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Carnitine

Clinical data
AHFS/Drugs.com	Micromedex Detailed Consumer Information
Routes of administration	Oral, intravenous
ATC code	A16AA01 (WHO) (L form)
Legal status
Legal status	US: OTC
Pharmacokinetic data
Bioavailability	<10%
Protein binding	None
Metabolism	slightly
Excretion	Urine (>95%)
Identifiers
IUPAC name 3-Hydroxy-4-(trimethylazaniumyl)butanoate
CAS Number	541-15-1
PubChem CID	288
DrugBank	DB00583
ChemSpider	282
UNII	0G389FZZ9M
KEGG	C00318
ChEBI	CHEBI:17126
ChEMBL	ChEMBL172513
CompTox Dashboard (EPA)	DTXSID3022744
ECHA InfoCard	100.006.343
Chemical and physical data
Formula	C7H15NO3
Molar mass	161.199 g/mol g·mol
3D model (JSmol)	Interactive image
SMILES C(C)(C)CC(CC(=O))O
InChI InChI=1S/C7H15NO3/c1-8(2,3)5-6(9)4-7(10)11/h6,9H,4-5H2,1-3H3 Key:PHIQHXFUZVPYII-UHFFFAOYSA-N
(what is this?)  (verify)

Carnitine (β-hydroxy-γ-N-trimethylaminobutyric acid, 3-hydroxy-4-N,N,N-trimethylaminobutyrate) is a quaternary ammonium compound involved in metabolism in most mammals, plants, and some bacteria. Carnitine exists as one of two stereoisomers (the two enantiomers d-carnitine and l-carnitine). Both are biologically active but only l-carnitine naturally occurs in animals and d-carnitine is toxic as it inhibits the activity of the l-form. At room temperature, pure carnitine is a white powder, and a water-soluble zwitterion with low toxicity. Carnitine, derived from an amino acid, is found in nearly all organisms and animal tissue. Carnitine is the generic expression for a number of compounds that include l-carnitine, acetyl-l-carnitine, and propionyl-l-carnitine. It is most accumulated in cardiac and skeletal muscles as it accounts for 0.1% of its dry matter. It was first derived from meat extracts in 1905, therefore the name carnitine is derived from Latin "carnus" or flesh. The body synthesizes enough carnitine from lysine side chains to keep up with the needs of energy production in the body as carnitine acts as a transporter of long-chain fatty acids into the mitochondria to be oxidized and produce energy. Some individuals with genetic or medical disorders (such as preterm infants) cannot make enough, so this makes carnitine a conditionally essential nutrient for them.

Biosynthesis and metabolism

Many eukaryotes have the ability to synthesize carnitine, including humans. Humans synthesize carnitine from the substrate TML (6-N-trimethyllysine), which is in turn derived from the methylation of the amino acid lysine. TML is then hydroxylated into hydroxytrimethyllysine (HTML) by trimethyllysine dioxygenase, requiring the presence of ascorbic acid and iron. HTML is then cleaved by HTML aldolase (a pyridoxal phosphate requiring enzyme), yielding 4-trimethylaminobutyraldehyde (TMABA) and glycine. TMABA is then dehydrogenated into gamma-butyrobetaine in an NAD-dependent reaction, catalyzed by TMABA dehydrogenase. Gamma-butyrobetaine is then hydroxylated by gamma butyrobetaine hydroxylase (a zinc binding enzyme) into L-carnitine, requiring iron in the form of Fe.

Carnitine is involved in transporting fatty acids across the mitochondrial membrane, by forming a long chain acetylcarnitine ester and being transported by carnitine palmitoyltransferase I and carnitine palmitoyltransferase II. Carnitine also plays a role in stabilizing Acetyl-CoA and coenzyme A levels through the ability to receive or give an acetyl group.

