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Riboflavin and energy metabolism

Riboflavin and energy metabolism

Individuals with FMO3 metabolims have increased levels of Riboflavin and energy metabolism in urine, sweat, and breath Alcohol Alcohol. A clear genotype-phenotype correlation has been reported with the heterogenous subtypes of MADD.

Riboflavin and energy metabolism -

Riboflavin is a key component of coenzymes involved with the growth of cells, energy production, and the breakdown of fats, steroids, and medications. For pregnancy and lactation, the amount increases to 1.

UL: A Tolerable Upper Intake Level UL is the maximum daily dose unlikely to cause adverse side effects in the general population. A UL has not been established for riboflavin, because a toxic level has not been observed from food sources or from longer-term intakes of high-dose supplements.

Because riboflavin assists many enzymes with various daily functions throughout the body, a deficiency can lead to health problems. Animal studies show that the brain and heart disorders and some cancers can develop from long-term riboflavin deficiency.

Riboflavin works to reduce oxidative stress and inflammation of nerves, which are contributors to migraine headaches. The vitamin is also needed for normal mitochondrial activities; migraines are sometimes caused by mitochondrial abnormalities in the brain. Therefore riboflavin has been studied as a prophylactic therapy for preventing migraines.

Because some people appear to benefit from the supplements, they are inexpensive, and side effects have been minimal, the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society concluded that riboflavin is probably effective for preventing migraine headaches and approved its use as a complementary treatment.

Riboflavin regulates circulating levels of homocysteine, an amino acid that enters the diet from animal protein foods like meat. High levels in the blood are a risk factor for cardiovascular disease CVD. Riboflavin works with other B vitamins like B6 , folate , and B12 to break down homocysteine in the body.

Animal studies show heart abnormalities and increased biomarkers for heart disease in riboflavin-deficient rodents, as well as cardioprotective effects of riboflavin by increasing the production of antioxidant enzymes.

Epidemiological studies have not shown that lowering homocysteine levels with B vitamin supplementation reduces the risk of heart attacks or deaths from CVD. Riboflavin is found mostly in meat and fortified foods but also in some nuts and green vegetables.

A riboflavin deficiency is very rare in the United States. Disorders of the thyroid can increase the risk of a deficiency. A riboflavin deficiency most often occurs with other nutrient deficiencies, such as in those who are malnourished.

Symptoms may include:. A toxic level of riboflavin has not been observed from food sources and supplements. Grey Solid. Light Grey Solid.

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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 , isolated in , and first synthesized in 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.

Riboflavin, also known as vitamin B 2 , is a water-soluble vitamin and is one of the B vitamins. 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.

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.

When heated to decompose, it releases toxic fumes containing nitric oxide. Riboflavin is essential to the formation of two major coenzymes, FMN and FAD. Redox reactions are processes that involve the transfer of electrons.

The flavin coenzymes support the function of roughly 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.

Riboflavin, FMN, and FAD are involved in the metabolism of niacin, vitamin B 6 , and folate. Dietary deficiency of riboflavin can decrease the production of NAD and NADP, thereby promoting niacin deficiency. 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.

The former is converted to L-3,4-dihydroxybutanonephosphate while the latter is transformed in a series of reactions that lead to 5-amino 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. In the final step of the biosynthesis, two molecules of 6,7-dimethylribityllumazine are combined by the enzyme riboflavin synthase in a dismutation reaction.

This generates one molecule of riboflavin and one of 5-amino 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.

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. 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.

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 , 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.

The first total synthesis of riboflavin was carried out by Richard Kuhn 's group. 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. In its guidelines, the American Academy of Neurology stated that high-dose riboflavin mg is "probably effective and should be considered for migraine prevention," [22] a recommendation also provided by the UK National Migraine Centre.

Riboflavin is used as a food coloring yellow-orange crystalline powder , [8] and is designated with the E number , E, in Europe for use as a food additive. The National Academy of Medicine updated the Estimated Average Requirements EARs and Recommended Dietary Allowances RDAs for riboflavin in The EARs [update] for riboflavin for women and men aged 14 and over are 0.

RDAs are higher than EARs to provide adequate intake levels for individuals with higher than average requirements. The RDA during pregnancy is 1. For infants up to the age of 12 months, the Adequate Intake AI is 0.

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. The PRI during pregnancy is 1. For children aged 1—14 years the PRIs increase with age from 0.

These PRIs are higher than the U. National Academy of Medicine, decided that there was not sufficient information to set an UL.

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.

Abdominal pains and diarrhea were among the side effects reported. For U. 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.

Riboflavin is also added to baby foods , breakfast cereals , pastas and vitamin-enriched meal replacement products. Free riboflavin is naturally present in animal-sourced foods along with protein-bound FMN and FAD.

Cows' milk contains mainly free riboflavin, but both FMN and FAD are present at low concentrations. Some countries require or recommend fortification of grain foods. The amounts stipulated range from 1. For example, the Indian government recommends 4.

Absorption occurs via a rapid active transport system, with some additional passive diffusion occurring at high concentrations. Riboflavin is reversibly converted to FMN and then FAD. From riboflavin to FMN is the function of zinc-requiring riboflavin kinase ; the reverse is accomplished by a phosphatase.

From FMN to FAD is the function of magnesium-requiring FAD synthase; the reverse is accomplished by a pyrophosphatase. FAD appears to be an inhibitory end-product that down-regulates its own formation. When excess riboflavin is absorbed by the small intestine, it is quickly removed from the blood and excreted in urine.

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.

Riboflavin deficiency is uncommon in the United States and in other countries with wheat flour or corn meal fortification programs. For the non-supplement users, the dietary intake of adult women averaged 1.

These amounts exceed the RDAs for riboflavin of 1. 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.

People at risk of having low riboflavin levels include alcoholics , vegetarian athletes, and practitioners of veganism. Riboflavin deficiency is usually found together with other nutrient deficiencies, particularly of other water-soluble vitamins.

Derivatives Ruboflavin the vitamin riboflavin, FAD and FMN, are Riboflavij cofactors Ribofalvin a multitude of Anthocyanins and blood pressure regulation reactions, indispensable Cranberry baking recipes lipid metabolism and also are requisites Anthocyanins and blood pressure regulation Riboflain oxidative stress. Given that a balance between all rnergy processes contributes to anx maintenance of metabllism homeostasis, effective regulation of riboflavin Healthy snacks to curb appetite in the Riboflavin and energy metabolism is paramount. However, various genetic Non-prescription mood lifter dietary factors have brought to fore pathological conditions that co-occur with a suboptimal level of flavins in the retina. Our focus in this review is to, comprehensively summarize all the possible metabolic and oxidative reactions which have been implicated in various retinal pathologies and to highlight the contribution flavins may have played in these. Recent research has found a sensitive method of measuring flavins in both diseased and healthy retina, presence of a novel flavin binding protein exclusively expressed in the retina, and the presence of flavin specific transporters in both the inner and outer blood-retina barriers. In light of these exciting findings, it is even more imperative to shift our focus on how the retina regulates its flavin homeostasis and what happens when this is disrupted.

Riboflavin and energy metabolism -

Circa , riboflavin was also referred to as "Vitamin G". Sebrell and Roy E. Women fed a diet low in riboflavin developed stomatitis and other signs of deficiency, which were reversed when treated with synthetic riboflavin.

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Micronutrient Information Center, Linus Pauling Institute, Oregon State University. Public Health Nutr. MetaCyc Metabolic Pathway Database. Retrieved 21 November Journal of Pharmaceutical Sciences. Textbook of Biochemistry: with Clinical Correlations 7th ed.

Applied and Environmental Microbiology. Bibcode : ApEnM.. Applied Microbiology and Biotechnology. Angewandte Chemie. Berichte der Deutschen Chemischen Gesellschaft A and B Series in German. A review of the state of the art of the technique and new perspectives".

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Toggle limited content width. Chemical structure. Many [1]. lactochrome, lactoflavin, vitamin G [2]. If the vitamin is exposed to too much light, it can be deactivated from its usable form. Therefore milk is now typically sold in cartons or opaque plastic containers to block light.

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Search for:. Home Nutrition News What Should I Eat? Vitamin B2 and Health Because riboflavin assists many enzymes with various daily functions throughout the body, a deficiency can lead to health problems.

Migraines Riboflavin works to reduce oxidative stress and inflammation of nerves, which are contributors to migraine headaches. A randomized controlled trial of 55 adults with migraines were given either mg daily of riboflavin or a placebo and followed for four months. The authors noted that a beneficial effect of riboflavin did not start until after the first month, and showed maximum benefit after three months of use.

A systematic review of 11 clinical trials on riboflavin as a prophylactic treatment for migraines found mixed results. The dose for adults was typically mg daily, and for children mg daily, given for three months.

There were no negative side effects observed from the supplements. Cardiovascular disease Because riboflavin assists many enzymes with various daily functions throughout the body, a deficiency can lead to health problems.

References U. Department of Health and Human Services. Vitamin B2 Fact Sheet for Health Professionals. Institute of Medicine. Food and Nutrition Board. Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline.

Washington, DC: National Academy Press; Schoenen J, Jacquy J, Lenaerts M. Thompson DF, Saluja HS. Prophylaxis of migraine headaches with riboflavin: a systematic review.

