Carnitine

The primary biological functions of carnitine in humans include the following: • fatty acid transport across the mitochondrial membrane by forming long-chain acylcarnitine esters which are shuttled into the mitochondria, where they undergo β-oxidation to produce ATP, the cell's main energy currency; • acetyl-CoA and coenzyme A stabilization by transferring acetyl groups for maintaining metabolic flexibility and energy production, particularly during fasting or exercise; • detoxification of acyl groups by forming acylcarnitine, which is then excreted to prevent the accumulation of potentially toxic fatty acyl intermediates; • regulation of cellular metabolism by participating in the conversion and utilization of different fuel sources, enabling cells to switch between carbohydrate and fatty acid metabolism as needed; • antioxidant action to protect cells from oxidative stress (caused by free radical toxicity) and damage. == Biochemistry ==

Chemical properties Carnitine is a zwitterion, meaning it has both positive and negative charges in its structure. In an aqueous solution, L-carnitine is freely soluble and its ionizable groups, COO− and N+(CH3)3, are over 90% dissociated at physiological pH (~7.4) for humans. Biosynthesis and metabolism Physiological effects in humans As an example of normal biosynthesis of carnitine in humans, a person would produce 11–34 mg of carnitine per day.) into -carnitine, requiring iron in the form of Fe2+. Fatty acid transport Carnitine is involved in transporting fatty acids across the mitochondrial membrane, by forming a long chain acylcarnitine ester and being transported by carnitine palmitoyltransferase I and carnitine palmitoyltransferase II. Acetyl-CoA stabilization Carnitine plays a role in stabilizing acetyl-CoA and coenzyme A levels through the ability to receive or give an acetyl group. 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 (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 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 through carnitine-acylcarnitine translocase (CACT) located on the inner mitochondrial membrane. This antiporter 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. Regulation of fatty acid β oxidation Balance 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 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, 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. 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 the heart muscle are glucose and lactate, but in the neonatal heart, fatty acids are the main fuel that 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 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. 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 farthest from the carboxyl group (in contrast to \beta oxidation which occurs at the carboxyl end of fatty acid, in the mitochondria). ==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 showed no signs of carnitine deficiency. Infants, especially premature infants, have low stores of carnitine, necessitating use of carnitine-fortified infant formulas as a replacement for breast milk, 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 antibiotics, malnutrition, and poor absorption following digestion. ==Supplementation==

Pharmacokinetics The plasma half-life of L-carnitine taken as a supplementation is approximately 17.4 hours. and facilitate recovery after such performance, but their results are inconclusive, since various studies used various regimens of carnitine supplementation and intensity of exercise. At supplement amounts of per day over a month, there was no consistent evidence that carnitine affected exercise or physical performance on moderate-intensity exercises, whereas on high-intensity exercises results were mixed. There is no evidence that L-carnitine influences fat metabolism 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. 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, there is insufficient research to determine its overall efficacy in lowering the risk or treating cardiovascular diseases. 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 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 ==

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. Treatment with the anticonvulsants 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 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 under the brand name Carnitor on December 27, 1985. == See also ==