Tissue distribution of carnitine-biosynthetic enzymes

Rebouche and Engel had investigated the tissue distribution of carnitine-biosynthetic enzymes in humans. They found TMLD to be active in the liver, heart, muscle, brain and highest in kidney. HTMLA activity is found primarily in the liver. The rate of TMABA oxidation is greatest in the liver, with considerable activity also found in the kidney, however is low in brain, heart and muscle. These results indicate that all the investigated tissues have the ability to convert TML into butyrobetaine through containing the required enzymes for it but not all of them can convert butyrobetaine into carnitine, only the kidney, liver and brain are capable of that.

Carnitine shuttle: Activation and transportation of fatty acids into the mitochondria

The free-floating fatty acids, released from adipose tissues to the blood, bind to carrier protein molecule known as serum albumin that carry the fatty acids to the cytoplasm of target cells such as the heart, skeletal muscle, and other tissue cells, where they are used for fuel. But before the target cells can use the fatty acids for ATP production and β oxidation, the fatty acids with chain lengths of 14 or more carbons must be activated and subsequently transported into mitochondrial matrix of the cells in three enzymatic reactions of the carnitine shuttle.

The first reaction of the carnitine shuttle is a two-step process catalyzed by a family of isozymes of acyl-CoA synthetase that are found in the outer mitochondrial membrane, where they promote the activation of fatty acids by forming a thioester bond between the fatty acid carboxyl group and the thiol group of coenzyme A to yield a fatty acyl–CoA.

In the first step of the reaction, acyl-CoA synthetase catalyzes the transfer of adenosine monophosphate group (AMP) from an ATP molecule onto the fatty acid generating a fatty acyl–adenylate intermediate and a pyrophosphate group (PP_i). The pyrophosphate, formed from the hydrolysis of the two high-energy bonds in ATP, is immediately hydrolyzed to two molecule of P_i by inorganic pyro phosphatase. This reaction is highly exergonic which drives the activation reaction forward and makes it more favorable. In the second step, the thiol group of a cytosolic coenzyme A attacks the acyl-adenylate, displacing AMP to form thioester fatty acyl-CoA.

In the second reaction, the activated fatty acids that are intended for mitochondrial oxidation are transported into the matrix by a carrier protein, but first the acyl-CoA must be transiently attached to the hydroxyl group of carnitine to form fatty acyl–carnitine. This transesterification is catalyzed by an enzyme found in the outer membrane of the mitochondria known as carnitine acyltransferase 1 (also called carnitine palmitoyltransferase 1, CPT1).

The fatty acyl–carnitine ester formed then diffuses across the intermembrane space of the mitochondria and enters the matrix by passive transport through the acyl-carnitine/carnitine cotransporter that is found in inner mitochondrial membrane. This cotransporter return one molecule of carnitine from the matrix to the intermembrane space as one molecule of fatty acyl– carnitine moves into the matrix.

In the third and final reaction of the carnitine shuttle, the fatty acyl group is transferred back from fatty acyl-carnitine in the matrix to intramitochondrial coenzyme A regenerating fatty acyl–CoA and a free carnitine molecule. This reaction is catalyzed by carnitine acyltransferase 2 (also called CPT2), which is placed on the inner face of the inner mitochondrial membrane. The carnitine molecule formed is then shuttled back into the intermembrane space by the same cotransporter while the fatty acyl-CoA is oxidized and used for ATP production.

Regulation of fatty acid β oxidation

The carnitine-mediated entry process is a rate-limiting factor for fatty acid oxidation and is an important point of regulation.

Inhibition

The liver starts actively making triglycerides from excess glucose when it is supplied with glucose that cannot be oxidized or stored as glycogen. This increases the concentration of malonyl-CoA, the first intermediate in fatty acid synthesis, leading to the inhibition of carnitine acyltransferase 1, thereby preventing fatty acid entry into the mitochondrial matrix for β oxidation. This inhibition prevents fatty acid breakdown while synthesis is happening.

