acylcarnitine
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Carnitine is a
quaternary ammonium compound In chemistry, quaternary ammonium cations, also known as quats, are positively charged polyatomic ions of the structure , R being an alkyl group or an aryl group. Unlike the ammonium ion () and the primary, secondary, or tertiary ammonium catio ...
involved in
metabolism Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...
in most mammals, plants, and some bacteria. In support of energy metabolism, carnitine transports long-chain fatty acids into
mitochondria A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...
to be
oxidized Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a d ...
for energy production, and also participates in removing products of metabolism from cells. Given its key metabolic roles, carnitine is concentrated in tissues like
skeletal A skeleton is the structural frame that supports the body of an animal. There are several types of skeletons, including the exoskeleton, which is the stable outer shell of an organism, the endoskeleton, which forms the support structure inside ...
and
cardiac muscle Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle th ...
that metabolize fatty acids as an energy source. Generally individuals, including strict vegetarians, synthesize enough L-carnitine
in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...
. Carnitine exists as one of two stereoisomers (the two
enantiomer In chemistry, an enantiomer ( /ɪˈnænti.əmər, ɛ-, -oʊ-/ ''ih-NAN-tee-ə-mər''; from Ancient Greek ἐνάντιος ''(enántios)'' 'opposite', and μέρος ''(méros)'' 'part') – also called optical isomer, antipode, or optical ant ...
s -carnitine (''S''-(+)-) and -carnitine (''R''-(−)-)). Both are biologically active, but only -carnitine naturally occurs in animals, and -carnitine is toxic as it inhibits the activity of the -form. At room temperature, pure carnitine is a whiteish powder, and a water-soluble zwitterion with relatively low toxicity. Derived from amino acids, carnitine was first
extracted ''Extracted'', also known as ''Extraction'' in the UK, is an independent 2012 American science fiction thriller directed and written by Nir Paniry. Sasha Roiz stars as a scientist whose consciousness becomes trapped in the mind of a convict (Dom ...
from meat extracts in 1905, leading to its name from Latin, "''caro/carnis''" or flesh. Some individuals with genetic or medical disorders (such as preterm infants) cannot make enough carnitine, requiring dietary supplementation. Despite common carnitine supplement consumption among
athlete An athlete (also sportsman or sportswoman) is a person who competes in one or more sports that involve physical strength, speed, or endurance. Athletes may be professionals or amateurs. Most professional athletes have particularly well-devel ...
s for improved exercise performance or recovery, there is insufficient high-quality clinical evidence to indicate it provides any benefit.


Biosynthesis and metabolism

Many
eukaryote Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...
s 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 In the chemical sciences, methylation denotes the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These t ...
of the amino acid
lysine Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. It contains an α-amino group (which is in the protonated form under biological conditions), an α-carboxylic acid group (which is in the deprotonated −C ...
. TML is then hydroxylated into hydroxytrimethyllysine (HTML) by
trimethyllysine dioxygenase In enzymology, a trimethyllysine dioxygenase (TMLH; ) is an enzyme that catalyzes the chemical reaction :N6,N6,N6-trimethyl-L-lysine + 2-oxoglutarate + O2 \rightleftharpoons 3-hydroxy-N6,N6,N6-trimethyl-L-lysine + succinate + CO2 TMLH is a memb ...
(TMLD), requiring the presence of
ascorbic acid Vitamin C (also known as ascorbic acid and ascorbate) is a water-soluble vitamin found in citrus and other fruits and vegetables, also sold as a dietary supplement and as a topical 'serum' ingredient to treat melasma (dark pigment spots) an ...
and iron. HTML is then cleaved by HTML aldolase (a pyridoxal phosphate requiring enzyme), yielding 4-trimethylaminobutyraldehyde (TMABA) and glycine. TMABA is then
dehydrogenated In chemistry, dehydrogenation is a chemical reaction that involves the removal of hydrogen, usually from an organic molecule. It is the reverse of hydrogenation. Dehydrogenation is important, both as a useful reaction and a serious problem. At ...
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 -carnitine, requiring iron in the form of Fe2+. 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 O-palmitoyltransferase 2, mitochondrial is an enzyme that in humans is encoded by the ''CPT2'' gene. Function Carnitine palmitoyltransferase II precursor (CPT2) is a mitochondrial membrane protein which is transported to the mitochon ...
. Carnitine also plays a role in stabilizing
Acetyl-CoA Acetyl-CoA (acetyl coenzyme A) is a molecule that participates in many biochemical reactions in protein, carbohydrate and lipid metabolism. Its main function is to deliver the acetyl group to the citric acid cycle (Krebs cycle) to be oxidized for ...
and
coenzyme A Coenzyme A (CoA, SHCoA, CoASH) is a coenzyme, notable for its role in the synthesis and oxidation of fatty acids, and the oxidation of pyruvate in the citric acid cycle. All genomes sequenced to date encode enzymes that use coenzyme A as a subs ...
levels through the ability to receive or give an acetyl group.


