Biotin (vitamin b7)

From Wikipedia, the free encyclopedia

Biotin

Names
IUPAC name 5-[(3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl]pentanoic acid
Other names Vitamin B7; Vitamin H; Coenzyme R; Biopeiderm
Identifiers
CAS Number	58-85-5
3D model (JSmol)	Interactive image Interactive image
ChEBI	CHEBI:15956
ChEMBL	ChEMBL857
ChemSpider	149962
DrugBank	DB00121
ECHA InfoCard	100.000.363
IUPHAR/BPS	4787
KEGG	D00029
PubChem CID	171548
UNII	6SO6U10H04
CompTox Dashboard (EPA)	DTXSID7022679
InChI[show]
SMILES[show]
Properties
Chemical formula	C10H16N2O3S
Molar mass	244.31 g·mol−1
Appearance	White crystalline needles
Melting point	232 to 233 °C (450 to 451 °F; 505 to 506 K)
Solubility in water	22 mg/100 mL
Pharmacology
ATC code	A11HA05 (WHO)
Hazards
NFPA 704	1 1 0
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Biotin is a water-soluble B vitamin, also called vitamin B₇ and formerly known as vitamin H or coenzyme R. It is involved in a wide range of metabolic processes, both in humans and in other organisms, primarily related to the utilization of fats, carbohydrates, and amino acids.

Biotin deficiency can be caused by inadequate dietary intake or inheritance of one or more inborn genetic disorders that affect biotin metabolism. Subclinical deficiency can cause mild symptoms, such as hair thinning or skin rash typically on the face. Neonatal screening for biotinidase deficiency began in the United States in 1984, with many countries testing for this disorder at birth. Individuals born prior to 1984 are unlikely to have been screened, obscuring the true prevalence of the disorder.

General

Dean Burk, American biochemist working on isolation of biotin.

 

Biotin is an important component of enzymes involved in metabolizing fats and carbohydrates, influencing cell growth, and affecting amino acids involved in protein synthesis. Biotin assists in various metabolic reactions involving the transfer of carbon dioxide. It may also be helpful in maintaining a steady blood sugar level. Biotin is often recommended as a dietary supplement for strengthening hair and nails, though scientific data supporting these outcomes are weak. Nevertheless, biotin is found in many cosmetics and health products for the hair and skin.

Biotin deficiency is rare. The amounts needed are small, a wide range of foods contain biotin, and intestinal bacteria synthesize biotin, which is then absorbed by the host animal. For that reason, statutory agencies in various countries, for example the USA and Australia, have not formally established a recommended daily intake of biotin. Instead, an adequate intake (AI) is identified based on the theory that average intake meets needs. Future research could result in biotin AIs with EARs and RDAs.

A number of rare metabolic disorders exist in which an individual's metabolism of biotin is abnormal, such as deficiency in the holocarboxylase synthetase enzyme which covalently links biotin onto the carboxylase, where the biotin acts as a cofactor.

Biotin is composed of a ureido ring fused with a tetrahydrothiophene ring. The ureido ring acts as the carbon dioxide carrier in carboxylation reactions. A valeric acid substituent is attached to one of the carbon atoms of the tetrahydrothiophene ring. Biotin is a coenzyme for multiple carboxylase enzymes, which are involved in the digestion of carbohydrates, synthesis of fatty acids, and gluconeogenesis. Biotin is also required for the catabolism and utilization of the three branched-chain amino acids: leucine, isoleucine, and valine.

Discovery

In 1916, W.G. Bateman observed that a diet high in raw egg whites caused toxic symptoms in dogs, cats, rabbits, and humans. This study was followed in 1927 by Margaret Averil Boas, who found that a diet of only egg whites caused dermatitis, alopecia, and loss of muscular coordination in rats. She called this syndrome "egg white injury". In 1939, six years after he began investigating the cause of egg white injury, Hungarian scientist Paul Gyorgy confirmed the existence of a protecting factor, which he called vitamin H. By this point, many independent groups had isolated biotin. In 1936, Kögl and Tönnis isolated a growth factor from egg yolk they called bios. After experiments performed with yeast and Rhizobium R, West and Wilson isolated a compound called co-enzyme R. In 1940, Gyorgy proved that vitamin H and bios and coenzyme were the same substance; he called it biotin.

Biosynthesis

Biotin has an unusual structure (above figure), with two rings fused together via one of their sides. The two rings are ureido and thiophene moieties. Biotin is a heterocyclic, S-containing monocarboxylic acid. It is made from two precursors, alanine and pimeloyl-CoA via three enzymes. 8-Amino-7-oxopelargonic acid synthase is a pyridoxal 5'-phosphate enzyme. The pimeloyl-CoA, could be produced by a modified fatty acid pathway involving a malonyl thioester as the starter. 7,8-Diaminopelargonic acid (DAPA) aminotransferase is unusual in using S-adenosyl methionine (SAM) as the NH₂ donor. Dethiobiotin synthetase catalyzes the formation of the ureido ring via a DAPA carbamate activated with ATP. Biotin synthase reductively cleaves SAM into a deoxyadenosyl radical, which abstracts an H atom from dethiobiotin to give an intermediate that is trapped by the sulfur donor. This sulfur donor is an iron-sulfur cluster.

