Riboflavin

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. ==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. 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. ==Synthesis==

Biosynthesis Biosynthesis takes place in bacteria, fungi and plants, but not animals. : 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. : Industrial synthesis '' (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), ==Dietary recommendations==

The National Academy of Medicine updated the Estimated Average Requirements (EARs) and Recommended Dietary Allowances (RDAs) for riboflavin in 1998. 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 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. 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. A table of the old and new adult daily values is provided at Reference Daily Intake. ==Sources==

More than 90% of riboflavin in the diet is in the form of protein-bound FMN and FAD. Absorption occurs via a rapid active transport system, with some additional passive diffusion occurring at high concentrations. Infants with mutations in the genes encoding these transport proteins can be treated with riboflavin administered orally. However, riboflavin supplementation in large excess of requirements causes urine to appear more yellow than normal. With normal dietary intake, about two-thirds of urinary output is riboflavin, the remainder having been partially metabolized to hydroxymethylriboflavin from oxidation within cells, and as other metabolites. When consumption exceeds the ability to absorb, riboflavin passes into the large intestine, where it is catabolized by bacteria to various metabolites that can be detected in feces. ==Deficiency==

Prevalence Riboflavin deficiency is uncommon in the United States and in other countries with wheat flour or corn meal fortification programs. For all age groups, on average, consumption from food exceeded the RDAs. A 2001-02 U.S. survey reported that less than 3% of the population consumed less than the Estimated Average Requirement of riboflavin. Signs and symptoms Riboflavin deficiency (also called ariboflavinosis) results in stomatitis, symptoms of which include chapped and fissured lips, inflammation of the corners of the mouth (angular stomatitis), sore throat, painful red tongue, and hair loss. Prolonged riboflavin insufficiency may cause degeneration of the liver and nervous system. Risk factors People at risk of having low riboflavin levels include alcoholics, vegetarian athletes, and practitioners of veganism. One of these is riboflavin transporter deficiency, previously known as Brown–Vialetto–Van Laere syndrome. Riboflavin excretion rates decrease as a person ages, but increase during periods of chronic stress and the use of some prescription drugs. Indicators used in humans are erythrocyte glutathione reductase (EGR), erythrocyte flavin concentration and urinary excretion. The erythrocyte glutathione reductase activity coefficient (EGRAC) provides a measure of tissue saturation and long-term riboflavin status. Results are expressed as an activity coefficient ratio, determined by enzyme activity with and without the addition of FAD to the culture medium. An EGRAC of 1.0 to 1.2 indicates that adequate amounts of riboflavin are present; 1.2 to 1.4 is considered low, greater than 1.4 indicates deficient. For the less sensitive "erythrocyte flavin method", values greater than 400 nmol/L are considered adequate and values below 270 nmol/L are considered deficient. Urinary excretion is expressed as nmol of riboflavin per gram of creatinine. Low is defined as in the range of 50 to 72 nmol/g. Deficient is below 50 nmol/g. Urinary excretion load tests have been used to determine dietary requirements. For adult men, as oral doses were increased from 0.5 mg to 1.1 mg, there was a modest linear increase in urinary riboflavin, reaching 100 micrograms for a subsequent 24-hour urine collection. Beyond a load dose of 1.1 mg, urinary excretion increased rapidly, so that with a dose of 2.5 mg, urinary output was 800 micrograms for a 24-hour urine collection. ==History==

The name "riboflavin" comes from "ribose" (the sugar whose reduced form, ribitol, forms part of its structure) and "flavin", the ring-moiety that imparts the yellow color to the oxidized molecule (from Latin flavus, "yellow").) Vitamin B was further thought to have two components, a heat-labile substance called B1 and a heat-stable substance called B2. Vitamin B2 was tentatively identified to be the factor necessary for preventing pellagra, but that was later confirmed to be due to niacin (vitamin B3) deficiency. The confusion was due to the fact that riboflavin (B2) deficiency causes stomatitis symptoms similar to those seen in pellagra, but without the widespread peripheral skin lesions. For this reason, early in the history of identifying riboflavin deficiency in humans the condition was sometimes called "pellagra sine pellagra" (pellagra without pellagra). In 1935, Paul Gyorgy, in collaboration with chemist Richard Kuhn and physician T. Wagner-Jauregg, reported that rats kept on a B2-free diet were unable to gain weight. Isolation of B2 from yeast revealed the presence of a bright yellow-green fluorescent product that restored normal growth when fed to rats. The growth restored was directly proportional to the intensity of the fluorescence. This observation enabled the researchers to develop a rapid chemical bioassay in 1933, and then isolate the factor from egg white, calling it ovoflavin. In 1938, Richard Kuhn was awarded the Nobel Prize in Chemistry for his work on vitamins, which had included B2 and B6. In 1939, it was confirmed that riboflavin is essential for human health through a clinical trial conducted by William H. Sebrell and Roy E. Butler. Women fed a diet low in riboflavin developed stomatitis and other signs of deficiency, which were reversed when treated with synthetic riboflavin. The symptoms returned when the supplements were stopped. ==See also==