Journal of clinical pharmacy and therapeutics. Holland S, Silberstein SD, Freitag F, Dodick DW, Argoff C, Ashman E.

The food constituent, riboflavin, fnergy is the Anthocyanins and blood pressure regulation of Ribofoavin health claim, is sufficiently characterised. Contribution to normal energy-yielding metabolism is metanolism Non-prescription mood lifter Nutritional guidelines effect for infants and young children. Mehabolism claim on African mango fruit extract and contribution to normal energy-yielding metabolism in the general population has already been assessed with a favourable outcome. The Panel notes that the role of riboflavin on normal energy-yielding metabolism applies to all ages, including infants and young children from birth to three years. The Panel concludes that a cause and effect relationship has been established between the dietary intake of riboflavin and contribution to normal energy-yielding metabolism. Riboflavin and energy metabolism

The food constituent, riboflavin, which is Riboflavin and energy metabolism subject of the health Roboflavin, is sufficiently characterised. Contribution to Natural cholesterol remedies energy-yielding mmetabolism is a beneficial physiological effect for infants and young children.

A claim on riboflavin and Rivoflavin to normal energy-yielding metabolism in the general population has already been assessed with metabo,ism favourable outcome. The Panel notes that the role Non-prescription mood lifter riboflavin on normal energy-yielding metabolism adn to all ages, Ribofllavin infants and young children from birth to three years.

Riboflavin and energy metabolism Panel concludes that metbolism cause and effect relationship has been established between the dietary intake of riboflavin and contribution to normal energy-yielding metabolism. An official EU website. An official website of the European Union. Other sites EFSA Open EFSA EFSA Journal Connect.

Published :. Adopted :. Wiley Online Library. Full article :. Read online at EFSA Journal. Full article online viewer. Meta data DOI. riboflavin, vitamin B2, infants, children, energy-yielding metabolism, health claims. On request from.

Competent Authority of France following an application by Specialised Nutrition Europe formerly IDACE. Question Number. Nutrition, Novel Foods and Food Allergens. Panel members at the time of adoption.

Carlo Agostoni, Roberto Berni Canani, Susan Fairweather-Tait, Marina Heinonen, Hannu Korhonen, Sébastien La Vieille, Rosangela Marchelli, Ambroise Martin, Androniki Naska, Monika Neuhäuser-Berthold, Grażyna Nowicka, Yolanda Sanz, Alfonso Siani, Anders Sjödin, Martin Stern, Sean J.

Strain, Inge Tetens, Daniel Tomé, Dominique Turck and Hans Verhagen. nda efsa. Related topic s Claims on disease risk reduction and child development or health under Article 14 Nutrition.

: Riboflavin and energy metabolism

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Sharper Image Journey Lite 28" Hardside Check. One such example is highlighted by Petrovski et al. But she was completely non-responsive to this treatment and only upon exome sequencing it was discovered that the child had a compound heterozygous genotype of two loss of function mutations in SLC52A2 , a brain-specific riboflavin transporter.

But recent discoveries are indicating that the effects of riboflavin deficiency are not limited to only neurological disorders in new-born babies Olsen et al.

In another recent case report, a previously healthy year old woman was suddenly presented with severe hearing and vision loss within 6 months and subsequently led to bilateral optic nerve atrophy, dysphagia, severe dyspnea, and quadriplegia Camargos et al.

Upon whole-exome sequencing, she was found to be carrying a novel homozygous insertion of 60 bp in SLC52A3 , another riboflavin transporter Camargos et al. Similarly, adult patients suffering from riboflavin deficiency due to malnutrition have been previously reported to have developed significant vision problems, including reduced rod and cone responses Kruse et al.

However, the majority of these studies date back a few decades and the renewed spotlight on vision loss due to riboflavin transporter mutation, calls for a comprehensive review of how diet or genetically induced riboflavin deficiency may affect the retina.

The retina is a complex tissue lying at the back of the eye and formed of multiple layers of neuronal cells Figure 1. Being metabolically active in both darkness and under light makes the retina Figure 1 one of the most energy-consuming tissue as well as one of the most flavin enriched tissues.

Thus, our focus in this review is to lay the foundation for future research on flavin homeostasis in the retina by highlighting the metabolic pathways flavins are intrinsically involved in and how dysregulation of these pathways is known to be associated with various debilitating retinal pathologies.

Figure 1. Graphical illustration of the cellular layers of retina and the activity during the light and dark cycles. The chemical structure of the tricyclic molecule riboflavin aka 7,8-dimethylbenzo-pteridine-2,4-dione is constituted of a ribitil side chain attached to an isoalloxazine ring, which is a benzene ring attached to a pteridine ring system Figure 2 ; Massey, ; Powers, The presence of the pteridine ring gives it the name benzopteridine and reflects its relationship with another pteridine-based biochemical, i.

For biological functioning, riboflavin is converted either to a phosphorylated flavin mononucleotide, FMN or an adenylated flavin adenine dinucleotide, FAD form of active redox coenzymes Saedisomeolia and Ashoori, The conversion of riboflavin to FMN is catalyzed by the enzyme flavokinase or riboflavin kinase, which is an ATP dependent phosphotransferase EC 2.

Most FMN is then converted to FAD by FAD synthetase, which is an adenylyltransferase EC 2. Even though multiple mutations in FAD synthetase have been reported to result in critical flavin deficient conditions, interestingly, none of these patients were found to have any structural or functional abnormalities in vision.

Figure 2. Structures of various flavins and their subsequent excitation upon blue-light exposure. Isoalloxazine ring is shown in red while riboflavin structure is shown as highlighted in orange. Reaction 1 is catalyzed by riboflavin kinase and reaction 2 is catalyzed by FAD synthetase.

The importance of flavins is underlined by the chemistry of the compound Massey, The biological activity of flavins is governed by the chemical versatility of the isoalloxazine ring.

This is because it can exist in three different forms: oxidized, one-electron reduced, and the two-electron reduced state Figure 2 ; Rivlin, It is important to note that these possible active states of all three flavins have mostly been detected in biological systems as protein-bound form and not in free form.

This is of relevance as, compared to the free form in aqueous state, association with proteins markedly alters the stability of the one-electron reduced state Joosten and van Berkel, ; McDonald et al. Though both non-covalent and covalent association can modulate flavin redox properties, but they act in a differential manner and is contingent upon the type of interaction Massey, ; McDonald et al.

Interestingly, most of the flavoenzymes have non-covalently than covalently bound FAD or FMN as cofactors Joosten and van Berkel, Being tricyclic gives flavins the ability to efficiently function as a transformer between electron donors and electron acceptors while the central dihydropyrazine ring of dihydroflavins is highly reactive to molecular oxygen, thus acting as a cofactor for reduction of molecular oxygen to hydrogen peroxide and also for reductive activity of monooxygenation reactions Giulian et al.

All three forms of flavins, i. There are primarily two forms of photosensitization reactions they can take part in: I direct reaction between biomolecules and photosensitized flavins and II oxygen-dependent interaction between photosensitized flavins and biomolecules Insinska-Rak and Sikorski, ; Fuentes-Lemus and Lopez-Alarcon, ; Fuentes-Lemus et al.

However, both these oxidation reactions are undertaken when the isoalloxazine ring of flavins is excited upon exposure to blue light Cardoso et al. As stated in the above section, both the one-electron and two-electron reduced forms of flavins Figure 2 are highly reactive and thus leads to the formation of free radicals Lopez-Alarcon et al.

Due to this, flavins have been found to execute photosensitized oxidation of both lipid and protein biomolecules Cardoso et al. In type-I reactions, the two-electron reduced flavin Figure 2 is quenched by the amino acid or lipid moieties most prone to be oxidized, resulting in the formation of a biomolecule radical cation and a flavin radical anion.

The flavin radical anion can either react with oxygen to yield superoxide radical or accept a proton from the biomolecule radical cation or other donors to yield neutral free radicals. Subsequently, these neutral free radicals react with oxygen to form peroxyl radicals and eventually lead to the formation of hydroperoxides Insinska-Rak and Sikorski, ; Fuentes-Lemus and Lopez-Alarcon, These species are further prone to decomposition in presence of redox active metal ions to yield alkoxyl radicals, which can add to the oxidative damage Cardoso et al.

Detailed investigations have revealed that among all the amino acids, tryptophan is most susceptible to such flavin-sensitized photo-oxidation in an oxygen-independent mechanism Bhatia et al. Excited state riboflavin binds to tryptophan under a light-induced reaction and leads to cytotoxicities like axonal degeneration and further cascade of photo-adduct formation Silva et al.

Lipid peroxidation is also a common pathological marker of blue light mediated photo-toxicity in the retina Wenzel et al.

The retina is known to harbor a hypoxic environment and is frequently exposed to blue light for an extended period of time even in artificially lit conditions, thus making a hotspot for such oxygen independent flavin photosensitization reactions Jaadane et al. In type-II reactions, the two-electron reduced flavin directly reacts with O 2 to convert it into the singlet state oxygen.

This highly reactive form of oxygen can diffuse across a radius of 50— nm away from the site of formation and rapidly oxidize biomolecules like tryptophan, tyrosine, histidine, methionine, and cysteine amino acid residues since their kinetic rate constants are in the range of 10 6 —10 7 M —1 s —1.