Cofactor biochemistry

D-(+)-Biotin is a cofactor responsible for carbon dioxide transfer in several carboxylase enzymes:

• Acetyl-CoA carboxylase alpha
• Acetyl-CoA carboxylase beta
• Methylcrotonyl-CoA carboxylase
• Propionyl-CoA carboxylase
• Pyruvate carboxylase

Biotin is important in fatty acid synthesis, branched-chain amino acid catabolism, and gluconeogenesis. It covalently attaches to the epsilon-amino group of specific lysine residues in these carboxylases. This biotinylation reaction requires ATP and is catalyzed by holocarboxylase synthetase. In bacteria, biotin is attached to biotin carboxyl carrier protein (BCCP) by biotin protein ligase (BirA in E. coli). The attachment of biotin to various molecules, biotinylation, is used as an important laboratory technique to study various processes, including protein localization, protein interactions, DNA transcription, and replication. Biotinidase itself is known to be able to biotinylate histone proteins, but little biotin is found naturally attached to chromatin. 

Biotin binds tightly to the tetrameric protein avidin (also streptavidin and neutravidin), with a dissociation constant K_d on the order of 10⁻¹⁵ M, which is one of the strongest known protein-ligand interactions. This is often used in different biotechnological applications. Until 2005, very harsh conditions were thought to be required to break the biotin-streptavidin interaction.

Dietary recommendations

The U.S. Institute of Medicine (IOM) updated Estimated Average Requirements (EARs), Recommended Dietary Allowances (RDAs) and Tolerable Upper Intake Levels (ULs) for many vitamins in 1998. At that time there was insufficient information to establish EARs and RDAs for biotin. In instances such as this, the IOM sets Adequate Intakes (AIs) with the understanding that at some later date, when the physiological effects of biotin are better understood, AIs will be replaced by more exact information. Collectively EARs, RDAs, AIs and ULs are referred to as Dietary Reference Intakes (DRIs).

The biotin AIs for males are: 5 μg/day of biotin for 0-6-month-old males, 6 μg/day of biotin for 7-12-month-old males, 8 μg/day of biotin for 1-3-year-old males, 12 μg/day of biotin for 4-8-year-old males, 20 μg/day of biotin for 9-13-year-old males, 25 μg/day of biotin for 14-18-year-old males, and 30 μg/day of biotin for males that are 19-years old and older. 

The biotin AIs for females are: 5 μg/day of biotin for 0-6-month-old females, 6 μg/day of biotin for 7-12-month-old females, 8 μg/day of biotin for 1-3-year-old females, 12 μg/day of biotin for 4-8-year-old females, 20 μg/day of biotin for 9-13-year-old females, 25 μg/day of biotin for 14-18-year-old females, and 30 μg/day of biotin for females that are 19-years old and older. The biotin AIs for females who are either pregnant or lactating, respectively, are: 30 μg/day of biotin for pregnant females 14-50-years old; 35 μg/day of biotin for lactating females 14-50-years old.

The European Food Safety Authority (EFSA) refers to the collective set of information as Dietary Reference Values, with Population Reference Intake instead of RDA, and Average Requirement instead of EAR. AI and UL are defined the same as in United States. For women and men over age 18, the Adequate Intake is set at 40 μg/day. The AI for pregnancy is 40 μg/day per day, and 45 μg/day during breastfeeding. For children ages 1–17 years, the AIs increase with age from 20 to 35 μg/day.

For the United States food and dietary supplement labeling purposes, the amount in a serving is expressed as a percent of Daily Value (DV). For biotin labeling purposes, 100% of the Daily Value was revised in 2016 to 30 μg/day to bring it into agreement with the AI. The deadline to be in compliance was set at January 1, 2020 for large companies and January 1, 2021 for small companies.

Safety

The U.S. Institute of Medicine estimates upper limits (ULs) for vitamins and minerals when evidence for a true limit is sufficient. For biotin, however, there is no UL because adverse effects of high biotin intake have not been determined. EFSA also reviewed safety and reached the same conclusion as in United States that there is insufficient evidence to set a UL for biotin.

Sources

Biotin is synthesized by intestinal bacteria, but there is a lack of good quality studies about how much biotin they provide.

Biotin is stable at room temperature and is not destroyed by cooking. Sources with appreciable content are:

• Chicken liver, cooked: 138 μg per 74g serving
• Beef or pork liver, cooked: up to 35 μg per 3 ounce serving
• Egg, cooked: up to 25 μg per large egg
• Yeast, baker's, dried: up to 14 μg per 7 gram packet
• Avocado: up to 6 μg per avocado
• Peanuts, roasted, salted: can vary between 5 μg and 28 μg per 28g serving
• Salmon, cooked: up to 5 μg per 3 ounce serving
• Sunflower seeds, roasted, salted: 2.4 μg per 31g serving

Raw egg whites contain a protein (avidin) that blocks the absorption of biotin, so people who regularly consume a large number of raw eggs may become biotin-deficient. The dietary biotin intake in Western populations has been estimated to be as high as 60 μg per day. Biotin is also available in dietary supplements, individually or as an ingredient in multivitamins.

