riboflavin riboflavin riboflavin, also known as vitamin b2, is a vitamin found in food and sold as a dietary supplement. it is essential to the formation of two major coenzymes, flavin mononucleotide and flavin adenine dinucleotide. these coenzymes are involved in energy metabolism, cellular respiration, and antibody production, as well as normal growth and development. the coenzymes are also required for the metabolism of niacin, vitamin b6, and folate. riboflavin is prescribed to treat corneal thinning, and taken orally, may reduce the incidence of migraine headaches in adults. riboflavinchemical structureclinical datatrade namesmanyother nameslactochrome, lactoflavin, vitamin gahfs/drugs.commonographlicense data us dailymed: riboflavin routes ofadministrationby mouth, intramuscular, intravenousatc codea11ha04 (who) s01xa26 (who)legal statuslegal status us: dietary supplement pharmacokinetic dataelimination half-life66 to 84 minutesexcretionurineidentifiers iupac name 7,8-dimethyl-10-benzopteridine-2,4-dione cas number83-88-5 ypubchem cid493570iuphar/bps6578drugbankdb00140 ychemspider431981 yuniitlm2976ofrkeggd00050 ychebichebi:17015 ychemblchembl1534 ye numbere101, e101(iii) (colours) comptox dashboard (epa)dtxsid8021777 echa infocard100.001.370 chemical and physical dataformulac17h20n4o6molar mass376.369 g·mol−13d model (jsmol)interactive image smiles c12cc(c)c(c)cc1n=c3c(=o)nc(=o)n=c3n2c(o)(o)(o)co inchi inchi=inchi=1s/c17h20n4o6/c1-7-3-9-10(4-8(7)2)21(5-11(23)14(25)12(24)6-22)15-13(18-9)16(26)20-17(27)19-15/h3-4,11-12,14,22-25h,5-6h2,1-2h3,(h,20,26,27)/t11-,12+,14-/m0/s1 ykey:aunganrzjhbgpy-scrdcrapsa-n y riboflavin deficiency is rare and is usually accompanied by deficiencies of other vitamins and nutrients. it may be prevented or treated by oral supplements or by injections. as a water-soluble vitamin, any riboflavin consumed in excess of nutritional requirements is not stored; it is either not absorbed or is absorbed and quickly excreted in urine, causing the urine to have a bright yellow tint. natural sources of riboflavin include meat, fish and fowl, eggs, dairy products, green vegetables, mushrooms, and almonds. some countries require its addition to grains. riboflavin was discovered in 1920, isolated in 1933, and first synthesized in 1935. in its purified, solid form, it is a water-soluble yellow-orange crystalline powder. in addition to its function as a vitamin, it is used as a food coloring agent. biosynthesis takes place in bacteria, fungi and plants, but not animals. industrial synthesis of riboflavin was initially achieved using a chemical process, but current commercial manufacturing relies on fermentation methods using strains of fungi and genetically modified bacteria. definition riboflavin, also known as vitamin b2, is a water-soluble vitamin and is one of the b vitamins. unlike folate and vitamin b6, which occur in several chemically related forms known as vitamers, riboflavin is only one chemical compound. it is a starting compound in the synthesis of the coenzymes flavin mononucleotide (fmn, also known as riboflavin-5'-phosphate) and flavin adenine dinucleotide (fad). fad is the more abundant form of flavin, reported to bind to 75% of the number of flavin-dependent protein encoded genes in the all-species genome (the flavoproteome) and serves as a co-enzyme for 84% of human-encoded flavoproteins. in its purified, solid form, riboflavin is a yellow-orange crystalline powder with a slight odor and bitter taste. it is soluble in polar solvents, such as water and aqueous sodium chloride solutions, and slightly soluble in alcohols. it is not soluble in non-polar or weakly polar organic solvents such as chloroform, benzene or acetone. in solution or during dry storage as a powder, riboflavin is heat stable if not exposed to light. when heated to decompose, it releases toxic fumes containing nitric oxide. functions riboflavin is essential to the formation of two major coenzymes, fmn and fad. these coenzymes are involved in energy metabolism, cell respiration, antibody production, growth and development. riboflavin is essential for the metabolism of carbohydrates, protein and fats. fad contributes to conversion of tryptophan to niacin (vitamin b3) and the conversion of vitamin b6 to the coenzyme pyridoxal 5'-phosphate requires fmn. riboflavin is involved in maintaining normal circulating levels of homocysteine; in riboflavin deficiency, homocysteine levels increase, elevating the risk of cardiovascular diseases. redox reactions redox reactions are processes that involve the transfer of electrons. the flavin coenzymes support the