted from meat extracts in 1905,hence its name from the Latin,"caro/carnis" or meat.Some people with genetic or medical conditions (such as premature babies) do not make enough carnitine and need dietary supplements.Although it is commonly consumed by athletes to improve athletic performance or recovery, there is insufficient high-quality clinical evidence that it provides any benefit.

Biosynthesis and Metabolism

Many eukaryotes have the ability to synthesize carnitine,including humans.Humans synthesize carnitine from the substrate TML (6-N-trimethyllysine),which in turn is derived from the methylation of the amino acid lysine.TML is then hydroxylated to hydroxytrimethyllysine (HTML) by trimethyllysine dioxygenase (TMLD),requiring the presence of ascorbic acid and iron.HTML is then cleaved by HTML aldolase,an enzyme that requires pyridoxal phosphate,to produce 4-trimethylaminobutyraldehyde (TMABA) and glycine.TMABA is then dehydrogenated to γ-butylbetaine in an NAD+-dependent reaction,catalyzed by TMABA dehydrogenase.Then, γ-butylbetaine is hydroxylated to L-carnitine by γ-butylbetaine hydroxylase, a zinc-binding enzyme[8], requiring iron in the form of Fe2+.Carnitine is involved in the transport of fatty acids across the mitochondrial membrane by forming long-chain acetylcarnitine esters and transported bycarnitine palmitoyltransferase I and carnitine palmitoyltransferase II.Carnitine also plays a role in stabilizing acetyl-CoA and CoA levels through its ability to accept or donate acetyl groups.

Tissue distribution of carnitine biosynthetic enzymes

Tissue distribution of carnitine biosynthetic enzymes in humans shows that TMLD is most active in liver,heart,muscle,brain and kidney.HTMLA activity is primarily found in the liver.TMABA oxidation rates are highest in the liver and also have considerable activity in the kidneys.

L-carnitine

Glycine Propionyl-L-Carnitine (GPLC) is the propionyl ester of carnitine,including an additional glycine component.Due to tissue esterase,GPLC should act as a prodrug and produce glycine,carnitine and propionate in vivo.

Nitric oxide stimulants

Two studies have shown that GPLC causes increased levels of nitrate/nitrite (surrogate markers of nitric oxide;not a direct measure of nitric oxide) in the blood when used at a daily dose of 4.5 grams.In one study,GPLC was given to previously sedentary men and women who were also assigned to supervised aerobic exercise for eight weeks.Compared with placebo (in a double-blind design),subjects receiving GPLC had significantly increased resting levels of nitrate/nitrite in blood.Subjects treated with GPLC also noted lower levels of malondialdehyde,a biomarker of lipid peroxidation that indicates free radical-mediated lipid oxidation.Increased free radical production may be linked to impaired nitric oxide bioavailability.In another study, GPLC or placebo were given to resistance-trained men for four weeks at a time,with a two-week washout period in between,in a double-blind design.At the end of every 4 weeks,resting blood samples were taken in addition to the post-isometric exercise blood samples,and the patients treated with GPLC showed a significant increase in plasma nitrate/nitrite. This increase in nitrate/nitrite may be related to increased blood flow during acute exercise.

Antioxidant

In addition to regular exercise,nutritional antioxidants can also fight the formation of free radicals-as reported by GPLC.In this study,subjects took GPLC orally at a dose of 1.5 or 4.5 grams per day during an eight-week intervention period.Post-intervention levels of malondialdehyde,a marker of lipid peroxidation,were reduced at both doses compared to pre-intervention values.This was not the case for the subjects who received the placebo.These findings highlight the remarkable antioxidant properties of GPLC.Additional work using GPLC against resistance exercise-induced lipid peroxidation also noted favorable findings (unpublished data). Although many athletes now use GPLC as an integral part of their dietary supplement regimen.Propionyl-L-carnitine has potent antioxidant properties.