This is interesting since elevated methionine and cysteine oxidation and multiple protein oxidation markers are a common phenomenon in various age related retinal pathologies, especially age-related macular degeneration Organisciak et al.

Since the eye is directly exposed to light, the cytotoxic effect of flavins acting as photosensitizers is even more common and specifically such photo-induced protein oxidation of retinal ganglion cells have been found to compromise mitochondrial efficiency Silva et al. Such protein oxidation and lipid peroxidation can compromise protein function, enzymatic activity, and membrane integrity, as well as elevate reactive oxygen species Huvaere et al.

Also increased fluorescence of the oxidized form of mitochondrial flavoproteins has come up as a new tool to diagnose oxidative stress in retinal diseases, especially diabetic retinopathy and age-related macular degeneration Spaide and Klancnik, ; Elner et al.

However, whether flavins as photosensitizers can affect the structure and function of photoreceptors or the retinal pigment epithelium RPE needs to be investigated. This is especially important given these two cells have the highest demand for riboflavin in the retina Sinha et al. Blue light induced damage to the retina has been extensively investigated for decades and it is well established that the mechanism involves mitochondrial complexes as potential initiators of this phototoxic effect [reviews in Wenzel et al.

Further mechanistic evaluation of blue light toxicity to the retina is outside the scope of this review. Here we focused on elucidating that flavins as photosensitizers can also be a major factor in blue light induced retinal damage and need to be considered in future mechanistic studies.

Besides facilitating oxidation, exposure to light in acellular aqueous phase can lead to degradation of riboflavin itself, as has been previously reviewed Sheraz et al. However, when we recently looked at the various conditions affecting riboflavin stability in the retina, we found protecting the retina from light by dark adaptation did not result in a change in retinal flavin levels Sinha et al.

Thus, it is likely that retinal riboflavin, similar to retinoids Gonzalez-Fernandez et al. The neural retina NR and the RPE together comprise the retina, which is one of the hotspots of highly reactive species in the whole body.

The extremely high metabolic state of this tissue coupled with the high rate of oxygen consumption and the presence of multiple highly reactive phototransduction intermediates makes the retina vulnerable to various oxidative reactions. Thus, it is not surprising that to maintain homeostasis, the retina has developed an efficient system that counts on the ready availability of multiple electron acceptors and free radical scavengers.

This is probably one of the reasons why both FAD and FMN are so highly enriched in the NR and the RPE Sinha et al. The whole eye as an organ harbors arguably the highest level of riboflavin in the whole body normalized to total protein content , and even though the cornea takes the major share of this, but it uses riboflavin mostly for structural purposes Batey and Eckhert, , ; Batey et al.

The RPE and closely followed by the NR have the highest concentration of both the functional forms of riboflavin, FAD and FMN, and they are used critically as metabolic cofactors and free radical scavengers Sinha et al.

It has been well elucidated that the glutathione based free radical scavenging system is highly dependent on flavins Beutler, Glutathione peroxidase GPx reduces the intracellular H 2 O 2 and toxic fatty acid hydroperoxides to water and in turn, GSH reduced form to GSSG oxidized form.

Glutathione reductase GR , the enzyme that restores intracellular GSH reduced form levels by reducing GSSG oxidized form in an NADPH-mediated reaction, utilizes FAD as a cofactor Higashi et al.

Imbalance in the glutathione system has been shown to cause elevated retinal lipid peroxidation Puertas et al. GSH depletion itself is a major cause of RPE ferroptosis and autophagy in a mitochondria independent manner Sun et al. Absence of GSH downregulated RPE GPx GPx4 , a ferroptosis modulator, and increased LC3 expression, an autophagic marker Sun et al.

That riboflavin deficiency in experimental animals results in downregulation of GSH expression, reduced activity of GPx and increased lipid peroxidation in the eye, further raises the question if similar comorbidity happens in patients with retinal pathologies Hirano et al.

If GSH cannot be recycled from GSSG due to reduced flavins, the RPE is unable to take up GSH exogenously and instead resorts to synthesizing it from secondary sources like glutamate, glycine, and cysteine Davidson et al.

This has a cascade effect on cellular metabolism as multiple metabolic resources now need to be repurposed to facilitate the adequate supply of these three amino acids. As an example, glucose is partially shunted away from glycolysis into the serine biosynthesis pathway, which is then converted to glycine Sekhar et al.

The RPE already harbors an efficient serine biosynthesis pathway in physiological conditions that may be upregulated to support enhanced GSH requirements.

Interestingly, in the NR, even though the photoreceptors lack the repertoire for serine biosynthesis, Müller Cells MC has been shown to have the ability to synthesize serine and glycine for GSH production Zhang et al.

Another close association between flavin deficiency and oxidative imbalance is via impaired mitochondrial redox balance, which is a major risk factor for ocular diseases like macular degeneration and diabetic retinopathy Datta et al.

Patterson Patterson and Bates, observed reduced oxygen consumption by the mitochondria in weanling rats fed riboflavin deficient diet associated with reduced weight gain per unit of food consumed Tandler et al.

Extremely hypoxic conditions can trigger reverse electron transfer and induce FMN to undergo reductive dissociation from complex-I of mitochondria, resulting in a robust decrease in complex-I function Gostimskaya et al.

Furthermore, significant accumulation of the reduced FMN can result in an equimolar amount of H 2 O 2 in the mitochondrial matrix and can significantly contribute to oxidative stress Massey, ; Kahl et al.

Absence of flavins would also affect the β-oxidation of fatty acids in the RPE, which in turn would affect the flow of β-hydroxybutyrate to the retinal microenvironment, thus negatively impacting both the metabolic needs of the photoreceptors as well as the expression of oxidative stress resistance factors, as noted in other neurodegenerative disorders Shimazu et al.

At the opposite extreme, Eckhert Eckhert et al. However, this is the only report exhibiting toxicity from excess riboflavin in the eye.

Interestingly the following work by the same group showed that rats fed excess riboflavin were unable to increase the residual amount of flavins in the retina Batey et al. So, what contributed to the degeneration is still a mystery.

Indeed, it was shown that fold higher levels of FMN can potently inhibit GR activity in in vitro conditions Schorah and Messenger, But in physiological conditions, excess riboflavin is rapidly cleared out from the body Yang and McCormick, Thus, to speculate that excess riboflavin could be responsible for oxidative damage, it is important to first investigate what conditions can result in a buildup of excess riboflavin in the retina.

It has been shown that riboflavin plays a very prominent role in energy and glucose metabolism Reddi et al. The retina is a metabolically active tissue with a high rate of energy demand and glucose consumption Futterman and Kinoshita, a , b.

This is further validated by the highest activity of hexokinase in the inner segment of photoreceptors compared to the other cells of the NR as well as the brain Burch et al. This high activity is required for visual transduction as well as for the synthesis of new photoreceptor OS proteins, building new OS discs, and the shedding process.

Using radioactive methionine, Young et al. showed that in rat, mouse, and frog, proteins synthesized in the photoreceptor IS are trafficked to OS in an ordered fashion, get accumulated in the lamellae in OS and subsequently are removed via shedding from the tip of OS in a light-dependent manner Young, For this to effectively occur, a constant supply of energy and metabolites is required in the vicinity of the photoreceptors.

To accommodate the high energy requirement, research on cattle and rabbit retinas demonstrated that high oxygen and glucose consumption occur via glycolysis, TCA cycle, and pentose phosphate pathway Winkler, Ames and colleagues showed that the retinal energy reserves are small, and withdrawal of glucose affects both the scotopic-a and b-wave of ERG electroretinogram , which is an in vivo electrophysiological measurement of the retina Ames et al.

Surprisingly though, it had no immediate effect on oxygen consumption, indicating an alternate source of substrates for oxidative phosphorylation Ames, This is in agreement with ex vivo results by Winkler showing that most of the glucose in the NR is converted to lactate and that inhibition of GAPDH glycolytic enzyme prevents the photoreceptors from having any extracellular potential, which is an ex vivo electrophysiological measurement of the photoreceptors and is similar to scotopic a-wave of the ERG.

Oxygen withdrawal, on the other hand, leads to a Pasteur-effect with 2. The large Pasteur-effect was explained by the hypothesis that in hypoxic conditions, dark current was partly supported by glycolysis. Following published work describing the utilization of non-oxidative metabolism of glucose by neuronal cells of the retina, Pellerin and colleagues showed that upon glutamate release at excitatory synapses, glucose utilization and lactate production were stimulated Pellerin and Magistretti, Thus, glycolytic lactate production in the retina is tied with neurotransmission in the dark current Pellerin and Magistretti, Poitry-Yamate et al.

also argued that this lactate was observed to be a better substrate for photoreceptor oxidative metabolism, even though they do take up both lactate and glucose Poitry-Yamate et al. Winkler et al. Acknowledging species difference, the authors used rat NR as the avascular model and guinea pig NR as the vascular model.

Interestingly, their results showed that under aerobic conditions, photoreceptors tend to depend upon glucose as the principal energy substrate, as long as the supply is adequate Winkler et al.

To specifically delineate the metabolism of the outer retina, Wang et al. highlighted the importance of oxidative phosphorylation and aerobic glycolysis-based lactate formation under light and darkness Wang et al.