Activation

Carnitine activation occurs due to a need for fatty acid oxidation which is required for energy production. During vigorous muscle contraction or during fasting, ATP concentration decrease and AMP concentration increase which leads to the activation of AMP-activated protein kinase (AMPK). AMPK phosphorylates acetyl-CoA carboxylase which catalyzes malonyl-CoA synthesis. This phosphorylation inhibits the acetyl-CoA carboxylase which in turn lowers the concentration of malonyl-CoA and as a result it relieves the inhibition of fatty acyl–carnitine transport into mitochondria, thus allowing β oxidation to replenish the supply of ATP.

Transcription factors

Peroxisome proliferator-activated receptor alpha (PPARα) is a nuclear receptor that functions as a transcription factor. It acts in muscle, adipose tissue, and liver to turn on a set of genes essential for fatty acid oxidation, including the fatty acid transporters carnitine acyltransferases 1 and 2, the fatty acyl–CoA dehydrogenases for short, medium, long, and very long acyl chains, and related enzymes.

PPARα functions as a transcription factor in two cases; as mentioned before when there is an increased demand for energy from fat catabolism, such as during a fast between meals or long-term starvation. Besides that, the transition from fetal to neonatal metabolism in the heart. In the fetus, fuel sources in heart muscle are glucose and lactate, but in the neonatal heart, fatty acids are the main fuel which require the PPARα to be activated so it is able in turn to activate the genes essential for fatty acid metabolism in this stage.

Metabolic defects of fatty acids oxidation

More than 20 human genetic defects in fatty acid transport or oxidation have been approved. In case of Fatty acid oxidation defects, acyl-carnitines accumulate in mitochondria and are transferred into the cytosol, and then into the blood. Plasma levels of acyl-carnitine in new born infants can be detected in a small blood sample by tandem mass spectrometry.

When β oxidation is defective because of either mutation or deficiency in carnitine, the ω Oxidation of Fatty Acids becomes more important in mammals. Actually, the ω Oxidation of Fatty Acids is another pathway for F-A degradation in some species of vertebrates and mammals that occurs in the endoplasmic reticulum of liver and kidney, it is the oxidation of the ω (omega) carbon—the carbon most far from the carboxyl group (in contrast to ${\displaystyle \beta }$ oxidation which occurs at the carboxyl end of fatty acid, in the mitochondria).

Physiological effects

Deficiency

There are two types of carnitine deficiency, primary and secondary carnitine deficiency. Under these circumstances there is a specific and scientific value of carnitine intake. Primary carnitine deficiency is a genetic disorder of the cellular carnitine-transporter system that typically appears by the age of five with symptoms of cardiomyopathy, skeletal-muscle weakness, and hypoglycemia. Secondary carnitine deficiencies may happen as the result of certain disorders such as chronic renal failure, or under conditions that reduce carnitine absorption or increase its excretion, for example taking antibiotics, malnutrition, and poor absorption.

Supplementation

Some research has been successfully carried out on carnitine supplementation in athletes, given its role in fatty acid metabolism; however, individual responses varied significantly in the 300 people involved in one study. Carnitine has been studied in various cardiometabolic conditions, with a bit of evidence pointing towards efficacy as an adjunct in heart disease and diabetes. However, there are insufficient trials to determine its efficacy. Carnitine has no effect on preventing mortality associated with cardiovascular conditions. Carnitine has no effect on serum lipids, except a possible lowering of LDL. Carnitine has no effect on most parameters in end stage kidney disease, however it possibly has an effect on c-reactive protein. The effects on mortality and disease outcome are unknown.

Male infertility

The carnitine content of seminal fluid is directly related to sperm count and motility, suggesting that the compound might be of value in treating male infertility. One study concluded that carnitine supplementation may improve sperm quality, and the reported benefits may relate to increased mitochondrial fatty-acid oxidation (providing more energy for sperm) and reduced cell death in the testes of mice subjected to physical stress to the testes.

