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 substrate , and around 4% of cellular enzymes use it (or a thioester ) as a substrate. In humans, CoA biosynthesis requires cysteine , pantothenate (vitamin B 5 ), and adenosine triphosphate (ATP).
50-645: Carnitine is a quaternary ammonium compound involved in metabolism in most mammals, plants, and some bacteria. In support of energy metabolism, carnitine transports long-chain fatty acids from the cytosol into mitochondria to be oxidized for free energy production, and also participates in removing products of metabolism from cells. Given its key metabolic roles, carnitine is concentrated in tissues like skeletal and cardiac muscle that metabolize fatty acids as an energy source. Generally individuals, including strict vegetarians , synthesize enough L-carnitine in vivo . Carnitine exists as one of two stereoisomers :
100-399: A thiol , it can react with carboxylic acids to form thioesters , thus functioning as an acyl group carrier. It assists in transferring fatty acids from the cytoplasm to mitochondria . A molecule of coenzyme A carrying an acyl group is also referred to as acyl-CoA . When it is not attached to an acyl group, it is usually referred to as 'CoASH' or 'HSCoA'. This process facilitates
150-419: A 70-kilogram (150 lb) person would produce 11–34 mg of carnitine per day. Adults eating mixed diets of red meat and other animal products 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 before entering the blood. The total body content of carnitine is about 20 grams (0.71 oz) in
200-491: 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 molecules of P i by inorganic pyrophosphatase. This reaction
250-425: 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
300-405: A person weighing 70 kilograms (150 lb), 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. 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
350-402: A primordial prebiotic world. Coenzyme A is produced commercially via extraction from yeast, however this is an inefficient process (yields approximately 25 mg/kg) resulting in an expensive product. Various ways of producing CoA synthetically, or semi-synthetically have been investigated although none are currently operating at an industrial scale. Since coenzyme A is, in chemical terms,
400-513: 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
450-447: A stable molecule in organisms. Acyl carrier proteins (ACP) (such as ACP synthase and ACP degradation) are also used to produce 4′-phosphopantetheine. This pathway allows for 4′-phosphopantetheine to be replenished in the cell and allows for the conversion to coenzyme A through enzymes, PPAT and PPCK. A 2024 article detailed a plausible chemical synthesis mechanism for the pantetheine component (the main functional part) of coenzyme A in
500-428: Is a highly versatile molecule, serving metabolic functions in both the anabolic and catabolic pathways. Acetyl-CoA is utilised in the post-translational regulation and allosteric regulation of pyruvate dehydrogenase and carboxylase to maintain and support the partition of pyruvate synthesis and degradation. Coenzyme A was identified by Fritz Lipmann in 1946, who also later gave it its name. Its structure
550-423: 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 of body weight, accounting for 75% of carnitine in the body. Humans endogenously produce 1.2 μmol/kg of body weight of carnitine on a daily basis, accounting for 25% of
SECTION 10
#1732859370209600-419: 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
650-406: Is implemented by regulation of acetyl-CoA carboxylase , which catalyzes the committed step in fatty acid synthesis. Insulin stimulates acetyl-CoA carboxylase, while epinephrine and glucagon inhibit its activity. During cell starvation, coenzyme A is synthesized and transports fatty acids in the cytosol to the mitochondria. Here, acetyl-CoA is generated for oxidation and energy production. In
700-499: Is insufficient high-quality clinical evidence to indicate it provides any benefit. The primary biological functions of carnitine in humans include the following: 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(CH 3 ) 3 , are over 90% dissociated at physiological pH (~7.4) for humans. As an example of normal biosynthesis of carnitine in humans,
750-402: Is insufficient research to determine its overall efficacy in lowering the risk or treating cardiovascular diseases . 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 or lowering fasting levels of blood glucose . The kidneys contribute to overall homeostasis in
800-436: 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 . The carnitine-mediated entry process is a rate-limiting factor for fatty acid oxidation and is an important point of regulation. The liver starts actively making triglycerides from excess glucose when it