Linking oxygen consumption to the bioenergetics, Okawa et al. further looked at the difference in ATP consumption in light versus dark by rod photoreceptors Okawa et al. The authors found that the vertebrate rods consume about 10 8 ATP molecules per sec.

The most dominant energy consumption is due to the ion fluxes associated with phototransduction and synaptic transmission.

The authors also showed that the cones are more energy consuming than rods Okawa et al. Oxidative phosphorylation also seems to be the highest in photoreceptors compared to the rest of the NR since the highest cytochrome C activity electron transport chain enzyme is in the photoreceptors Kageyama and Wong-Riley, ; Giulian et al.

Stone et al. Working on the avascular retinas of zebrafish, Linton et al. However, in the vascularized retina, the dependency is less on creatine kinase Linton et al.

Perkins et al. Using ferret, cat, and monkey, Riley et al. showed similar evidence demonstrating that the IS of cones is more densely packed with mitochondria than that of rods Kageyama and Wong-Riley, This was supportive of the previous evidence that the cones consume more energy Scarpelli and Craig, The high density of mitochondria also reflects higher flavin requirement by the photoreceptors as most of the mitochondrial enzymes are flavin-dependent Ragan and Garland, Furthermore, the above also supports the notion that the inner segment of a photoreceptor is fueled by flavin based oxidative phosphorylation while the functioning of the outer segment could be fueled by aerobic glycolysis.

Ames found that the sodium-potassium ATPase transporters consumed about half of all the energy used by the NR, i. Since flavins play an important role in oxidative phosphorylation and all the critical components of oxidative phosphorylation are concentrated in the inner segment, it is logical to assume that the inner segment must have a pool of riboflavin derivatives.

It has been shown that the activity of some enzymes involved in oxidative phosphorylation is significantly lower in riboflavin deficient rats Zaman and Verwilghen, , thus indicating how an imbalance in flavin homeostasis can affect the retinal energy metabolism.

Powers et al. showed in various cell culture systems the importance of riboflavin for energy generation Lee et al. In fact, in absence of riboflavin, the cells seem to be under considerable oxidative stress due to the increasing supply-demand gap of ATP. Cells deficient in riboflavin have lower ATP levels and as flavokinase activity is less sensitive to ATP levels due to a fold lower Km than FAD synthetase, the levels of FAD drop further with diminishing levels of ATP Lee et al.

So even if excess riboflavin is provided at this point, until ATP levels reach the threshold in a flavin-independent mechanism, riboflavin would not be converted to FAD and oxidative phosphorylation cannot begin again. Thus, it is essential to maintain riboflavin homeostasis in the NR, such that glucose metabolism keeps functioning efficiently to meet the energy requirement of the photoreceptors.

It is evident that oxidative phosphorylation and glycolysis for both ATP production and biomolecular substrate generation in the NR have very unique dynamics. We know how important flavins are for all these processes.

Thus, it is justified that to maintain the dynamicity, effective flavin transport and homeostasis are crucial to the retina. This highlights the significance of lipid metabolism to the proper functionality of photoreceptors. Riboflavin deficient chicken embryos exhibit dysfunctional fatty acid metabolism whereby the significantly reduced activity of FAD-dependent medium acyl CoA dehydrogenases leads to the build-up of C10, C12, and C14 fatty acids Abrams et al.

The authors argue that the impairment of fatty acid oxidation drains out the carbohydrate reserves and in turn negatively impacts energy metabolism. The authors note that the only difference between the chicken and the adult humans and rats under riboflavin deficiency is that there is an increase of dicarboxylic acids fin both adult mammals but not for the chicken embryo Abrams et al.

There are several reports in the literature showing an impairment of β-oxidation of fatty acids as an effect of flavin deficient diet and the rationale behind this could be the depressed activity of the flavin-dependent dehydrogenases Olpin and Bates, ; Liao and Huang, ; Parsons and Dias, It is noteworthy that these dehydrogenases include all three alternate dehydrogenases; short, medium and long-chain fatty acyl-coenzyme A dehydrogenase.

All of these dehydrogenases are involved in the very first step of β-oxidation of fatty acids Tandler et al. The rate-limiting step seemed to be the flavin-dependent acyl-CoA dehydrogenase activity Tandler et al. The authors observed that the oxidation rates of both long-chain and intermediate chain fatty acid substrates dropped sharply as a result of ariboflavinosis Tandler et al.

It is widely accepted that impaired β-oxidation of fatty acids can significantly contribute to vision loss and that it causes hypoglycemia Taroni and Uziel, ; Kompare and Rizzo, Hypoketotic hypoglycemia, developed by patients having severely impaired β-oxidation of fatty acids Taroni and Uziel, and 3-hydroxyacyl-CoA dehydrogenase deficiencies Eaton et al.

Khan et al. This occurs in both normal subjects and those suffering from Type 1 diabetes, whereby, the central retina is preferentially affected Khan et al. In another study, Adijanto et al. The authors show that RPE cells produce a high amount of β-hydroxybutyrate by β-oxidation of fatty acids, and it is then shuttled to the photoreceptors via the monocarboxylate transporter 1 MCT1 Adijanto et al.

The substrate for ketogenesis via β-oxidation of fatty acids may come from the vast pool of fatty acids shed as photoreceptor OS, which is constitutively taken up by the RPE cells Boesze-Battaglia and Schimmel, It is also possible that β-hydroxybutyrate, besides helping in the metabolic needs of the photoreceptors, may act as a neuroprotective agent by suppressing oxidative stress in the retinal microenvironment Shimazu et al.

Thus, when the photoreceptor layer gets parched for riboflavin its fatty acid oxidation can be adversely affected. This, in turn, can have a cascading effect on the lipid metabolism of the RPE. Also, if riboflavin moves from the inner retina to the RPE Kubo et al.

Since mammals have lost the ability to de novo synthesize riboflavin, it is acquired from the diet Muller, Riboflavin absorption in the small intestine of rats and rabbits occurs across the brush border membrane in a specific carrier-mediated fashion, which is modulated by the level of riboflavin present in the vicinity Said and Mohammadkhani, ; Subramanian et al.

However, the body seems to get rid of excess plasma riboflavin within a span of a few hours, as has been reported for both animals Yang and McCormick, and humans Zempleni et al. In blood, riboflavin associates with plasma proteins like albumin Wang et al.

In the last decade, it has been found that the brain has different transporters that are specific to riboflavin transport Green et al. These are the same ones that have been identified earlier in other tissues. Recently, similar transporters were speculated to be present in the endothelial and epithelial cells of the inner and outer retina, respectively, as sh-RNA mediated knockdown and biochemical inhibition of these transporters resulted in decreased riboflavin uptake in TR-iBRB2, RPE-J and ARPE cells Said et al.

It was also shown that cultured RPE cells can take up riboflavin Said et al. At this juncture, it is important to state that most of the cellular riboflavin is known to be phosphorylated as in metabolic trapping to prevent its diffusion out of the cell Gastaldi et al.

The free form of riboflavin diffuses out of the cells into the plasma and is eventually excreted out in the urine Aw et al. However, it is not clear what happens to the riboflavin of the extracellular matrix.

Extracellular proteins, like riboflavin carrier proteins, may bind to riboflavin and prevent it from diffusing back to the plasma. That may explain why riboflavin carrier proteins have been reported in all those tissues where the concentration of riboflavin is more than that of blood plasma, making these proteins as major players in flavin homeostasis in these tissues Prasad et al.

Examples of these proteins are the riboflavin binding protein RBP of the chicken egg Rhodes et al. Based on these studies, a schematic depicting possible routes of flavin transport through the inner and outer retina is shown in Figure 3. Figure 3.

Potential routes of flavin transport into and out of the retina and enrichment around photoreceptors. Here we have shown the two potential routes for inflow and outflow of riboflavin through yet to be identified transporters present in both the RPE outer blood retina barrier and endothelial cells inner blood retina barrier.

Also shown is the localization of the retinal riboflavin binding protein, retbindin, and its enrichment of bound flavins around the photoreceptor inner segments and RPE-outer segment junction.

The concentration of total bound and free flavins riboflavin, FAD, and FMN in each tissue is determined by the metabolic demands of the tissue Muller, Hepatic and plasma levels have been quantified linking them to various pathologies Patterson and Bates, Besides liver and plasma, analyses of flavin levels in the brain have recently gained importance due to riboflavin transporter diseases receiving attention Yoshimatsu et al.

But despite the higher metabolic activity of the retina Ames et al. Euler and Adler were perhaps the first to report that the retina has a high riboflavin content Pirie, Batey et al.

then reported that rat NR harbors Subsequently, riboflavin content in fish and mammalian eyes were found to be high compared to other tissues Pirie, Later, Batey et al.

The mammalian cell does not have the machinery to retain excess riboflavin and hence it is excreted out in the urine within a short time Zempleni et al. The riboflavin absorption, distribution, and clearance in rats have long been extensively studied by Bessey et al.

using radioactive compounds Bessey et al. The animal flavoproteome known so far can be widely divided into two types: One type is the coenzyme form of flavin derivatives binding to apoproteins either by covalent or noncovalent bonds Macheroux et al.