Cardiovascular and peripheral arterial diseases

Several studies have approved the effectiveness of supplemental carnitine in the management of cardiac ischemia (restriction of blood flow to the heart) and peripheral arterial disease. In fact, levels of carnitine are low in the failing heart muscle, supplemental amounts might counteract the toxic effects of free fatty acids and improve carbohydrate metabolism. Carnitine has had anti-ischemic properties when given orally and by injection.

Atherosclerosis

An important interaction between diet and the intestinal microbiome brings into play additional metabolic factors that aggravate atherosclerosis beyond dietary cholesterol. This may help to explain some benefits of the Mediterranean diet. Work by Robert Koeth et al., from the Cleveland Clinic reported that carnitine from animal flesh (four times as much in red meat as in fish or chicken), as well as phosphatidylcholine from egg yolk, are converted by intestinal bacteria to trimethylamine (the compound that causes uremic breath to smell fishy). Trimethylamine is oxidized in the liver to trimethylamine N-oxide (TMAO), which causes atherosclerosis in animal models. Patients in the top quartile of TMAO had a 2.5-fold increase in the 3-year risk of stroke, death, or myocardial infarction.

A key issue is that vegans who consumed L-carnitine did not produce TMAO because they did not have the intestinal bacteria that produce TMA from carnitine.

Diabetes mellitus type 2

Type 2 diabetes which is marked by insulin resistance may be associated with a defect in fatty acid oxidation in muscle. Several studies suggest that carnitine supplementation may have a beneficial effect on glucose utilization and reduce diabetic neuropathy. However carnitine may also increase overall cardio-metabolic risk.

AIDS and HIV

Generally HIV infected patients accumulate fat in some areas of the body and lose fat in other areas, besides having high blood levels of fats (hyperlipidemia) and insulin resistance which is known as the lipdystrophy syndrome. This syndrome causes a deficiency in l-carnitine which causes defects in fat metabolism in mitochondria. Supplementation with carnitine in HIV-infected individuals may slow the death of lymphocytes, reduce neuropathy and favorably affect blood lipid levels.

End stage renal disease and Hemodialysis

The kidneys contribute to overall homeostasis in the body, including carnitine levels. In the case of renal impairment, urinary elimination of carnitine increasing, endogenous synthesis decreasing, and poor nutrition as a result of disease-induced anorexia can result in carnitine deficiency. Carnitine blood levels and muscle stores can become very low, which may contribute to anemia, muscle weakness, fatigue, altered levels of blood fats, and heart disorders. Some studies have shown that supplementation of high doses of l-carnitine (often injected) may aid in anemia management.

Sources

Carnitine is a chiral molecule, meaning that it exists as two isomers (l-carnitine and d-carnitine), each of which is a mirror image of the other. The form present in the body is l-carnitine, which is also the form present in food. Food sources rich in l-carnitine are animal products such as meat, poultry, fish, and milk. Redder meats tend to have higher levels of l-carnitine. Adults eating diverse diets that contain animal products attain about 60–180 milligrams of carnitine per day. Vegans get noticeably less (about 10–12 milligrams) since their diets lack these carnitine-rich animal-derived foods. Approximately 54% to 86% of dietary carnitine is absorbed in the small intestine and then enters the bloodstream. Even carnitine-poor diets have little effect on the body’s total carnitine content as the kidneys conserve carnitine very efficiently. The carnitine content of several foods is listed in Table 1.

In general omnivorous humans consume 2–12 µmol of carnitine per day per kg of body weight that forms 75% of body carnitine. Humans produce 1.2 µmol per day per kg of body weight of carnitine endogenously which is 25% of body carnitine. Strict vegetarians obtain very little of carnitine from diet (0.1 µmol per day per kg of body weight) as carnitine is mainly found in foods coming from animals. . However this difference of plasma levels of carnitine between omnivorous humans and strict vegetarians is possibly not of any clinical significance.