Tissue distribution of carnitine-biosynthetic enzymes

The tissue distribution of carnitine-biosynthetic enzymes in humans indicates TMLD to be active in the liver, heart, muscle, brain and highest in the kidneys. HTMLA activity is found primarily in the liver. The rate of TMABA oxidation is greatest in the liver, with considerable activity also in the kidneys.


Carnitine shuttle system

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 In organic chemistry, thioesters are organosulfur compounds with the functional group . They are analogous to carboxylate esters () with the sulfur in the thioester playing the role of the linking oxygen in the carboxylate ester, as implied by t ...
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 (PPi). The pyrophosphate, formed from the hydrolysis of the two high-energy bonds in ATP, is immediately hydrolyzed to two molecules of Pi by inorganic pyrophosphatase. 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 Coenzyme A (CoA, SHCoA, CoASH) is a coenzyme, notable for its role in the synthesis and oxidation of fatty acids, and the oxidation of pyruvate in the citric acid cycle. All genomes sequenced to date encode enzymes that use coenzyme A as a subs ...
attacks the acyl-adenylate, displacing AMP to form thioester fatty acyl-CoA. In the second reaction, acyl-CoA is transiently attached to the hydroxyl group of carnitine to form fatty acylcarnitine. 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 acylcarnitine ester formed then diffuses across the intermembrane space and enters the matrix by
facilitated diffusion Facilitated diffusion (also known as facilitated transport or passive-mediated transport) is the process of spontaneous passive transport (as opposed to active transport) of molecules or ions across a biological membrane via specific transmembra ...
through carnitine-acylcarnitine translocase (CACT) located on the inner mitochondrial membrane. This
antiporter An antiporter (also called exchanger or counter-transporter) is a cotransporter and integral membrane protein involved in secondary active transport of two or more different molecules or ions across a phospholipid membrane such as the plasma memb ...
returns one molecule of carnitine from the matrix to the intermembrane space for every one molecule of fatty acyl–carnitine that moves into the matrix. In the third and final reaction of the carnitine shuttle, the fatty acyl group is transferred from fatty acyl-carnitine to coenzyme A, regenerating fatty acyl–CoA and a free carnitine molecule. This reaction takes place in the mitochondrial matrix and is catalyzed by carnitine acyltransferase 2 (also called carnitine palmitoyltransferase 2, CPT2), which is located 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 (CACT) while the fatty acyl-CoA enters
β-oxidation In biochemistry and metabolism, beta-oxidation is the catabolic process by which fatty acid molecules are broken down in the cytosol in prokaryotes and in the mitochondria in eukaryotes to generate acetyl-CoA, which enters the citric acid cycle, ...
.


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 Malonyl-CoA is a coenzyme A derivative of malonic acid. Functions It plays a key role in chain elongation in fatty acid biosynthesis and polyketide biosynthesis. Fatty acid biosynthesis Malonyl-CoA provides 2-carbon units to fatty acids and commi ...
, 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 occurs.


Activation

Carnitine shuttle 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 decreases and AMP concentration increases leading to the activation of AMP-activated protein kinase (AMPK). AMPK phosphorylates
acetyl-CoA carboxylase Acetyl-CoA carboxylase (ACC) is a biotin-dependent enzyme () that catalyzes the irreversible carboxylation of acetyl-CoA to produce malonyl-CoA through its two catalytic activities, biotin carboxylase (BC) and carboxyltransferase (CT). ACC is ...
, which normally catalyzes malonyl-CoA synthesis. This phosphorylation inhibits acetyl-CoA carboxylase, which in turn lowers the concentration of malonyl-CoA. Lower levels of malonyl-CoA disinhibit carnitine acyltransferase 1, allowing fatty acid import to the mitochondria, ultimately replenishing the supply of
ATP ATP may refer to: Companies and organizations * Association of Tennis Professionals, men's professional tennis governing body * American Technical Publishers, employee-owned publishing company * ', a Danish pension * Armenia Tree Project, non ...
.