Examples of this type would be acyl-CoA dehydrogenase Lienhart et al. The other type is proteins that associate with flavins and mostly act as flavin carriers or function to enrich flavins in specific tissues Powers et al. Examples of this type would be RBP found in a chicken egg Rhodes et al.

In a comprehensive review, Lienhart provides a detailed report on the human flavoproteome Lienhart et al. This underlines the importance of flavins in the proper physiological functioning of mammalian proteins. It is also important to note that most of the dysfunctionalities in flavoprotein pathologies are related to the mitochondrial, endoplasmic reticulum, and peroxisomal dysfunctionalities Lienhart et al.

This is not surprising in the case of the mitochondrial dysfunctionalities since a good number of the flavoproteins are located in the mitochondria and play a role in energy metabolism Chance et al. Flavoproteins associated endoplasmic and peroxisomal dysfunctionalities, on the other hand, point to the role flavins play in the exclusive functions performed by both organelles to aid in lipid metabolism Lienhart et al.

Among all the flavoproteins, the mammalian retinal Rtbdn is unique. Rtbdn has the highest sequence homology to RBP of the chicken egg Kelley et al. In mammals, primarily rod photoreceptors express Rtbdn and it is the only known riboflavin binding protein to be present in the retina Kelley et al.

What is most interesting is that Rtbdn is a peripheral membrane protein present on the extracellular side and attached to the membrane via electrostatic interactions Kelley et al.

Probably this enables the protein to bind to riboflavin present in the extracellular matrix. Rtbdn localizes mainly in two pools: one at the outer segment-RPE interface and the other around the inner segment of the photoreceptors Kelley et al.

Since multiple nutrients are exchanged between the NR and the RPE at the outer segment-RPE junction, it makes sense for Rtbdn to be highly enriched at this location to facilitate riboflavin transport back and forth between the NR and RPE Figure 3.

It would be worthwhile to validate this by investigating the rate of photoreceptor oxidative phosphorylation in absence of Rtbdn. But the importance of Rtbdn to a healthy retina is most obvious from the finding that in absence of Rtbdn, gradual degeneration is triggered Kelley et al.

Further, that this coincides with a decline in NR flavin levels, emphasizes how important Rtbdn is to maintain the retinal flavin demands.

But mechanistic understanding behind this is lacking. Rtbdn may interact with other accessory membrane proteins which facilitate the internalization of flavins from Rtbdn itself.

Also, since other flavoproteins are known to be unstable in absence of adequate flavins, whether the association of Rtbdn with the membrane is dependent on its binding to riboflavin is to be determined.

Blindness is reportedly the disease that can be caused by the most diverse set of gene mutations than any other disease known Punzo et al. Mutations in over different genes or gene loci are known to be associated with inherited retinal diseases IRDs RetNet, , Accessed May 27th, Metabolic vulnerability and predisposition to oxidative stress have been touted as an underlying facilitator for such multi-genic retinal diseases Leveillard et al.

Unsurprisingly, therapeutic interventions targeted to ameliorate metabolic stress has shown that it is indeed a promising approach to treat such a wide spectrum of blinding diseases Hurley and Chao, ; Wert et al. Given the importance of flavins in many metabolic pathways that are essential for retinal homeostasis, it is imperative to maintain optimum levels of flavins for a healthy retina.

As reported by Amemiya , the retina of rats fed with riboflavin deficient diet for 3 months showed clear signs of degeneration with edematous and disoriented MCs, disintegrating OS discs and RPE full of an abnormal number of lamellae. Interestingly, these seemed to be reversible since animals recovered when they were placed on a riboflavin enriched diet.

In absence of literature presenting ultrastructural images of the effects of long term riboflavin deficiency, one can assume that the high number of lamellae in the RPE even after 7 h shedding stops usually within few hours after the onset of the light cycle , is due to either slower rate of phagocytosis by the RPE or enhanced degenerating OS contributing to extended phagocytosis.

This is further supportive of previous evidence that rods express specific proteins that are essential for cone health Chalmel et al. Further, a significant reduction in retinal flavin levels in only rod specific degeneration models indicated they are responsible for the majority of retinal flavins Sinha et al.

Thus, rod death during retinitis pigmentosa or other retinal pathologies could result in a local ariboflavinic environment around the photoreceptors, leading to a starving condition for the cones, triggering cone death that usually follows rod death as observed in RP patients and in models of IRDs Punzo et al.

Due to its role in retinal homeostasis, when Rtbdn was eliminated from a model of cone-rod dystrophy, the degenerative process was exacerbated Genc et al. Expression of elevated levels of Rtbdn during retinal degeneration further indicated that the protein could be playing a protective role Genc et al.

It is possible that when confronted with a stressful condition as degeneration, the retina needs a higher level of energy, hence an increased need for flavins, to mitigate this insult and thus overexpresses Rtbdn.

It is worth mentioning that the absence of Rtbdn triggered a compromise in retinal vasculature integrity and led to the formation of vascular tufts Genc et al.

It would be worthwhile to see if such a trend is mimicked in other models of retinal degeneration as well and whether there is a difference between the behaviors of models of cone dominant mutations versus those resulting from rod dominant mutation.

A previous study Venkataswamy, described the various ways ariboflavinosis can affect different parts of the eye. The authors mention two previous reports by Pollak in and by Gordon in , emphasizing the ability of riboflavin alone to improve dark adaptation Pollak, However, supplementary evidence is lacking on these lines and needs to be validated by further research.

Given the fact that pathology as riboflavin transporter disease improves with flavin-enriched diet Timmerman and De Jonghe, ; Bashford et al. Putting all the research into perspective, it seems very important to look at both: 1 the role of flavin homeostasis in retinal physiology as well as 2 the role of flavin homeostasis in retinal pathologies, especially those where metabolic vulnerability and oxidative stress susceptibility is involved.

One of the tools available to us to assess the role of flavins in retinal homeostasis is the Rtbdn knockout model Kelley et al. The presence of a highly regulated barrier like the blood-retinal barrier, combined with the high energy metabolism in the retina, such specialized proteins seems critical for retinal homeostasis.

It is possible, that like RBP of the egg, Rtbdn, helps in the transport of riboflavin across the interphotoreceptor matrix and thus maintaining the high intracellular pool of riboflavin in the photoreceptors. It will also be beneficial to specifically identify the transporters that may be involved in riboflavin transport to the retina and investigate what happens if their levels are selectively altered, both in health and disease.

Future research should also focus on identifying mutations in either Rtbdn or any of the riboflavin transporters that cause or modify retinal degenerative diseases. Moreover, since so little is known about any of retinal riboflavin carrier proteins, biochemical and biophysical characterization of both Rtbdn and riboflavin transporters would provide us with a greater understanding as to how such high flavin levels are maintained in the retina.

Similarly, it will be worthwhile to investigate if flavin deficiency confounds retinal dystrophy in patients and whether maintaining optimum flavins provides better prognosis when the retina is under metabolic or oxidative stress.

Thus, it seems important to do more work on the role of flavin homeostasis with respect to the structural and functional integrity of the retina and further our knowledge on the criticality of this underappreciated vitamin to the retina. TS, MN, and MA-U contributed to writing and editing the manuscript.

All authors contributed to the article and approved the submitted version. This study was supported by a grant from the National Eye Institute EY to MN and MA-U.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Macy's | Hawthorn Mall Identification and characterization of new variants in FOXRED1 an expands the eenrgy spectrum associated metabolksm mitochondrial complex Detoxification and mental health deficiency. No use, distribution enervy reproduction is permitted which Riboflavin and energy metabolism not comply with these terms. Milk, Dnergy products, eenergy, and Riboflavin and energy metabolism meat are a major source of dietary riboflavin, but most plant- and animal derived foods contain at least small amounts of this vitamin 1, 6. Brown-Vialetto-Van Laere and Fazio Londe syndrome is associated with a riboflavin transporter defect mimicking mild MADD: a new inborn error of metabolism with potential treatment. Health Conditions Health Products Discover Tools Connect. Taylor RW, Pyle A, Griffin H, Blakely EL, Duff J, et al. Am J Physiol Cell Physiol ;C
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Open Access. Open Access Articles. Other sites EFSA Open EFSA EFSA Journal Connect. Published :. Adopted :. Wiley Online Library. Full article :. Read online at EFSA Journal. Full article online viewer. Meta data DOI. 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.

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. When heated to decompose, it releases toxic fumes containing nitric oxide.

Riboflavin is essential to the formation of two major coenzymes, FMN and FAD. Redox reactions are processes that involve the transfer of electrons. The flavin coenzymes support the function of roughly 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.

Riboflavin, FMN, and FAD are involved in the metabolism of niacin, vitamin B 6 , and folate. Dietary deficiency of riboflavin can decrease the production of NAD and NADP, thereby promoting niacin deficiency. 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.

The former is converted to L-3,4-dihydroxybutanonephosphate while the latter is transformed in a series of reactions that lead to 5-amino 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.

In the final step of the biosynthesis, two molecules of 6,7-dimethylribityllumazine are combined by the enzyme riboflavin synthase in a dismutation reaction. This generates one molecule of riboflavin and one of 5-amino 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. 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.

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.

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 , 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.