850-455: Is naturally synthesized from pantothenate (vitamin B 5 ), which is found in food such as meat, vegetables, cereal grains, legumes, eggs, and milk. In humans and most living organisms, pantothenate is an essential vitamin that has a variety of functions. In some plants and bacteria, including Escherichia coli , pantothenate can be synthesised de novo and is therefore not considered essential. These bacteria synthesize pantothenate from
900-576: Is regulated by product inhibition. CoA is a competitive inhibitor for Pantothenate Kinase, which normally binds ATP. Coenzyme A, three ADP, one monophosphate, and one diphosphate are harvested from biosynthesis. Coenzyme A can be synthesized through alternate routes when intracellular coenzyme A level are reduced and the de novo pathway is impaired. In these pathways, coenzyme A needs to be provided from an external source, such as food, in order to produce 4′-phosphopantetheine . Ectonucleotide pyrophosphates (ENPP) degrade coenzyme A to 4′-phosphopantetheine,
950-428: 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. Carnitine shuttle activation occurs due to
1000-597: Is termed protein CoAlation (Protein-S-SCoA), which plays a similar role to protein S -glutathionylation by preventing the irreversible oxidation of the thiol group of cysteine residues. Using anti-coenzyme A antibody and liquid chromatography tandem mass spectrometry ( LC-MS/MS ) methodologies, more than 2,000 CoAlated proteins were identified from stressed mammalian and bacterial cells. The majority of these proteins are involved in cellular metabolism and stress response. Different research studies have focused on deciphering
1050-819: Is termed protein deCoAlation. So far, two bacterial proteins, Thioredoxin A and Thioredoxin-like protein (YtpP), are shown to deCoAlate proteins. Coenzyme A is available from various chemical suppliers as the free acid and lithium or sodium salts. The free acid of coenzyme A is detectably unstable, with around 5% degradation observed after 6 months when stored at −20 °C, and near complete degradation after 1 month at 37 °C. The lithium and sodium salts of CoA are more stable, with negligible degradation noted over several months at various temperatures. Aqueous solutions of coenzyme A are unstable above pH 8, with 31% of activity lost after 24 hours at 25 °C and pH 8. CoA stock solutions are relatively stable when frozen at pH 2–6. The major route of CoA activity loss
SECTION 20
#17328593702091100-420: Is the primary input in the citric acid cycle and is obtained from glycolysis , amino acid metabolism, and fatty acid beta oxidation. This process is the body's primary catabolic pathway and is essential in breaking down the building blocks of the cell such as carbohydrates , amino acids , and lipids . When there is excess glucose, coenzyme A is used in the cytosol for synthesis of fatty acids. This process
1150-460: 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 plays a role in stabilizing acetyl-CoA and coenzyme A levels through
1200-430: Is under preliminary research for its potential as an adjunct in heart disease 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 , there
1250-489: The methylation of the amino acid lysine . TML is then hydroxylated into hydroxytrimethyllysine (HTML) by trimethyllysine dioxygenase (TMLD), requiring the presence of ascorbic acid and iron. HTML is then cleaved by HTML aldolase (HTMLA, 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
1300-428: The ability to receive or give an acetyl group. 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. The free-floating fatty acids , released from adipose tissues to
1350-442: The amino acid aspartate and a metabolite in valine biosynthesis. In all living organisms, coenzyme A is synthesized in a five-step process that requires four molecules of ATP, pantothenate and cysteine (see figure): Enzyme nomenclature abbreviations in parentheses represent mammalian, other eukaryotic, and prokaryotic enzymes respectively. In mammals steps 4 and 5 are catalyzed by a bifunctional enzyme called COASY . This pathway
1400-489: The amount of carnitine in muscle. The underlying mechanisms on how carnitine can improve physical performance, if at all, are not clearly understood. There is no evidence that L-carnitine influences fat metabolism or aids in weight loss. 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. Carnitine has been studied in various cardiometabolic conditions, indicating it
1450-445: 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
1500-474: The body is l -carnitine, which is also the form present in food. Food sources rich in l -carnitine are animal products, particularly beef and pork. Red meats tend to have higher levels of l -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
1550-721: 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 l -carnitine (often injected) may aid in anemia management. The form present in
Carnitine - Misplaced Pages Continue
