Carnitine

Not to be confused with carnosine or creatine.

Carnitine

200px
200px
Systematic (IUPAC) name
3-Hydroxy-4-(trimethylazaniumyl)butanoate
Clinical data
AHFS/Drugs.com	Micromedex Detailed Consumer Information
Pregnancy category	US: B (No risk in non-human studies)
Legal status	US: OTC
Routes of administration	Oral, intravenous
Pharmacokinetic data
Bioavailability	< 10%
Protein binding	None
Metabolism	slightly
Excretion	Urine (> 95%)
Identifiers
CAS Number	541-15-1 Y
ATC code	A16AA01 (WHO) (L form)
PubChem	CID: 288
DrugBank	DB00583 N
ChemSpider	282 Y
UNII	0G389FZZ9M Y
KEGG	C00318 Y
ChEBI	CHEBI:17126 Y
ChEMBL	CHEMBL172513 Y
Chemical data
Formula	C7H15NO3
Molecular mass	161.199 g/mol
SMILES C[N+](C)(C)CC(CC(=O)[O-])O
InChI InChI=1S/C7H15NO3/c1-8(2,3)5-6(9)4-7(10)11/h6,9H,4-5H2,1-3H3 Y Key:PHIQHXFUZVPYII-UHFFFAOYSA-N Y
NY (what is this?)  (verify)

Carnitine is a quaternary ammonium compound biosynthesized from the amino acids lysine and methionine.

In eukaryotic cells, it is required for the transport of fatty acids from the intermembraneous space in the mitochondria, into the mitochondrial matrix during the breakdown of lipids (fats) for the generation of metabolic energy. It is widely available as a nutritional supplement. Carnitine was originally found as a growth factor for mealworms and labeled vitamin B_T, although carnitine is not a proper vitamin. Carnitine exists in two stereoisomers: its biologically active form is L-carnitine, whereas its enantiomer, D-carnitine, is biologically inactive.

Biometrical calculations

Biosynthesis

Main article: carnitine biosynthesis

In animals, the biosynthesis of carnitine occurs primarily in the liver and kidneys from the amino acids lysine (via trimethyllysine) and methionine. Vitamin C (ascorbic acid) is not essential to the synthesis of carnitine.

Role in fatty acid metabolism

Carnitine transports long-chain acyl groups from fatty acids into the mitochondrial matrix, so they can be broken down through β-oxidation to acetyl CoA to obtain usable energy via the citric acid cycle. In some organisms, such as fungi, the acetate is used in the glyoxylate cycle for gluconeogenesis and formation of carbohydrates. Fatty acids must be activated before being covalently linked to the carnitine molecule to form acylcarnitine for transport. The free fatty acid in the cytosol is first adenylated by reaction with ATP, then attached with a thioester bond to coenzyme A (CoA), with expulsion of AMP. This reaction is catalyzed by the enzyme fatty acyl-CoA synthetase and driven to completion by inorganic pyrophosphatase.

The acyl group on CoA can now be transferred to carnitine and the resulting acylcarnitine transported into the mitochondrial matrix. This occurs via a series of similar steps:

1. Acyl CoA is transferred to the hydroxyl group of carnitine by carnitine acyltransferase I (palmitoyltransferase) located on the outer mitochondrial membrane
2. Acylcarnitine is shuttled inside by a carnitine-acylcarnitine translocase
3. Acylcarnitine is converted to acyl CoA by carnitine acyltransferase II (palmitoyltransferase) located on the inner mitochondrial membrane. The liberated carnitine returns to the cytosol.

Human genetic disorders, such as primary carnitine deficiency, carnitine palmitoyltransferase I deficiency, carnitine palmitoyltransferase II deficiency and carnitine-acylcarnitine translocase deficiency, affect different steps of this process.

Carnitine acyltransferase I and peroxisomal carnitine octanoyl transferase (CROT) undergo allosteric inhibition as a result of malonyl-CoA, an intermediate in fatty acid biosynthesis, to prevent futile cycling between β-oxidation and fatty acid synthesis.

Physiological effects

Atherosclerosis

Main article: Trimethylamine N-oxide

There may be a link between dietary consumption of carnitine and atherosclerosis, but there is also evidence that it lowers the risk of mortality and arrythmias after an acute myocardial infarction.

When certain species of intestinal bacteria were exposed to carnitine from food, they produced a waste product, trimethylamine, which is transformed in the liver to trimethylamine N-oxide (TMAO). TMAO may be associated with atherosclerosis. The presence of large amounts of TMAO-producing bacteria was a consequence of a long-term diet rich in meat. However, when the authors compared the risk of cardiovascular events to the levels of carnitine and TMAO, they found that the risk was higher in those with higher TMAO levels, independent of the carnitine levels.