Bioavailability

Biotin is also called vitamin H (the H represents Haar und Haut, German words for "hair and skin") or vitamin B₇. Studies on its bioavailability have been conducted in rats and in chicks. Based on these studies, biotin bioavailability may be low or variable, depending on the type of food being consumed. In general, biotin exists in food as protein-bound form or biocytin. Proteolysis by protease is required prior to absorption. This process assists free biotin release from biocytin and protein-bound biotin. The biotin present in corn is readily available; however, most grains have about a 20-40% bioavailability of biotin.

The wide variability in biotin bioavailability may be due to the ability of an organism to break various biotin-protein bonds from food. Whether an organism has an enzyme with that ability will determine the bioavailability of biotin from the foodstuff.

Factors that affect biotin requirements

The frequency of marginal biotin status is not known, but the incidence of low circulating biotin levels in alcoholics has been found to be much greater than in the general population. Also, relatively low levels of biotin have been reported in the urine or plasma of patients who have had a partial gastrectomy or have other causes of achlorhydria, burn patients, epileptics, elderly individuals, and athletes. Pregnancy and lactation may be associated with an increased demand for biotin. In pregnancy, this may be due to a possible acceleration of biotin catabolism, whereas, in lactation, the higher demand has yet to be elucidated. Recent studies have shown marginal biotin deficiency can be present in human gestation, as evidenced by increased urinary excretion of 3-hydroxyisovaleric acid, decreased urinary excretion of biotin and bisnorbiotin, and decreased plasma concentration of biotin. Additionally, smoking may further accelerate biotin catabolism in women.

Deficiency

Biotin deficiency typically occurs from absence of the vitamin in the diet, particularly in breastfeeding mothers. Daily consumption of raw egg whites for several months may result in biotin deficiency, due to their avidin content. 

Deficiency can be addressed with nutritional supplementation.

Deficiency symptoms include:

• Brittle and thin fingernails
• Hair loss (alopecia)
• Conjunctivitis
• Dermatitis in the form of a scaly, red rash around the eyes, nose, mouth, and genital area.
• Neurological symptoms in adults, such as depression, lethargy, hallucination, and numbness and tingling of the extremities

The neurological and psychological symptoms can occur with only mild deficiencies. Dermatitis, conjunctivitis, and hair loss will generally occur only when deficiency becomes more severe. Individuals with hereditary disorders of biotin deficiency have evidence of impaired immune system function, including increased susceptibility to bacterial and fungal infections. Pregnant women tend to have a higher risk of biotin deficiency. Nearly half of pregnant women have abnormal increases of 3-hydroxyisovaleric acid, which reflects reduced status of biotin.

Metabolic disorders

Inherited metabolic disorders characterized by deficient activities of biotin-dependent carboxylases are termed multiple carboxylase deficiency. These include deficiencies in the enzymes holocarboxylase synthetase or biotinidase. Holocarboxylase synthetase deficiency prevents the body's cells from using biotin effectively, and thus interferes with multiple carboxylase reactions. Biochemical and clinical manifestations include: ketolactic acidosis, organic aciduria, hyperammonemia, skin rash, feeding problems, hypotonia, seizures, developmental delay, alopecia, and coma.

Biotinidase deficiency is not due to inadequate biotin, but rather to a deficiency in the enzymes that process it. Biotinidase catalyzes the cleavage of biotin from biocytin and biotinyl-peptides (the proteolytic degradation products of each holocarboxylase) and thereby recycles biotin. It is also important in freeing biotin from dietary protein-bound biotin. General symptoms include decreased appetite and growth. Dermatologic symptoms include dermatitis, alopecia, and achromotrichia (absence or loss of pigment in the hair). Perosis (a shortening and thickening of bones) is seen in the skeleton. Fatty liver and kidney syndrome and hepatic steatosis also can occur.

Use in biotechnology

Biotin is widely used throughout the biotechnology industry to conjugate proteins for biochemical assays. Biotin's small size means the biological activity of the protein will most likely be unaffected. This process is called biotinylation. Because both streptavidin and avidin bind biotin with high affinity (K_d of 10⁻¹⁴ to 10⁻¹⁵ M) and specificity, biotinylated proteins of interest can be isolated from a sample by exploiting this highly stable interaction. The sample is incubated with streptavidin/avidin beads, allowing capture of the biotinylated protein of interest. Any other proteins binding to the biotinylated molecule will also stay with the bead and all other unbound proteins can be washed away. However, due to the extremely strong streptavidin-biotin interaction, very harsh conditions are needed to elute the biotinylated protein from the beads (typically 6 M guanidine HCl at pH 1.5), which often will denature the protein of interest. To circumvent this problem, beads conjugated to monomeric avidin can be used, which has a decreased biotin-binding affinity of ≈10⁻⁸ M, allowing the biotinylated protein of interest to be eluted with excess free biotin. 