The first total synthesis of riboflavin was carried out by Richard Kuhn 's group. 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. In its guidelines, the American Academy of Neurology stated that high-dose riboflavin mg is "probably effective and should be considered for migraine prevention," [22] a recommendation also provided by the UK National Migraine Centre.

Riboflavin is used as a food coloring yellow-orange crystalline powder , [8] and is designated with the E number , E, in Europe for use as a food additive.

The National Academy of Medicine updated the Estimated Average Requirements EARs and Recommended Dietary Allowances RDAs for riboflavin in The EARs [update] for riboflavin for women and men aged 14 and over are 0. RDAs are higher than EARs to provide adequate intake levels for individuals with higher than average requirements.

The RDA during pregnancy is 1. For infants up to the age of 12 months, the Adequate Intake AI is 0. 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. The PRI during pregnancy is 1. For children aged 1—14 years the PRIs increase with age from 0. These PRIs are higher than the U.

National Academy of Medicine, decided that there was not sufficient information to set an UL. 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.

Abdominal pains and diarrhea were among the side effects reported. For U. 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.

Riboflavin is also added to baby foods , breakfast cereals , pastas and vitamin-enriched meal replacement products.

Free riboflavin is naturally present in animal-sourced foods along with protein-bound FMN and FAD. Cows' milk contains mainly free riboflavin, but both FMN and FAD are present at low concentrations.

Some countries require or recommend fortification of grain foods. The amounts stipulated range from 1. For example, the Indian government recommends 4. Absorption occurs via a rapid active transport system, with some additional passive diffusion occurring at high concentrations. Riboflavin is reversibly converted to FMN and then FAD.

From riboflavin to FMN is the function of zinc-requiring riboflavin kinase ; the reverse is accomplished by a phosphatase.

From FMN to FAD is the function of magnesium-requiring FAD synthase; the reverse is accomplished by a pyrophosphatase. FAD appears to be an inhibitory end-product that down-regulates its own formation. When excess riboflavin is absorbed by the small intestine, it is quickly removed from the blood and excreted in urine.

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. Riboflavin deficiency is uncommon in the United States and in other countries with wheat flour or corn meal fortification programs.

For the non-supplement users, the dietary intake of adult women averaged 1. These amounts exceed the RDAs for riboflavin of 1. 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.

People at risk of having low riboflavin levels include alcoholics , vegetarian athletes, and practitioners of veganism. Riboflavin deficiency is usually found together with other nutrient deficiencies, particularly of other water-soluble vitamins.

caused by poor vitamin sources in the regular diet or secondary, which may be a result of conditions that affect absorption in the intestine. Secondary deficiencies are typically caused by the body not being able to use the vitamin, or by an increased rate of excretion of the vitamin.

There are rare genetic defects that compromise riboflavin absorption, transport, metabolism or use by flavoproteins. Treatment with oral supplementation of high amounts of riboflavin is lifesaving. Other inborn errors of metabolism include riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency, also known as a subset of glutaric acidemia type 2 , and the CT variant of the methylenetetrahydrofolate reductase enzyme, which in adults has been associated with risk of high blood pressure.

The assessment of riboflavin status is essential for confirming cases with non-specific symptoms whenever deficiency is suspected.

Total riboflavin excretion in healthy adults with normal riboflavin intake is about micrograms per day, while excretion of less than 40 micrograms per day indicates deficiency. Indicators used in humans are erythrocyte glutathione reductase EGR , erythrocyte flavin concentration and urinary excretion.

An EGRAC of 1. Urinary excretion load tests have been used to determine dietary requirements.

Vitamin B2: Role, sources, and deficiency

Animal studies show that the brain and heart disorders and some cancers can develop from long-term riboflavin deficiency. Riboflavin works to reduce oxidative stress and inflammation of nerves, which are contributors to migraine headaches. The vitamin is also needed for normal mitochondrial activities; migraines are sometimes caused by mitochondrial abnormalities in the brain.

Therefore riboflavin has been studied as a prophylactic therapy for preventing migraines. Because some people appear to benefit from the supplements, they are inexpensive, and side effects have been minimal, the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society concluded that riboflavin is probably effective for preventing migraine headaches and approved its use as a complementary treatment.

Riboflavin regulates circulating levels of homocysteine, an amino acid that enters the diet from animal protein foods like meat. High levels in the blood are a risk factor for cardiovascular disease CVD. Riboflavin works with other B vitamins like B6 , folate , and B12 to break down homocysteine in the body.

Animal studies show heart abnormalities and increased biomarkers for heart disease in riboflavin-deficient rodents, as well as cardioprotective effects of riboflavin by increasing the production of antioxidant enzymes. Epidemiological studies have not shown that lowering homocysteine levels with B vitamin supplementation reduces the risk of heart attacks or deaths from CVD.

Riboflavin is found mostly in meat and fortified foods but also in some nuts and green vegetables. A riboflavin deficiency is very rare in the United States. Disorders of the thyroid can increase the risk of a deficiency. A riboflavin deficiency most often occurs with other nutrient deficiencies, such as in those who are malnourished.

Symptoms may include:. A toxic level of riboflavin has not been observed from food sources and supplements. The gut can only absorb a limited amount of riboflavin at one time, and an excess is quickly excreted in the urine.

The reason is due to riboflavin. If the vitamin is exposed to too much light, it can be deactivated from its usable form. Therefore milk is now typically sold in cartons or opaque plastic containers to block light. B Vitamins Vitamins and Minerals. The contents of this website are for educational purposes and are not intended to offer personal medical advice.

You should seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.

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Vitamin B2 and Health Because riboflavin assists many enzymes with various daily functions throughout the body, a deficiency can lead to health problems. Migraines Riboflavin works to reduce oxidative stress and inflammation of nerves, which are contributors to migraine headaches.

If GSH cannot be recycled from GSSG due to reduced flavins, the RPE is unable to take up GSH exogenously and instead resorts to synthesizing it from secondary sources like glutamate, glycine, and cysteine Davidson et al.

This has a cascade effect on cellular metabolism as multiple metabolic resources now need to be repurposed to facilitate the adequate supply of these three amino acids. As an example, glucose is partially shunted away from glycolysis into the serine biosynthesis pathway, which is then converted to glycine Sekhar et al.

The RPE already harbors an efficient serine biosynthesis pathway in physiological conditions that may be upregulated to support enhanced GSH requirements. Interestingly, in the NR, even though the photoreceptors lack the repertoire for serine biosynthesis, Müller Cells MC has been shown to have the ability to synthesize serine and glycine for GSH production Zhang et al.

Another close association between flavin deficiency and oxidative imbalance is via impaired mitochondrial redox balance, which is a major risk factor for ocular diseases like macular degeneration and diabetic retinopathy Datta et al. Patterson Patterson and Bates, observed reduced oxygen consumption by the mitochondria in weanling rats fed riboflavin deficient diet associated with reduced weight gain per unit of food consumed Tandler et al.

Extremely hypoxic conditions can trigger reverse electron transfer and induce FMN to undergo reductive dissociation from complex-I of mitochondria, resulting in a robust decrease in complex-I function Gostimskaya et al. Furthermore, significant accumulation of the reduced FMN can result in an equimolar amount of H 2 O 2 in the mitochondrial matrix and can significantly contribute to oxidative stress Massey, ; Kahl et al.

Absence of flavins would also affect the β-oxidation of fatty acids in the RPE, which in turn would affect the flow of β-hydroxybutyrate to the retinal microenvironment, thus negatively impacting both the metabolic needs of the photoreceptors as well as the expression of oxidative stress resistance factors, as noted in other neurodegenerative disorders Shimazu et al.

At the opposite extreme, Eckhert Eckhert et al. However, this is the only report exhibiting toxicity from excess riboflavin in the eye. Interestingly the following work by the same group showed that rats fed excess riboflavin were unable to increase the residual amount of flavins in the retina Batey et al.

So, what contributed to the degeneration is still a mystery. Indeed, it was shown that fold higher levels of FMN can potently inhibit GR activity in in vitro conditions Schorah and Messenger, But in physiological conditions, excess riboflavin is rapidly cleared out from the body Yang and McCormick, Thus, to speculate that excess riboflavin could be responsible for oxidative damage, it is important to first investigate what conditions can result in a buildup of excess riboflavin in the retina.

It has been shown that riboflavin plays a very prominent role in energy and glucose metabolism Reddi et al. The retina is a metabolically active tissue with a high rate of energy demand and glucose consumption Futterman and Kinoshita, a , b.

This is further validated by the highest activity of hexokinase in the inner segment of photoreceptors compared to the other cells of the NR as well as the brain Burch et al. This high activity is required for visual transduction as well as for the synthesis of new photoreceptor OS proteins, building new OS discs, and the shedding process.

Using radioactive methionine, Young et al. showed that in rat, mouse, and frog, proteins synthesized in the photoreceptor IS are trafficked to OS in an ordered fashion, get accumulated in the lamellae in OS and subsequently are removed via shedding from the tip of OS in a light-dependent manner Young, For this to effectively occur, a constant supply of energy and metabolites is required in the vicinity of the photoreceptors.

To accommodate the high energy requirement, research on cattle and rabbit retinas demonstrated that high oxygen and glucose consumption occur via glycolysis, TCA cycle, and pentose phosphate pathway Winkler, Ames and colleagues showed that the retinal energy reserves are small, and withdrawal of glucose affects both the scotopic-a and b-wave of ERG electroretinogram , which is an in vivo electrophysiological measurement of the retina Ames et al.