Vegetarian and vegans who ate a single meal of meat had much lower levels of TMAO in their bloodstream than did regular meat-eaters, as vegetarian and vegans had lower levels of the intestinal bacteria that converts carnitine into TMAO.

Another study has found evidence of a second path for atherogenic activity of carnitine, passing through a different metabolite: γ-butyrobetaine (γBB)

Effects on bone mass

In the course of human aging, carnitine concentration in cells diminishes, affecting fatty acid metabolism in various tissues. Particularly adversely affected are bones, which require continuous reconstructive and metabolic functions of osteoblasts for maintenance of bone mass. A 2008 study found that supplementing with L-carnitine decreased bone turnover and increased bone mineral density in rats.

Effect on thyroid hormone action

A 2004 study found that L-carnitine acts as a peripheral antagonist of thyroid hormone action. In particular, L-carnitine inhibits both triiodothyronine (T3) and thyroxine (T4) entry into the cell nuclei. For this reason, L-carnitine has been proposed as a supplement to treat hyperthyroidism. A 2001 study found that L-carnitine was useful in both reversing and preventing hyperthyroid symptoms.

Possible health effects

Carnitine has been proposed as a supplement to treat a variety of health conditions including heart attack, heart failure, angina, narcolepsy, and diabetic neuropathy, but not improving exercise performance, nor wasting syndrome (weight loss). In all of these cases, both positive and negative findings, the results are preliminary, proposed, and not part of routine treatment.

There is also some suggestion that use of acetyl carnitine and L-arginine may improve sperm motility in men with sperm abnormalities.

Sources

Food

The highest concentrations of carnitine are found in red meat. Carnitine can be found at significantly lower levels in many other foods including nuts and seeds (e.g. pumpkin, sunflower, sesame), legumes or pulses (beans, peas, lentils, peanuts), vegetables (artichokes, asparagus, beet greens (young leaves of the beetroot), broccoli, brussels sprouts, collard greens, garlic, mustard greens, okra, parsley, kale), fruits (apricots, bananas), cereals (buckwheat, corn, millet, oatmeal, rice bran, rye, whole wheat, wheat bran, wheat germ) and other foods (bee pollen, brewer's yeast, carob).

Product	Quantity	Carnitine
Lamb	100 g	190 mg
Beef steak	100 g	95 mg
Ground beef	100 g	94 mg
Pork	100 g	27.7 mg
Bacon	100 g	23.3 mg
Tempeh	100 g	19.5 mg
Cod fish	100 g	5.6 mg
Chicken breast	100 g	3.9 mg
American cheese	100 g	3.7 mg
Ice cream	100 ml	3.7 mg
Whole milk	100 ml	3.3 mg
Avocado	one medium	2 mg
Cottage cheese	100 g	1.1 mg
Whole-wheat bread	100 g	0.36 mg
Asparagus	100 g	0.195 mg
White bread	100 g	0.147 mg
Macaroni	100 g	0.126 mg
Peanut butter	100 g	0.083 mg
Rice (cooked)	100 g	0.0449 mg
Egg	100 g	0.0121 mg
Orange juice	100 ml	0.0019 mg
Lentil	100 g	2.1 mg
Potato	100 g	2.4 mg
Sweet Potato	100 g	1.1 mg
Banana	100 g	0.2 mg
Carrot	100 g	0.3 mg

In general, 20 to 200 mg are ingested per day by those on an omnivorous diet, whereas those on a strict vegetarian or vegan diet may ingest as little as 1 mg/day. However, even strict vegetarians (vegans) show no signs of carnitine deficiency, despite the fact that most dietary carnitine is derived from animal sources. No advantage appears to exist in giving an oral dose greater than 2 g at one time, since absorption studies indicate saturation at this dose.

Health Canada

Other sources may be found in over-the-counter vitamins, energy drinks and various other products. Products containing L-carnitine can now be marketed as "natural health products" in Canada. As of 2012, Parliament has allowed carnitine products and supplements to be imported into Canada (Health Canada). The Canadian government did issue an amendment in December 2011 allowing the sale of L-carnitine without a prescription.

See also

• Acetylcarnitine
• Gamma-butyrobetaine dioxygenase
• Meldonium
• Systemic primary carnitine deficiency

External links

• Molecule of the Month at University of Bristol