As one of the strongest non-covalent interactions, the binding of biotin to streptavidin is commonly used as the target molecular interaction in the research of biosensors and cell sorting.

ELISAs often make use of biotinylated detection antibodies against the antigen of interest, followed by a detection step using streptavidin conjugated to a reporter molecule, such as horseradish peroxidase or alkaline phosphatase.

Medical laboratory testing

Biotin in samples taken from people ingesting high levels of biotin in dietary supplements may affect diagnostic test results.

Vitamin B6

From Wikipedia, the free encyclopedia

Vitamin B6
Pyridoxal phosphate
Class identifiers
Use	Vitamin B6 deficiency
ATC code	A11HA02
Biological target	enzyme cofactor
Clinical data
Drugs.com	International Drug Names
External links
MeSH	D025101

Vitamin B₆ refers to a group of chemically similar compounds which can be interconverted in biological systems. Vitamin B₆ is part of the vitamin B group of essential nutrients. Its active form, pyridoxal 5′-phosphate, serves as a coenzyme in some 100 enzyme reactions in amino acid, glucose, and lipid metabolism.

Forms

Pyridoxine.

 

Pyridoxamine.

 

• Pyridoxine (PN), the form most commonly given as vitamin B₆ supplement
• Pyridoxine 5′-phosphate (P5P)
• Pyridoxal (PL)
• Pyridoxal 5′-phosphate (PLP), the metabolically active form
• Pyridoxamine (PM)
• Pyridoxamine 5′-phosphate (PMP)
• 4-Pyridoxic acid (PA), the catabolite which is excreted in urine
• Pyritinol, a semi-synthetic derivative of pyridoxine, where two pyridoxine moieties are bound by a disulfide bridge.

All forms except pyridoxic acid and pyritinol can be interconverted. Absorbed pyridoxamine is converted to PMP by pyridoxal kinase, which is further converted to PLP by pyridoxamine-phosphate transaminase or pyridoxine 5′-phosphate oxidase which also catalyzes the conversion of PNP to PLP. Pyridoxine 5′-phosphate oxidase is dependent on flavin mononucleotide (FMN) as a cofactor produced from riboflavin (vitamin B₂).

Functions

PLP, the metabolically active form of vitamin B₆, is involved in many aspects of macronutrient metabolism, neurotransmitter synthesis, histamine synthesis, hemoglobin synthesis and function, and gene expression. PLP generally serves as a coenzyme (cofactor) for many reactions including decarboxylation, transamination, racemization, elimination, replacement, and beta-group interconversion. The liver is the site for vitamin B₆ metabolism.

Amino acid metabolism

1. PLP is a cofactor in the biosynthesis of five important neurotransmitters: serotonin, dopamine, epinephrine, norepinephrine, and gamma-aminobutyric acid (GABA). PLP is also involved in the synthesis of histamine.
2. Transaminases break down amino acids with PLP as a cofactor. The proper activity of these enzymes is crucial for the process of moving amine groups from one amino acid to another.
3. Serine racemase which synthesizes the neuromodulator d-serine from its enantiomer is a PLP-dependent enzyme.
4. PLP is a coenzyme needed for the proper function of the enzymes cystathionine synthase and cystathionase. These enzymes catalyze reactions in the catabolism of methionine. Part of this pathway (the reaction catalyzed by cystathionase) also produces cysteine.
5. Selenomethionine is the primary dietary form of selenium. PLP is needed as a cofactor for the enzymes that allow selenium to be used from the dietary form. PLP also plays a cofactor role in releasing selenium from selenohomocysteine to produce hydrogen selenide, which can then be used to incorporate selenium into selenoproteins.
6. PLP is required for the conversion of tryptophan to niacin, so low vitamin B₆ status impairs this conversion.

Glucose metabolism

PLP is a required coenzyme of glycogen phosphorylase, the enzyme necessary for glycogenolysis to occur. PLP can catalyze transamination reactions that are essential for providing amino acids as a substrate for gluconeogenesis.

Lipid metabolism

PLP is an essential component of enzymes that facilitate the biosynthesis of sphingolipids. Particularly, the synthesis of ceramide requires PLP. In this reaction, serine is decarboxylated and combined with palmitoyl-CoA to form sphinganine, which is combined with a fatty acyl-CoA to form dihydroceramide. Dihydroceramide is then further desaturated to form ceramide. In addition, the breakdown of sphingolipids is also dependent on vitamin B₆ because sphingosine-1-phosphate lyase, the enzyme responsible for breaking down sphingosine-1-phosphate, is also PLP-dependent.

Hemoglobin synthesis and function

PLP aids in the synthesis of hemoglobin, by serving as a coenzyme for the enzyme ALA synthase. It also binds to two sites on hemoglobin to enhance the oxygen binding of hemoglobin.

Gene expression

PLP has been implicated in increasing or decreasing the expression of certain genes. Increased intracellular levels of the vitamin lead to a decrease in the transcription of glucocorticoids. Also, vitamin B₆ deficiency leads to the increased gene expression of albumin mRNA. Also, PLP influences expression of glycoprotein IIb by interacting with various transcription factors. The result is inhibition of platelet aggregation.