1600-718: The carnitine in the body. Strict vegetarians obtain little carnitine from dietary sources (0.1 μmol/kg of body weight daily), as it is mainly found in animal-derived foods. L-Carnitine, acetyl- l -carnitine , and propionyl- l -carnitine are available in dietary supplement 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 . Carnitine interacts with pivalate -conjugated antibiotics such as pivampicillin . Chronic administration of these antibiotics increases
1650-407: 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
1700-444: The citric acid cycle, coenzyme A works as an allosteric regulator in the stimulation of the enzyme pyruvate dehydrogenase . Discovery of the novel antioxidant function of coenzyme A highlights its protective role during cellular stress. Mammalian and Bacterial cells subjected to oxidative and metabolic stress show significant increase in the covalent modification of protein cysteine residues by coenzyme A. This reversible modification
1750-400: The coenzyme A-mediated regulation of proteins. Upon protein CoAlation, inhibition of the catalytic activity of different proteins (e.g. metastasis suppressor NME1 , peroxiredoxin 5 , GAPDH , among others) is reported. To restore the protein's activity, antioxidant enzymes that reduce the disulfide bond between coenzyme A and the protein cysteine residue play an important role. This process
1800-440: 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 . 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
1850-451: 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
1900-690: 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 β {\displaystyle \beta } oxidation which occurs at the carboxyl end of fatty acid , in the mitochondria). 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
1950-529: 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 3 grams (0.11 oz) 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 . Levocarnitine
2000-606: The factor from pig liver and discovered that its function was related to a coenzyme that was active in choline acetylation. Work with Beverly Guirard , Nathan Kaplan , and others determined that pantothenic acid was a central component of coenzyme A. The coenzyme was named coenzyme A to stand for "activation of acetate". In 1953, Fritz Lipmann won the Nobel Prize in Physiology or Medicine "for his discovery of co-enzyme A and its importance for intermediary metabolism". Coenzyme A
2050-443: 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
Carnitine - Misplaced Pages Continue
2100-535: 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. 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
2150-472: 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
2200-417: 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
2250-426: The production of fatty acids in cells, which are essential in cell membrane structure. Coenzyme A is also the source of the phosphopantetheine group that is added as a prosthetic group to proteins such as acyl carrier protein and formyltetrahydrofolate dehydrogenase . Coenzyme A is one of five crucial coenzymes that are necessary in the reaction mechanism of the citric acid cycle . Its acetyl-coenzyme A form
2300-531: The results of these studies are inconclusive, since various studies used various regimens of carnitine supplementation and intensity of exercise. At supplement amounts of 2–6 grams (0.071–0.212 oz) 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. Carnitine supplements does not seem to improve oxygen consumption or metabolic functions when exercising, nor do they increase
2350-769: The two enantiomers d -carnitine ( S -(+)-) and l -carnitine ( R -(−)-). 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 whiteish powder, and a water-soluble zwitterion with relatively low toxicity. Derived from amino acids, carnitine was first extracted 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 athletes for improved exercise performance or recovery, there
2400-597: The use of antibiotics , malnutrition , and poor absorption following digestion . The plasma half-life of L-carnitine taken as a supplementation is approximately 17.4 hours. 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. Despite some studies suggest that carnitine may improve high-intensity physical performance, and facilitate recovery after such performance,
2450-592: Was approved by the U.S. Food and Drug Administration as a new molecular entity under the brand name Carnitor on December 27, 1985. Quaternary ammonium compound Too Many Requests If you report this error to the Wikimedia System Administrators, please include the details below. Request from 172.68.168.132 via cp1112 cp1112, Varnish XID 375182273 Upstream caches: cp1112 int Error: 429, Too Many Requests at Fri, 29 Nov 2024 05:49:30 GMT Coenzyme A In its acetyl form , coenzyme A
2500-473: Was determined during the early 1950s at the Lister Institute , London, together by Lipmann and other workers at Harvard Medical School and Massachusetts General Hospital . Lipmann initially intended to study acetyl transfer in animals, and from these experiments he noticed a unique factor that was not present in enzyme extracts but was evident in all organs of the animals. He was able to isolate and purify
#208791