Recommended intakes of carnitine

In 1989, the Food and Nutrition Board (FNB) concluded that carnitine wasn't an essential nutrient as healthy human liver and kidneys synthesize sufficient quantities of carnitine from lysine and methionine to meet up with daily body requirements without the need of consuming it from supplements or food. Also, the FNB has not established Dietary Reference Intakes (DRIs) for carnitine.

Supplemental sources of carnitine

l-carnitine, acetyl-l-carnitine, and propionyl-l-carnitine are available in nutraceutical dietary supplement pills or powders. It is also a drug approved by the Food and Drug Administration to treat primary and certain secondary carnitine-deficiency syndromes.

Carnitine and medication interactions

1. Carnitine interacts with pivalate-conjugated antibiotics such as pivampicillin. Chronic administration of these antibiotics increases the excretion of pivaloyl-carnitine, which can lead to carnitine depletion.

2. Treatment with the anticonvulsants valproic acid, phenobarbital, phenytoin, or carbamazepine significantly reduces blood levels of carnitine. In addition, the use of valproic acid may cause hepatotoxicity. (l-carnitine administration may help treat valproic acid toxicity in children and adults.)

History

Levocarnitine was approved by the U.S. Food and Drug Administration as a new molecular entity under the brand name Carnitor on December 27, 1985.

See also

• Acetylcarnitine
• Gamma-butyrobetaine dioxygenase
• Glycine Propionyl-l-Carnitine (GPLC)
• Meldonium
• Systemic primary carnitine deficiency

References

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35. FDA approval letter

Further reading

• Stanley, Charles A.; Bennett, Michael J.; Longo, Nicolo (2000). "Plasma Membrane Carnitine Transport Defect". In Scriver, C.W.; Beaudet, A.L.; Sly, W.S.; Valle, D. (eds.). Metabolic and Molecular Bases of Inherited Disease (8th ed.). New York, NY, USA: McGraw Hill. doi:10.1036/ommbid.297. ISBN 978-0-07-913035-8. Retrieved 22 January 2016.
• Steiber A, Kerner J, Hoppel CL (2004). "Carnitine: a nutritional, biosynthetic, and functional perspective". Molecular Aspects of Medicine. 25 (5–6): 455–73. doi:10.1016/j.mam.2004.06.006. PMID 15363636.
• Marcovina SM, Sirtori C, Peracino A, Gheorghiade M, Borum P, Remuzzi G, Ardehali H (February 2013). "Translating the basic knowledge of mitochondrial functions to metabolic therapy: role of l-carnitine". Translational Research. 161 (2): 73–84. doi:10.1016/j.trsl.2012.10.006. PMC 3590819. PMID 23138103. {{cite journal}}: templatestyles stripmarker in |title= at position 90 (help)
• Johri AM, Heyland DK, Hétu MF, Crawford B, Spence JD (August 2014). "Carnitine therapy for the treatment of metabolic syndrome and cardiovascular disease: evidence and controversies" (print, online review). Nutrition, Metabolism, and Cardiovascular Diseases. 24 (8): 808–14. doi:10.1016/j.numecd.2014.03.007. PMID 24837277. Retrieved 22 January 2016. {{cite journal}}: Unknown parameter |last-author-amp= ignored (|name-list-style= suggested) (help)
• Dambrova M, Liepinsh E (February 2015). "Risks and benefits of carnitine supplementation in diabetes". Experimental and Clinical Endocrinology & Diabetes. 123 (2): 95–100. doi:10.1055/s-0034-1390481. PMID 25343268.
• Brown JM, Hazen SL (2015). "The gut microbial endocrine organ: bacterially derived signals driving cardiometabolic diseases". Annual Review of Medicine. 66: 343–59. doi:10.1146/annurev-med-060513-093205. PMC 4456003. PMID 25587655.

External links

• National Institutes of Health fact sheet on carnitine
• Molecule of the Month at University of Bristol

• Beta hydroxy acids
• Quaternary ammonium compounds
• Dietary supplements
• Amino acids