Nutrition

Food sources

Vitamin B₆ is widely distributed in foods in both its free and bound forms. Cooking, storage, and processing losses of vitamin B₆ vary and in some foods may be more than 50%, depending on the form of vitamin present in the food. Plant foods lose the least during processing, as they contain mostly pyridoxine, which is far more stable than the pyridoxal or pyridoxamine found in animal foods. For example, milk can lose 30–70% of its vitamin B₆ content when dried. Vitamin B₆ is found in the germ and aleurone layer of grains, and milling results in the reduction of this vitamin in white flour. The heating that occurs before most freezing and canning processes may also result in the loss of vitamin B₆ in foods.

Foods that contain large amounts of vitamin B₆ include:

• fortified breakfast cereals
• pork
• turkey
• beef
• bananas
• chickpeas
• dark chocolate
• potatoes
• pistachios

Dietary recommendations

The U.S. Institute of Medicine (renamed National Academy of Medicine in 2015) updated Estimated Average Requirements (EARs) and Recommended Dietary Allowances (RDAs) for vitamin B₆ in 1998. EARs for vitamin B₆ for women and men ages 14 and up increase with age from 1.0 to 1.3 mg/day and from 1.1 to 1.4 mg/day, respectively; the RDAs increase with age from 1.2 to 1.5 and from 1.3 to 1.7 mg/day, respectively. RDAs are higher than EARs so as to identify amounts that will cover people with higher than average requirements. RDA for pregnancy is 1.9 mg/day. RDA for lactation is 2.0 mg/day. For infants up to 12 months the Adequate Intake (AI) is 0.1–0.3 mg/day. and for children ages 1–13 years the RDA increases with age from 0.5 to 1.0 mg/day. As for safety, Tolerable upper intake levels (ULs) for vitamins and minerals are identified when evidence is sufficient. In the case of vitamin B₆ the UL is set at 100 mg/day. Collectively the EARs, RDAs, AIs and ULs are referred to as Dietary Reference Intakes (DRIs).

The European Food Safety Authority (EFSA) refers to the collective set of information as Dietary Reference Values, with Population Reference Intake (PRI) instead of RDA, and Average Requirement instead of EAR. AI and UL defined the same as in United States. For women and men ages 15 and older the PRI is set at 1.6 and 1.7 mg/day, respectively. AI for pregnancy is 1.8 mg/day, for lactation 1.7 mg/day. For children ages 1–14 years the PRIs increase with age from 0.6 to 1.4 mg/day. These PRIs are slightly higher than the U.S. RDAs. The EFSA also reviewed the safety question and set its UL at 25 mg/day.

For U.S. food and dietary supplement labeling purposes the amount in a serving is expressed as a percent of Daily Value (% DV). For vitamin B₆ labeling purposes 100% of the Daily Value was 2.0 mg, but as of May 27, 2016 it was revised to 1.7 mg to bring it into agreement with the RDA. A table of the old and new adult Daily Values is provided at Reference Daily Intake. Food and supplement companies have until January 1, 2020 to comply with the change.

Absorption and excretion

Vitamin B₆ is absorbed in the jejunum and ileum by passive diffusion. With the capacity for absorption being so great, animals are able to absorb quantities much greater than necessary for physiological demands. The absorption of pyridoxal phosphate and pyridoxamine phosphate involves their dephosphorylation catalyzed by a membrane-bound alkaline phosphatase. Those products and nonphosphorylated forms in the digestive tract are absorbed by diffusion, which is driven by trapping of the vitamin as 5′-phosphates through the action of phosphorylation (by a pyridoxal kinase) in the jejunal mucosa. The trapped pyridoxine and pyridoxamine are oxidized to pyridoxal phosphate in the tissue.

The products of vitamin B₆ metabolism are excreted in the urine, the major product of which is 4-pyridoxic acid. An estimated 40–60% of ingested vitamin B₆ is oxidized to 4-pyridoxic acid. Several studies have shown that 4-pyridoxic acid is undetectable in the urine of vitamin B₆-deficient subjects, making it a useful clinical marker to assess the vitamin B₆ status of an individual. Other products of vitamin B₆ metabolism excreted in the urine when high doses of the vitamin have been given include pyridoxal, pyridoxamine, and pyridoxine and their phosphates. A small amount of vitamin B₆ is also excreted in the feces.

Deficiency

Signs and symptoms

The classic clinical syndrome for vitamin B₆ deficiency is a seborrhoeic dermatitis-like eruption, atrophic glossitis with ulceration, angular cheilitis, conjunctivitis, intertrigo, and neurologic symptoms of somnolence, confusion, and neuropathy (due to impaired sphingosine synthesis) and sideroblastic anemia (due to impaired heme synthesis). 