function of roughly 70-80 flavoenzymes in humans (and hundreds more across all organisms, including those encoded by archeal, bacterial and fungal genomes) that are responsible for one- or two-electron redox reactions which capitalize on the ability of flavins to be converted between oxidized, half-reduced and fully reduced forms. fad is also required for the activity of glutathione reductase, an essential enzyme in formation of the endogenous antioxidant, glutathione. micronutrient metabolism riboflavin, fmn, and fad are involved in the metabolism of niacin, vitamin b6, and folate. the synthesis of the niacin-containing coenzymes, nad and nadp, from tryptophan involves the fad-dependent enzyme, kynurenine 3-monooxygenase. dietary deficiency of riboflavin can decrease the production of nad and nadp, thereby promoting niacin deficiency. conversion of vitamin b6 to its coenzyme, pyridoxal 5'-phosphate synthase, involves the enzyme, pyridoxine 5'-phosphate oxidase, which requires fmn. an enzyme involved in folate metabolism, 5,10-methylenetetrahydrofolate reductase, requires fad to form the amino acid, methionine, from homocysteine. riboflavin deficiency appears to impair the metabolism of the dietary mineral, iron, which is essential to the production of hemoglobin and red blood cells. alleviating riboflavin deficiency in people who are deficient in both riboflavin and iron improves the effectiveness of iron supplementation for treating iron-deficiency anemia. synthesis biosynthesis biosynthesis takes place in bacteria, fungi and plants, but not animals. the biosynthetic precursors to riboflavin are ribulose 5-phosphate and guanosine triphosphate. the former is converted to l-3,4-dihydroxy-2-butanone-4-phosphate while the latter is transformed in a series of reactions that lead to 5-amino-6-(d-ribitylamino)uracil. these two compounds are then the substrates for the penultimate step in the pathway, catalysed by the enzyme lumazine synthase in reaction ec 2.5.1.78. in the final step of the biosynthesis, two molecules of 6,7-dimethyl-8-ribityllumazine are combined by the enzyme riboflavin synthase in a dismutation reaction. this generates one molecule of riboflavin and one of 5-amino-6-(d-ribitylamino) uracil. the latter is recycled to the previous reaction in the sequence. conversions of riboflavin to the cofactors fmn and fad are carried out by the enzymes riboflavin kinase and fad synthetase acting sequentially. riboflavin is the biosynthetic precursor of fmn and fad industrial synthesis cultures of micrococcus luteus growing on pyridine (left) and succinic acid (right). the pyridine culture has turned yellow from the accumulation of riboflavin. the industrial-scale production of riboflavin uses various microorganisms, including filamentous fungi such as ashbya gossypii, candida famata and candida flaveri, as well as the bacteria corynebacterium ammoniagenes and bacillus subtilis. b. subtilis that has been genetically modified to both increase the production of riboflavin and to introduce an antibiotic (ampicillin) resistance marker, is employed at a commercial scale to produce riboflavin for feed and food fortification. by 2012, over 4,000 tonnes per annum were produced by such fermentation processes. in the presence of high concentrations of hydrocarbons or aromatic compounds, some bacteria overproduce riboflavin, possibly as a protective mechanism. one such organism is micrococcus luteus (american type culture collection strain number atcc 49442), which develops a yellow color due to production of riboflavin while growing on pyridine, but not when grown on other substrates, such as succinic acid. laboratory synthesis the first total synthesis of riboflavin was carried out by richard kuhn's group. a substituted aniline, produced by reductive amination using d-ribose, was condensed with alloxan in the final step: uses treatment of corneal thinning keratoconus is the most common form of corneal ectasia, a progressive thinning of the cornea. the condition is treated by corneal collagen cross-linking, which increases corneal stiffness. cross-linking is achieved by applying a topical riboflavin solution to the cornea, which is then exposed to ultraviolet a light. migraine prevention in its 2012 guidelines, the american academy of neurology stated that high-dose riboflavin (400 mg) is "probably effective and should be considered for migraine prevention," a recommendation also provided by the uk national migraine centre. a 2017 review reported that daily riboflavin taken at 400 mg per day for at least three months may reduce the frequency of migraine headaches