Transcription factors

Peroxisome proliferator-activated receptor alpha (PPAR''α'') 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. PPAR''α'' 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 the heart muscle are glucose and lactate, but in the neonatal heart, fatty acids are the main fuel that require the PPAR''α'' 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 acid oxidation

More than 20 human genetic defects in fatty acid transport or oxidation have been identified. 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 acylcarnitine in newborn 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 (omega) 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 the liver and kidney, it is the oxidation of the ω carbon—the carbon most far from the carboxyl group (in contrast to \beta oxidation which occurs at the carboxyl end of fatty acid, in the mitochondria).


Physiological effects

As an example of normal synthesis, a person would produce 11–34 mg of carnitine per day. Adults eating mixed diets of red meat and other
animal product An animal product is any material derived from the body of an animal. Examples are fat, flesh, blood, milk, eggs, and lesser known products, such as isinglass and rennet. Animal by-products, as defined by the USDA, are products harvested or man ...
s ingest some 60–180 mg of carnitine per day, while vegans consume about 10–12 mg per day. Most (54–86%) carnitine obtained from the diet is absorbed in the
small intestine The small intestine or small bowel is an organ in the gastrointestinal tract where most of the absorption of nutrients from food takes place. It lies between the stomach and large intestine, and receives bile and pancreatic juice through the p ...
before entering the blood. The total body content of carnitine is about in a person weighing , with nearly all of it contained within skeletal muscle cells. Carnitine metabolizes at rates of about 400 μmol (65mg) per day, an amount less than 1% of total body stores.


Deficiency

Carnitine deficiency is rare in healthy people without metabolic disorders, indicating that most people have normal, adequate levels of carnitine normally produced through fatty acid metabolism. One study found that
vegans Veganism is the practice of abstaining from the use of animal product—particularly in diet (nutrition), diet—and an associated philosophy that rejects the commodity status of animals. An individual who follows the diet or philosophy is kn ...
showed no signs of carnitine deficiency. Infants, especially
premature infants Preterm birth, also known as premature birth, is the birth of a baby at fewer than 37 weeks gestational age, as opposed to full-term delivery at approximately 40 weeks. Extreme preterm is less than 28 weeks, very early preterm birth is between 2 ...
, have low stores of carnitine, necessitating use of carnitine-fortified infant formulas as a replacement for
breast milk Breast milk (sometimes spelled as breastmilk) or mother's milk is milk produced by mammary glands located in the breast of a human female. Breast milk is the primary source of nutrition for newborns, containing fat, protein, carbohydrates ( lacto ...
, if necessary. Two types of carnitine deficiency states exist. 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 kidney failure, or under conditions that reduce carnitine absorption or increase its excretion, such as the use of
antibiotic An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention of ...
s, malnutrition, and poor absorption following digestion.


Supplementation

Despite widespread interest among athletes to use carnitine for improvement of exercise performance, inhibit muscle cramps, or enhance recovery from physical training, the quality of research for these possible benefits has been low, prohibiting any conclusion of effect. At supplement amounts of per day over a month, there was no consistent evidence that carnitine affected exercise or physical performance. Carnitine supplements do not improve oxygen consumption or metabolic functions when exercising, nor do they increase the amount of carnitine in muscle. There is no evidence that L-carnitine influences
fat metabolism Lipid metabolism is the synthesis and degradation of lipids in cells, involving the breakdown or storage of fats for energy and the synthesis of structural and functional lipids, such as those involved in the construction of cell membranes. In anim ...
or aids in weight loss.


Male fertility

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.


Diseases

Carnitine has been studied in various cardiometabolic conditions, indicating it is under preliminary research for its potential as an adjunct in
heart disease Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, hea ...
and diabetes, among numerous other disorders. Carnitine has no effect on preventing all-cause mortality associated with cardiovascular diseases, and has no significant effect on blood lipids. Although there is some evidence from meta-analyses that L-carnitine supplementation improved cardiac function in people with
heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, a ...
, there is insufficient research to determine its overall efficacy in lowering the risk or treating
cardiovascular disease Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, h ...
s. There is only preliminary clinical research to indicate the use of L-carnitine supplementation for improving symptoms of type 2 diabetes, such as improving
glucose tolerance Prediabetes is a component of the metabolic syndrome and is characterized by elevated blood sugar levels that fall below the threshold to diagnose diabetes mellitus. It usually does not cause symptoms but people with prediabetes often have obesit ...
or lowering fasting levels of blood glucose. 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 has no effect on most parameters in end-stage kidney disease, although it may lower C-reactive protein, a biomarker for systemic inflammation. Carnitine blood levels and muscle stores can become 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 -carnitine (often injected) may aid in anemia management.