Surprisingly though, it had no immediate effect on oxygen consumption, indicating an alternate source of substrates for oxidative phosphorylation Ames, This is in agreement with ex vivo results by Winkler showing that most of the glucose in the NR is converted to lactate and that inhibition of GAPDH glycolytic enzyme prevents the photoreceptors from having any extracellular potential, which is an ex vivo electrophysiological measurement of the photoreceptors and is similar to scotopic a-wave of the ERG.

Oxygen withdrawal, on the other hand, leads to a Pasteur-effect with 2. The large Pasteur-effect was explained by the hypothesis that in hypoxic conditions, dark current was partly supported by glycolysis.

Following published work describing the utilization of non-oxidative metabolism of glucose by neuronal cells of the retina, Pellerin and colleagues showed that upon glutamate release at excitatory synapses, glucose utilization and lactate production were stimulated Pellerin and Magistretti, Thus, glycolytic lactate production in the retina is tied with neurotransmission in the dark current Pellerin and Magistretti, Poitry-Yamate et al.

also argued that this lactate was observed to be a better substrate for photoreceptor oxidative metabolism, even though they do take up both lactate and glucose Poitry-Yamate et al. Winkler et al. Acknowledging species difference, the authors used rat NR as the avascular model and guinea pig NR as the vascular model.

Interestingly, their results showed that under aerobic conditions, photoreceptors tend to depend upon glucose as the principal energy substrate, as long as the supply is adequate Winkler et al. To specifically delineate the metabolism of the outer retina, Wang et al. highlighted the importance of oxidative phosphorylation and aerobic glycolysis-based lactate formation under light and darkness Wang et al.

Linking oxygen consumption to the bioenergetics, Okawa et al. further looked at the difference in ATP consumption in light versus dark by rod photoreceptors Okawa et al. The authors found that the vertebrate rods consume about 10 8 ATP molecules per sec.

The most dominant energy consumption is due to the ion fluxes associated with phototransduction and synaptic transmission. The authors also showed that the cones are more energy consuming than rods Okawa et al.

Oxidative phosphorylation also seems to be the highest in photoreceptors compared to the rest of the NR since the highest cytochrome C activity electron transport chain enzyme is in the photoreceptors Kageyama and Wong-Riley, ; Giulian et al.

Stone et al. Working on the avascular retinas of zebrafish, Linton et al. However, in the vascularized retina, the dependency is less on creatine kinase Linton et al. Perkins et al. Using ferret, cat, and monkey, Riley et al.

showed similar evidence demonstrating that the IS of cones is more densely packed with mitochondria than that of rods Kageyama and Wong-Riley, This was supportive of the previous evidence that the cones consume more energy Scarpelli and Craig, The high density of mitochondria also reflects higher flavin requirement by the photoreceptors as most of the mitochondrial enzymes are flavin-dependent Ragan and Garland, Furthermore, the above also supports the notion that the inner segment of a photoreceptor is fueled by flavin based oxidative phosphorylation while the functioning of the outer segment could be fueled by aerobic glycolysis.

Ames found that the sodium-potassium ATPase transporters consumed about half of all the energy used by the NR, i. Since flavins play an important role in oxidative phosphorylation and all the critical components of oxidative phosphorylation are concentrated in the inner segment, it is logical to assume that the inner segment must have a pool of riboflavin derivatives.

It has been shown that the activity of some enzymes involved in oxidative phosphorylation is significantly lower in riboflavin deficient rats Zaman and Verwilghen, , thus indicating how an imbalance in flavin homeostasis can affect the retinal energy metabolism.

Powers et al. showed in various cell culture systems the importance of riboflavin for energy generation Lee et al. In fact, in absence of riboflavin, the cells seem to be under considerable oxidative stress due to the increasing supply-demand gap of ATP.

Cells deficient in riboflavin have lower ATP levels and as flavokinase activity is less sensitive to ATP levels due to a fold lower Km than FAD synthetase, the levels of FAD drop further with diminishing levels of ATP Lee et al.

So even if excess riboflavin is provided at this point, until ATP levels reach the threshold in a flavin-independent mechanism, riboflavin would not be converted to FAD and oxidative phosphorylation cannot begin again.

Thus, it is essential to maintain riboflavin homeostasis in the NR, such that glucose metabolism keeps functioning efficiently to meet the energy requirement of the photoreceptors. It is evident that oxidative phosphorylation and glycolysis for both ATP production and biomolecular substrate generation in the NR have very unique dynamics.

We know how important flavins are for all these processes. Thus, it is justified that to maintain the dynamicity, effective flavin transport and homeostasis are crucial to the retina. This highlights the significance of lipid metabolism to the proper functionality of photoreceptors.

Riboflavin deficient chicken embryos exhibit dysfunctional fatty acid metabolism whereby the significantly reduced activity of FAD-dependent medium acyl CoA dehydrogenases leads to the build-up of C10, C12, and C14 fatty acids Abrams et al.

The authors argue that the impairment of fatty acid oxidation drains out the carbohydrate reserves and in turn negatively impacts energy metabolism.

The authors note that the only difference between the chicken and the adult humans and rats under riboflavin deficiency is that there is an increase of dicarboxylic acids fin both adult mammals but not for the chicken embryo Abrams et al.

There are several reports in the literature showing an impairment of β-oxidation of fatty acids as an effect of flavin deficient diet and the rationale behind this could be the depressed activity of the flavin-dependent dehydrogenases Olpin and Bates, ; Liao and Huang, ; Parsons and Dias, It is noteworthy that these dehydrogenases include all three alternate dehydrogenases; short, medium and long-chain fatty acyl-coenzyme A dehydrogenase.

All of these dehydrogenases are involved in the very first step of β-oxidation of fatty acids Tandler et al. The rate-limiting step seemed to be the flavin-dependent acyl-CoA dehydrogenase activity Tandler et al.

The authors observed that the oxidation rates of both long-chain and intermediate chain fatty acid substrates dropped sharply as a result of ariboflavinosis Tandler et al. It is widely accepted that impaired β-oxidation of fatty acids can significantly contribute to vision loss and that it causes hypoglycemia Taroni and Uziel, ; Kompare and Rizzo, Hypoketotic hypoglycemia, developed by patients having severely impaired β-oxidation of fatty acids Taroni and Uziel, and 3-hydroxyacyl-CoA dehydrogenase deficiencies Eaton et al.

Khan et al. This occurs in both normal subjects and those suffering from Type 1 diabetes, whereby, the central retina is preferentially affected Khan et al. In another study, Adijanto et al. The authors show that RPE cells produce a high amount of β-hydroxybutyrate by β-oxidation of fatty acids, and it is then shuttled to the photoreceptors via the monocarboxylate transporter 1 MCT1 Adijanto et al.

The substrate for ketogenesis via β-oxidation of fatty acids may come from the vast pool of fatty acids shed as photoreceptor OS, which is constitutively taken up by the RPE cells Boesze-Battaglia and Schimmel, It is also possible that β-hydroxybutyrate, besides helping in the metabolic needs of the photoreceptors, may act as a neuroprotective agent by suppressing oxidative stress in the retinal microenvironment Shimazu et al.

Thus, when the photoreceptor layer gets parched for riboflavin its fatty acid oxidation can be adversely affected. This, in turn, can have a cascading effect on the lipid metabolism of the RPE. Also, if riboflavin moves from the inner retina to the RPE Kubo et al.

Since mammals have lost the ability to de novo synthesize riboflavin, it is acquired from the diet Muller, Riboflavin absorption in the small intestine of rats and rabbits occurs across the brush border membrane in a specific carrier-mediated fashion, which is modulated by the level of riboflavin present in the vicinity Said and Mohammadkhani, ; Subramanian et al.

However, the body seems to get rid of excess plasma riboflavin within a span of a few hours, as has been reported for both animals Yang and McCormick, and humans Zempleni et al.

In blood, riboflavin associates with plasma proteins like albumin Wang et al. In the last decade, it has been found that the brain has different transporters that are specific to riboflavin transport Green et al.

These are the same ones that have been identified earlier in other tissues. Recently, similar transporters were speculated to be present in the endothelial and epithelial cells of the inner and outer retina, respectively, as sh-RNA mediated knockdown and biochemical inhibition of these transporters resulted in decreased riboflavin uptake in TR-iBRB2, RPE-J and ARPE cells Said et al.

It was also shown that cultured RPE cells can take up riboflavin Said et al. At this juncture, it is important to state that most of the cellular riboflavin is known to be phosphorylated as in metabolic trapping to prevent its diffusion out of the cell Gastaldi et al.

The free form of riboflavin diffuses out of the cells into the plasma and is eventually excreted out in the urine Aw et al.

However, it is not clear what happens to the riboflavin of the extracellular matrix. Extracellular proteins, like riboflavin carrier proteins, may bind to riboflavin and prevent it from diffusing back to the plasma. That may explain why riboflavin carrier proteins have been reported in all those tissues where the concentration of riboflavin is more than that of blood plasma, making these proteins as major players in flavin homeostasis in these tissues Prasad et al.