Less severe cases present with metabolic disease associated with insufficient activity of the coenzyme PLP. The most prominent of the lesions is due to impaired tryptophan–niacin conversion. This can be detected based on urinary excretion of xanthurenic acid after an oral tryptophan load. Vitamin B₆ deficiency can also result in impaired transsulfuration of methionine to cysteine. The PLP-dependent transaminases and glycogen phosphorylase provide the vitamin with its role in gluconeogenesis, so deprivation of vitamin B₆ results in impaired glucose tolerance.

Diagnosis

The assessment of vitamin B₆ status is essential, as the clinical signs and symptoms in less severe cases are not specific. The three biochemical tests most widely used are the activation coefficient for the erythrocyte enzyme aspartate aminotransferase, plasma PLP concentrations, and the urinary excretion of vitamin B₆ degradation products, specifically urinary PA. Of these, plasma PLP is probably the best single measure, because it reflects tissue stores. Plasma PLP less than 10 nmol/l is indicative of vitamin B₆ deficiency. A PLP concentration greater than 20 nmol/l has been chosen as a level of adequacy for establishing Estimated Average Requirements and Recommended Daily Allowances in the USA. Urinary PA is also an indicator of vitamin B₆ deficiency; levels of less than 3.0 mmol/day is suggestive of vitamin B₆ deficiency.

The classic syndrome for vitamin B₆ deficiency is rare, even in developing countries. A handful of cases were seen between 1952 and 1953, particularly in the United States, and occurred in a small percentage of infants who were fed a formula lacking in pyridoxine.

Causes

A deficiency of vitamin B₆ alone is relatively uncommon and often occurs in association with other vitamins of the B complex. The elderly and alcoholics have an increased risk of vitamin B₆ deficiency, as well as other micronutrient deficiencies. Evidence exists for decreased levels of vitamin B₆ in women with type 1 diabetes and in patients with systemic inflammation, liver disease, rheumatoid arthritis, and those infected with HIV. Use of oral contraceptives and treatment with certain anticonvulsants, isoniazid, cycloserine, penicillamine, and hydrocortisone negatively impact vitamin B₆ status. Hemodialysis reduces vitamin B₆ plasma levels.

Toxicity

Adverse effects have been documented from vitamin B₆ supplements, but never from food sources. Damage to the dorsal root ganglia is documented in human cases of overdose of pyridoxine. Although it is a water-soluble vitamin and is excreted in the urine, doses of pyridoxine in excess of the dietary upper limit (UL) over long periods cause painful and ultimately irreversible neurological problems. The primary symptoms are pain and numbness of the extremities. In severe cases, motor neuropathy may occur with "slowing of motor conduction velocities, prolonged F wave latencies, and prolonged sensory latencies in both lower extremities", causing difficulty in walking. Sensory neuropathy typically develops at doses of pyridoxine in excess of 1,000 mg per day, but adverse effects can occur with much less, so doses over 200 mg are not considered safe. Symptoms among women taking lower doses have been reported.

Existing authorizations and valuations vary considerably worldwide. As noted, the U.S. Institute of Medicine set an adult UL at 100 mg/day. The European Community Scientific Committee on Food defined intakes of 50 mg of vitamin B₆ per day as harmful and established a UL of 25 mg/day. The nutrient reference values in Australia and New Zealand recommend an upper limit of 50 mg/day in adults. "The same figure was set for pregnancy and lactation as there is no evidence of teratogenicity at this level. The UL was set based on metabolic body size and growth considerations for all other ages and life stages except infancy. It was not possible to set a UL for infants, so intake is recommended in the form of food, milk or formula." The ULs were set using results of studies involving long-term oral administration of pyridoxine at doses of less than 1 g/day. "A no-observed-adverse-effect level (NOAEL) of 200 mg/day was identified from the studies of Bernstein & Lobitz (1988) and Del Tredici et al (1985). These studies involved subjects who had generally been on the supplements for five to six months or less. The study of Dalton and Dalton (1987), however, suggested the symptoms might take substantially longer than this to appear. In this latter retrospective survey, subjects who reported symptoms had been on supplements for 2.9 years, on average. Those reporting no symptoms had taken supplements for 1.9 years."

History

In 1934, the Hungarian physician Paul György discovered a substance that was able to cure a skin disease in rats (dermatitis acrodynia). He named this substance vitamin B₆. In 1938, Samuel Lepkovsky isolated vitamin B₆ from rice bran. Harris and Folkers in 1939 determined the structure of pyridoxine, and, in 1945, Snell was able to show the two forms of vitamin B₆, pyridoxal and pyridoxamine. Vitamin B₆ was named pyridoxine to indicate its structural homology to pyridine.