Sources

The form present in the body is -carnitine, which is also the form present in food. Food sources rich in -carnitine are animal products, particularly beef and pork. Red meats tend to have higher levels of -carnitine. Adults eating diverse diets that contain animal products attain about 23-135 mg of carnitine per day. Vegans get noticeably less (about 10–12 mg) since their diets lack these carnitine-rich animal-derived foods. Approximately 54% to 86% of dietary carnitine is absorbed in the small intestine, then enters the blood. Even carnitine-poor diets have little effect on total carnitine content, as the kidneys conserve carnitine. In general, omnivorous humans each day consume between 2 and 12  µmol kg−1 of body weight, accounting for 75% of carnitine in the body. Humans endogenously produce 1.2 µmol kg−1 of body weight of carnitine on a daily basis, accounting for 25% of the carnitine in the body. Strict vegetarians obtain little carnitine from dietary sources (0.1 µmol kg−1 of body weight daily), as it is mainly found in animal-derived foods. L-Carnitine, acetyl--carnitine, and propionyl--carnitine are available in
dietary supplement A dietary supplement is a manufactured product intended to supplement one's diet by taking a pill, capsule, tablet, powder, or liquid. A supplement can provide nutrients either extracted from food sources or that are synthetic in order ...
pills or powders, with a daily amount of 0.5 to 1 g considered to be safe. It is also a drug approved by the Food and Drug Administration to treat primary and certain secondary carnitine-deficiency syndromes secondary to
inherited diseases A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders ...
.


Drug interactions and adverse effects

Carnitine interacts with
pivalate Pivalic acid is a carboxylic acid with a molecular formula of (CH3)3CCO2H. This colourless, odiferous organic compound is solid at room temperature. A common abbreviation for the pivalyl or pivaloyl group (''t''-BuC(O)) is Piv and for pivalic acid ...
-conjugated antibiotics such as
pivampicillin Pivampicillin is a pivaloyloxymethyl ester of ampicillin. It is a prodrug, which is thought to enhance the oral bioavailability of ampicillin because of its greater lipophilicity compared to that of ampicillin. Adverse effects Prodrugs that relea ...
. Chronic administration of these antibiotics increases the excretion of pivaloyl-carnitine, which can lead to carnitine depletion. Treatment with the
anticonvulsant Anticonvulsants (also known as antiepileptic drugs or recently as antiseizure drugs) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of b ...
s valproic acid, phenobarbital, phenytoin, or carbamazepine significantly reduces blood levels of carnitine. When taken in the amount of roughly per day, carnitine may cause nausea, vomiting, abdominal cramps, diarrhea, and
body odor Body odor or body odour (BO) is present in all animals and its intensity can be influenced by many factors (behavioral patterns, survival strategies). Body odor has a strong genetic basis, but can also be strongly influenced by various diseases ...
smelling like fish. Other possible adverse effects include skin rash, muscle weakness, or seizures in people with epilepsy.


History

Levocarnitine was approved by the U.S. Food and Drug Administration as a
new molecular entity A new chemical entity (NCE) is, according to the U.S. Food and Drug Administration, a novel, small, chemical molecule drug that is undergoing clinical trials or has received a first approval (not a new use) by the FDA in any other application submit ...
under the brand name Carnitor on December 27, 1985.


See also

*
Acetylcarnitine Acetyl-L-carnitine, ALCAR or ALC, is an acetylated form of L- carnitine. It is naturally produced by the human body, and it is available as a dietary supplement. Acetylcarnitine is broken down in the blood by plasma esterases to carnitine which ...
* Gamma-butyrobetaine dioxygenase * Glycine Propionyl--Carnitine (GPLC) * Meldonium *
Systemic primary carnitine deficiency Systemic primary carnitine deficiency (SPCD)Systemic primary carnit ...


References

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Beta hydroxy acids Quaternary ammonium compounds Dietary supplements Amino acids