Examples of these proteins are the riboflavin binding protein RBP of the chicken egg Rhodes et al. Based on these studies, a schematic depicting possible routes of flavin transport through the inner and outer retina is shown in Figure 3. Figure 3. Potential routes of flavin transport into and out of the retina and enrichment around photoreceptors.

Here we have shown the two potential routes for inflow and outflow of riboflavin through yet to be identified transporters present in both the RPE outer blood retina barrier and endothelial cells inner blood retina barrier.

Also shown is the localization of the retinal riboflavin binding protein, retbindin, and its enrichment of bound flavins around the photoreceptor inner segments and RPE-outer segment junction. The concentration of total bound and free flavins riboflavin, FAD, and FMN in each tissue is determined by the metabolic demands of the tissue Muller, Hepatic and plasma levels have been quantified linking them to various pathologies Patterson and Bates, Besides liver and plasma, analyses of flavin levels in the brain have recently gained importance due to riboflavin transporter diseases receiving attention Yoshimatsu et al.

But despite the higher metabolic activity of the retina Ames et al. Euler and Adler were perhaps the first to report that the retina has a high riboflavin content Pirie, Batey et al. then reported that rat NR harbors Subsequently, riboflavin content in fish and mammalian eyes were found to be high compared to other tissues Pirie, Later, Batey et al.

The mammalian cell does not have the machinery to retain excess riboflavin and hence it is excreted out in the urine within a short time Zempleni et al. The riboflavin absorption, distribution, and clearance in rats have long been extensively studied by Bessey et al.

using radioactive compounds Bessey et al. The animal flavoproteome known so far can be widely divided into two types: One type is the coenzyme form of flavin derivatives binding to apoproteins either by covalent or noncovalent bonds Macheroux et al.

Examples of this type would be acyl-CoA dehydrogenase Lienhart et al. The other type is proteins that associate with flavins and mostly act as flavin carriers or function to enrich flavins in specific tissues Powers et al.

Examples of this type would be RBP found in a chicken egg Rhodes et al. In a comprehensive review, Lienhart provides a detailed report on the human flavoproteome Lienhart et al. This underlines the importance of flavins in the proper physiological functioning of mammalian proteins.

It is also important to note that most of the dysfunctionalities in flavoprotein pathologies are related to the mitochondrial, endoplasmic reticulum, and peroxisomal dysfunctionalities Lienhart et al.

This is not surprising in the case of the mitochondrial dysfunctionalities since a good number of the flavoproteins are located in the mitochondria and play a role in energy metabolism Chance et al.

Flavoproteins associated endoplasmic and peroxisomal dysfunctionalities, on the other hand, point to the role flavins play in the exclusive functions performed by both organelles to aid in lipid metabolism Lienhart et al.

Among all the flavoproteins, the mammalian retinal Rtbdn is unique. Rtbdn has the highest sequence homology to RBP of the chicken egg Kelley et al. In mammals, primarily rod photoreceptors express Rtbdn and it is the only known riboflavin binding protein to be present in the retina Kelley et al.

What is most interesting is that Rtbdn is a peripheral membrane protein present on the extracellular side and attached to the membrane via electrostatic interactions Kelley et al.

Probably this enables the protein to bind to riboflavin present in the extracellular matrix. Rtbdn localizes mainly in two pools: one at the outer segment-RPE interface and the other around the inner segment of the photoreceptors Kelley et al.

Since multiple nutrients are exchanged between the NR and the RPE at the outer segment-RPE junction, it makes sense for Rtbdn to be highly enriched at this location to facilitate riboflavin transport back and forth between the NR and RPE Figure 3. It would be worthwhile to validate this by investigating the rate of photoreceptor oxidative phosphorylation in absence of Rtbdn.

But the importance of Rtbdn to a healthy retina is most obvious from the finding that in absence of Rtbdn, gradual degeneration is triggered Kelley et al. Further, that this coincides with a decline in NR flavin levels, emphasizes how important Rtbdn is to maintain the retinal flavin demands.

But mechanistic understanding behind this is lacking. Rtbdn may interact with other accessory membrane proteins which facilitate the internalization of flavins from Rtbdn itself. Also, since other flavoproteins are known to be unstable in absence of adequate flavins, whether the association of Rtbdn with the membrane is dependent on its binding to riboflavin is to be determined.

Blindness is reportedly the disease that can be caused by the most diverse set of gene mutations than any other disease known Punzo et al. Mutations in over different genes or gene loci are known to be associated with inherited retinal diseases IRDs RetNet, , Accessed May 27th, Metabolic vulnerability and predisposition to oxidative stress have been touted as an underlying facilitator for such multi-genic retinal diseases Leveillard et al.

Unsurprisingly, therapeutic interventions targeted to ameliorate metabolic stress has shown that it is indeed a promising approach to treat such a wide spectrum of blinding diseases Hurley and Chao, ; Wert et al.

Given the importance of flavins in many metabolic pathways that are essential for retinal homeostasis, it is imperative to maintain optimum levels of flavins for a healthy retina.

As reported by Amemiya , the retina of rats fed with riboflavin deficient diet for 3 months showed clear signs of degeneration with edematous and disoriented MCs, disintegrating OS discs and RPE full of an abnormal number of lamellae.

Interestingly, these seemed to be reversible since animals recovered when they were placed on a riboflavin enriched diet. In absence of literature presenting ultrastructural images of the effects of long term riboflavin deficiency, one can assume that the high number of lamellae in the RPE even after 7 h shedding stops usually within few hours after the onset of the light cycle , is due to either slower rate of phagocytosis by the RPE or enhanced degenerating OS contributing to extended phagocytosis.

This is further supportive of previous evidence that rods express specific proteins that are essential for cone health Chalmel et al. Further, a significant reduction in retinal flavin levels in only rod specific degeneration models indicated they are responsible for the majority of retinal flavins Sinha et al.

Thus, rod death during retinitis pigmentosa or other retinal pathologies could result in a local ariboflavinic environment around the photoreceptors, leading to a starving condition for the cones, triggering cone death that usually follows rod death as observed in RP patients and in models of IRDs Punzo et al.

Due to its role in retinal homeostasis, when Rtbdn was eliminated from a model of cone-rod dystrophy, the degenerative process was exacerbated Genc et al. Expression of elevated levels of Rtbdn during retinal degeneration further indicated that the protein could be playing a protective role Genc et al.

It is possible that when confronted with a stressful condition as degeneration, the retina needs a higher level of energy, hence an increased need for flavins, to mitigate this insult and thus overexpresses Rtbdn.

It is worth mentioning that the absence of Rtbdn triggered a compromise in retinal vasculature integrity and led to the formation of vascular tufts Genc et al.

It would be worthwhile to see if such a trend is mimicked in other models of retinal degeneration as well and whether there is a difference between the behaviors of models of cone dominant mutations versus those resulting from rod dominant mutation.

A previous study Venkataswamy, described the various ways ariboflavinosis can affect different parts of the eye. The authors mention two previous reports by Pollak in and by Gordon in , emphasizing the ability of riboflavin alone to improve dark adaptation Pollak, However, supplementary evidence is lacking on these lines and needs to be validated by further research.

Given the fact that pathology as riboflavin transporter disease improves with flavin-enriched diet Timmerman and De Jonghe, ; Bashford et al.

Putting all the research into perspective, it seems very important to look at both: 1 the role of flavin homeostasis in retinal physiology as well as 2 the role of flavin homeostasis in retinal pathologies, especially those where metabolic vulnerability and oxidative stress susceptibility is involved.

One of the tools available to us to assess the role of flavins in retinal homeostasis is the Rtbdn knockout model Kelley et al.

The presence of a highly regulated barrier like the blood-retinal barrier, combined with the high energy metabolism in the retina, such specialized proteins seems critical for retinal homeostasis.

It is possible, that like RBP of the egg, Rtbdn, helps in the transport of riboflavin across the interphotoreceptor matrix and thus maintaining the high intracellular pool of riboflavin in the photoreceptors. It will also be beneficial to specifically identify the transporters that may be involved in riboflavin transport to the retina and investigate what happens if their levels are selectively altered, both in health and disease.

Future research should also focus on identifying mutations in either Rtbdn or any of the riboflavin transporters that cause or modify retinal degenerative diseases. Moreover, since so little is known about any of retinal riboflavin carrier proteins, biochemical and biophysical characterization of both Rtbdn and riboflavin transporters would provide us with a greater understanding as to how such high flavin levels are maintained in the retina.

Similarly, it will be worthwhile to investigate if flavin deficiency confounds retinal dystrophy in patients and whether maintaining optimum flavins provides better prognosis when the retina is under metabolic or oxidative stress.

Thus, it seems important to do more work on the role of flavin homeostasis with respect to the structural and functional integrity of the retina and further our knowledge on the criticality of this underappreciated vitamin to the retina. TS, MN, and MA-U contributed to writing and editing the manuscript.

All authors contributed to the article and approved the submitted version. This study was supported by a grant from the National Eye Institute EY to MN and MA-U.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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B Vitamins - B1, B2, B3, B5, B6, B7, B9, B12

Author: Dulkree

2 thoughts on “Riboflavin and energy metabolism

  1. Ich denke, dass Sie nicht recht sind. Ich kann die Position verteidigen. Schreiben Sie mir in PM.

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