Pantothenic acid (vitamin b5)

From Wikipedia, the free encyclopedia

Pantothenic acid

Names
Preferred IUPAC name 3-[(2R)-2,4-Dihydroxy-3,3-dimethylbutanamido]propanoic acid
Systematic IUPAC name 3-[(2R)-(2,4-Dihydroxy-3,3-dimethylbutanoyl)amino]propanoic acid
Identifiers
CAS Number	599-54-2  79-83-4 (R)
3D model (JSmol)	Interactive image (R): Interactive image (S): Interactive image
3DMet	B00193
Beilstein Reference	1727062, 1727064 (R)
ChEBI	CHEBI:7916
ChEMBL	ChEMBL1594
ChemSpider	963  6361 (R)  4677898 (S)
DrugBank	DB01783
ECHA InfoCard	100.009.061
EC Number	209-965-4
KEGG	D07413
MeSH	Pantothenic+Acid
PubChem CID	988 6613 (R) 5748353 (S)
RTECS number	RU4729000
UNII	19F5HK2737
CompTox Dashboard (EPA)	DTXSID7047229
InChI[show]
SMILES[show]
Properties
Chemical formula	C9H17NO5
Molar mass	219.237 g·mol−1
Appearance	Yellow oil Colorless crystals (Ca2+ salt)
Odor	Odorless
Density	1.266 g/cm3 1.32 g/cm3 (Ca2+ salt)
Melting point	183.833 °C (362.899 °F; 456.983 K) 196–200 °C (385–392 °F; 469–473 K) decomposes (Ca2+ salt) 138 °C (280 °F; 411 K) decomposes (Ca2+ salt, monohydrate)
Solubility in water	Very soluble 2.11 g/mL (Ca2+ salt)
Solubility	Very soluble in C6H6, ether Ca2+ salt: Slightly soluble in alcohol, CHCl3
log P	−1.416
Acidity (pKa)	4.41
Basicity (pKb)	9.698
Chiral rotation ([α]D)	+37.5° +24.3° (Ca2+ salt)
Hazards
NFPA 704	1 2 0
Flash point	287.3 °C (549.1 °F; 560.5 K)
Lethal dose or concentration (LD, LC):
LD50 (median dose)	> 10 mg/g (Ca2+ salt)
Related compounds
Related alkanoic acids	Arginine Hopantenic acid 4-(γ-Glutamylamino)butanoic acid
Related compounds	Panthenol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Pantothenic acid, also called vitamin B₅ (a B vitamin), is a water-soluble vitamin. Pantothenic acid is an essential nutrient. Animals require pantothenic acid in order to synthesize coenzyme-A (CoA), as well as to synthesize and metabolize proteins, carbohydrates, and fats. The anion is called pantothenate.

Pantothenic acid is the amide between pantoic acid and β-alanine. Its name derives from the Greek pantothen, meaning "from everywhere", and small quantities of pantothenic acid are found in nearly every food, with high amounts in fortified whole-grain cereals, egg yolks, liver and dried mushrooms. It is commonly found as its alcohol analog, the provitamin panthenol (pantothenol), and as calcium pantothenate.

Pantothenic acid was discovered by Roger J. Williams in 1933.

Biological role

Only the dextrorotatory (D) isomer of pantothenic acid possesses biologic activity. The levorotatory (L) form may antagonize the effects of the dextrorotatory isomer.

Pantothenic acid is used in the synthesis of coenzyme A (CoA). Coenzyme A may act as an acyl group carrier to form acetyl-CoA and other related compounds; this is a way to transport carbon atoms within the cell. CoA is important in energy metabolism for pyruvate to enter the tricarboxylic acid cycle (TCA cycle) as acetyl-CoA, and for α-ketoglutarate to be transformed to succinyl-CoA in the cycle. CoA is also important in the biosynthesis of many important compounds such as fatty acids, cholesterol, and acetylcholine. CoA is incidentally also required in the formation of ACP, which is also required for fatty acid synthesis in addition to CoA.

Pantothenic acid in the form of CoA is also required for acylation and acetylation, which, for example, are involved in signal transduction and enzyme activation and deactivation, respectively.

Since pantothenic acid participates in a wide array of key biological roles, it is essential to all forms of life. As such, deficiencies in pantothenic acid may have numerous wide-ranging effects.

Sources

Dietary

Content of pantothenic acid varies among manufactured and natural foods, especially fortified ready-to-eat cereals, infant formulas, energy bars and dried foods. Major food sources of pantothenic acid are dried shiitake mushrooms, liver, kidney, egg yolks and sunflower seeds. Whole grains are another source of the vitamin, but milling removes much of the pantothenic acid, as it is found in the outer layers of whole grains. In animal feeds, the most important sources are alfalfa, cereal, fish meal, peanut meal, molasses, mushrooms, rice, wheat bran, and yeasts.

Supplementation

The derivative of pantothenic acid, pantothenol (panthenol), is a more stable form of the vitamin and is often used as a source of the vitamin in multivitamin supplements. Another common supplemental form of the vitamin is calcium pantothenate. Calcium pantothenate is often used in dietary supplements because, as a salt, it is more stable than pantothenic acid.