in adults. research on high-dose riboflavin for migraine prevention or treatment in children and adolescents is inconclusive, and so supplements are not recommended. food coloring riboflavin is used as a food coloring (yellow-orange crystalline powder), and is designated with the e number, e101, in europe for use as a food additive. dietary recommendations the national academy of medicine updated the estimated average requirements (ears) and recommended dietary allowances (rdas) for riboflavin in 1998. the ears for riboflavin for women and men aged 14 and over are 0.9 mg/day and 1.1 mg/day, respectively; the rdas are 1.1 and 1.3 mg/day, respectively. rdas are higher than ears to provide adequate intake levels for individuals with higher than average requirements. the rda during pregnancy is 1.4 mg/day and the rda for lactating females is 1.6 mg/day. for infants up to the age of 12 months, the adequate intake (ai) is 0.3–0.4 mg/day and for children aged 1–13 years the rda increases with age from 0.5 to 0.9 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 riboflavin 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 united states. for women and men aged 15 and older the pri is set at 1.6 mg/day. the pri during pregnancy is 1.9 mg/day and the pri for lactating females is 2.0 mg/day. for children aged 1–14 years the pris increase with age from 0.6 to 1.4 mg/day. these pris are higher than the u.s. rdas. the efsa also considered the maximum safe intake and like the u.s. national academy of medicine, decided that there was not sufficient information to set an ul. recommended dietary allowances united states age group (years) rda for riboflavin (mg/d) 0–6 months0.3* 6–12 months0.4* 1–30.5 4–80.6 9–130.9 females 14–181.0 males 14–181.3 females 19+1.1 males 19+1.3 pregnant females1.4 lactating females1.6 * adequate intake for infants, no rda/rdi yet established population reference intakes european union age group (years) pri for riboflavin (mg/d) 7–11 months0.4 1–30.6 4–60.7 7–101.0 11–141.4 15–adult1.6 pregnant females1.9 lactating females2.0 safety in humans, there is no evidence for riboflavin toxicity produced by excessive intakes and absorption becomes less efficient as dosage increases. any excess riboflavin is excreted via the kidneys into urine, resulting in a bright yellow color known as flavinuria. during a clinical trial on the effectiveness of riboflavin for treating the frequency and severity of migraines, subjects were given up to 400 mg of riboflavin orally per day for periods of 3–12 months. abdominal pains and diarrhea were among the side effects reported. labeling for u.s. food and dietary supplement labeling purposes the amount in a serving is expressed as a percent of daily value (%dv). for riboflavin labeling purposes 100% of the daily value was 1.7 mg, but as of may 27, 2016, it was revised to 1.3 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. sources the united states department of agriculture, agricultural research service maintains a food composition database from which riboflavin content in hundreds of foods can be searched. source amount (mg) (per 100 grams) beef liver, pan-fried3.42 chicken liver, pan-fried2.31 whey protein powder2.02 salmon, cooked, wild/farmed0.49/0.14 cows' milk, whole0.41 (one cup) turkey, cooked, dark/breast0.38/0.21 pork, cooked, chop0.23 chicken eggs, fried0.23 (one, large) chicken, cooked, thigh/breast0.19/0.11 beef, ground, cooked0.18 source amount (mg) (per 100 grams) cheese, cheddar0.43 yogurt, whole milk0.25 (one cup) almonds1.14 mushrooms, white, raw0.40 spinach, boiled0.24 bread, baked, fortified0.25 pasta, cooked, fortified0.14 corn grits0.06 rice, cooked, brown/white0.05/0.00 source amount (mg) (per 100 grams) avocado0.14 kale, boiled0.14 sweet potato baked0.11 peanuts, roasted0.11 tofu, firm0.10 beans, green0.10 brussels sprouts, boiled0.08 romaine lettuce0.07 potato, baked, with skin0.05 beans, baked0.04 the milling of wheat results in an 85% loss of riboflavin, so white flour is enriched in some countries. riboflavin is also added to baby foods, breakfast cereals, pastas and vitamin-enriched meal replacement products. it is difficult to incorporate riboflavin into liquid products because it has poor solubility in water, hence the requirement for riboflavin-5'-phosphate (fmn, also called e101 when used as colorant), a more soluble form of riboflavin. the enrichment of bread and ready-to-eat breakfast cereals contributes significantly to the dietary supply of the vitamin. free riboflavin is naturally present in animal-sourced foods along with protein-bound fmn and fad. cows' milk