Dietary recommendations

The U.S. Institute of Medicine (IOM) updated Estimated Average Requirements (EARs) and Recommended Dietary Allowances (RDAs) for B vitamins in 1998. At that time there was not sufficient information to establish EARs and RDAs for pantothenic acid. In instances such as this, the Board sets Adequate Intakes (AIs), with the understanding that at some later date, AIs will be replaced by more exact information. The current AI for teens and adults ages 14 and up is 5 mg/day. AI for pregnancy is 6 mg/day. AI for lactation is 7 mg/day. For infants up to 12 months the AI is 1.8 mg/day. For children ages 1–13 years the AI increases with age from 2 to 4 mg/day. As for safety, the IOM sets Tolerable upper intake levels (ULs) for vitamins and minerals when evidence is sufficient. In the case of pantothenic acid there is no UL, as there is no human data for adverse effects from high doses. Collectively the EARs, RDAs, AIs and ULs are referred to as Dietary Reference Intakes (DRIs).

The European Food Safety Authority (EFSA) refers to the collective set of information as Dietary Reference Values, with Population Reference Intake (PRI) instead of RDA, and Average Requirement instead of EAR. AI and UL are defined the same as in the U.S. For women and men over age 11 the Adequate Intake (AI) is set at 5 mg/day. AI for pregnancy is 5 mg/day, for lactation 7 mg/day. For children ages 1–10 years the AI is 4 mg/day. These AIs are similar to the U.S. AIs.^[18] The EFSA also reviewed the safety question and reached the same conclusion as in United States - that there was not sufficient evidence to set a UL for pantothenic acid.

For U.S. food and dietary supplement labeling purposes the amount in a serving is expressed as a percent of Daily Value (%DV). For pantothenic acid labeling purposes 100% of the Daily Value was 10 mg, but as of May 27, 2016 it was revised to 5 mg to bring it into agreement with the AI. A table of the old and new adult Daily Values is provided at Reference Daily Intake. Food and supplement companies have until January 1, 2020 to comply with the change.

Age group	Age	Adequate intake
Infants	0–6 months	1.7 mg
Infants	7–12 months	1.8 mg
Children	1–3 years	2 mg
Children	4–8 years	3 mg
Children	9–13 years	4 mg
Adult men and women	14+ years	5 mg
Pregnant women	(vs. 5)	6 mg
Breastfeeding women	(vs. 5)	7 mg

Absorption

When found in foods, most pantothenic acid is in the form of CoA or bound to acyl carrier protein (ACP). For the intestinal cells to absorb this vitamin, it must be converted into free pantothenic acid. Within the lumen of the intestine, CoA and ACP are hydrolyzed into 4'-phosphopantetheine. The 4'-phosphopantetheine is then dephosphorylated into pantetheine. Pantetheinase, an intestinal enzyme, then hydrolyzes pantetheine into free pantothenic acid.

Free pantothenic acid is absorbed into intestinal cells via a saturable, sodium-dependent active transport system. At high levels of intake, when this mechanism is saturated, some pantothenic acid may also be absorbed via passive diffusion. As intake increases 10-fold, however, absorption rate decreases to 10%.

Deficiency

Pantothenic acid deficiency is exceptionally rare and has not been thoroughly studied. In the few cases where deficiency has been seen (victims of starvation and limited volunteer trials), nearly all symptoms can be reversed with the return of pantothenic acid.

Symptoms of deficiency are similar to other vitamin B deficiencies. There is impaired energy production, due to low CoA levels, which could cause symptoms of irritability, fatigue, and apathy. Acetylcholine synthesis is also impaired; therefore, neurological symptoms can also appear in deficiency; they include numbness, paresthesia, and muscle cramps. Deficiency in pantothenic acid can also cause hypoglycemia, or an increased sensitivity to insulin. Insulin receptors are acylated with palmitic acid when they do not want to bind with insulin. Therefore, more insulin will bind to receptors when acylation decreases, causing hypoglycemia. Additional symptoms could include restlessness, malaise, sleep disturbances, nausea, vomiting, and abdominal cramps. In a few rare circumstances, more serious (but reversible) conditions have been seen, such as adrenal insufficiency and hepatic encephalopathy. 

Deficiency symptoms in other nonruminant animals include disorders of the nervous, gastrointestinal, and immune systems, reduced growth rate, decreased food intake, skin lesions and changes in hair coat, and alterations in lipid and carbohydrate metabolism.

Toxicity

Toxicity of pantothenic acid is unlikely. In fact, no Tolerable Upper Level Intake (UL) has been established. Large doses of the vitamin, when ingested, have no reported side effects and massive doses (e.g., 10 g/day) may only yield mild diarrhea. There are also no adverse reactions known following parenteral (injected) or topical (skin) applications of the vitamin. Pantothenic acid, in an animal study, was shown to induce adrenal hyper-responsiveness to stress stimulation.

Research

Although pantothenic acid supplementation is under preliminary research for a variety of human diseases, there is insufficient evidence to date that it has any effect.

Ruminant nutrition

No dietary requirement for pantothenic acid has been established as synthesis of pantothenic acid by ruminal microorganisms appears to be 20 to 30 times more than dietary amounts. Net microbial synthesis of pantothenic acid in the rumen of steer calves has been estimated to be 2.2 mg/kg of digestible organic matter consumed per day. The degradation of dietary intake of pantothenic acid is considered to be 78 percent. Supplementation of pantothenic acid at 5 to 10 times theoretic requirements did not improve performance of feedlot cattle.