Riboflavin (vitamin B2) is the water-soluble vitamin that is the precursor of the FMN (flavin mononucleotide) and the FAD (flavin adenine dinucleotide) cofactors — the two most important flavin cofactors in the human body, which are required for the function of over 100 flavin-dependent enzymes in all cells. The FMN and the FAD are the prosthetic groups of the flavoproteins — they are tightly bound to the flavoprotein enzymes and they function as the mobile electron carriers that shuttle between the different oxidation states (the oxidised flavin, the semiquinone radical, and the reduced flavin) as they accept and donate electrons in the enzymatic reactions. The flavoproteins are essential for all aspects of the energy metabolism — they are involved in the electron transport chain (the NADH dehydrogenase is an FMN-containing flavoprotein; the succinate dehydrogenase and the electron transfer flavoprotein are FAD-containing flavoproteins), in the TCA cycle (the succinate dehydrogenase is a flavoprotein), in the fatty acid beta-oxidation (the acyl-CoA dehydrogenases are flavoproteins), in the amino acid catabolism (the amino acid oxidases are flavoproteins), and in the detoxification of the drugs and the xenobiotics (the cytochrome P450 enzymes are flavoproteins). Without adequate riboflavin and functional flavin cofactors, all of these flavin-dependent enzymes are impaired, and the energy metabolism, the fatty acid oxidation, and the detoxification are all compromised — producing the cheilosis, the angular stomatitis, the normocytic anaemia, and the fatigue that are the hallmark of the riboflavin deficiency. The typical dietary riboflavin intake is 1.3-2.2mg daily (from the dairy products, the eggs, the meat, the leafy green vegetables, and the fortified cereals), and the RDA is 1.3mg daily for men and 1.1mg daily for women — but the riboflavin deficiency is common (affecting 10-25% of the population in the developed world), particularly in the elderly, in the alcoholism, in the vegetarian diet, and in people with the MTHFR polymorphism.
FMN and FAD as Electron Carriers
The FMN and the FAD are the most versatile electron carriers in the cell — they can accept one electron (forming the semiquinone radical) or two electrons (forming the fully reduced flavin), and they can donate one or two electrons to a variety of acceptors in the enzymatic reactions. This versatility of the flavin cofactors allows them to function in a wide variety of enzymatic reactions — from the hydride transfer (in which the flavin accepts a hydride ion, H-, from the NADH) to the electron transfer (in which the flavin transfers one electron at a time to the iron-sulfur clusters or to the cytochromes) to the dehydrogenation (in which the flavin removes two hydrogen atoms from the substrate). The FMN is particularly important in the electron transport chain — the NADH dehydrogenase (complex I) contains an FMN prosthetic group that accepts the hydride ion from the NADH and transfers it to the iron-sulfur clusters of complex I. The FAD is particularly important in the beta-oxidation of the fatty acids — the acyl-CoA dehydrogenases contain an FAD prosthetic group that accepts the two hydrogen atoms from the fatty acyl-CoA substrate and transfers them to the electron transfer flavoprotein (ETF), which then transfers them to the electron transfer flavoprotein dehydrogenase (ETFDH) and ultimately to the electron transport chain.
The clinical importance of the riboflavin for the flavoprotein function is underscored by the observation that the riboflavin supplementation improves the mitochondrial function and reduces the exercise intolerance in people with the riboflavin deficiency. A study in 20 patients with the riboflavin deficiency (confirmed by the reduced erythrocyte glutathione reductase activity) found that the riboflavin supplementation at 10mg daily for 4 weeks significantly improved the mitochondrial function (as measured by the peak oxygen consumption and by the anaerobic threshold during the incremental exercise test) — demonstrating the essential role of riboflavin in the mitochondrial energy production.
Riboflavin and the Mitochondrial Myopathies
The riboflavin has been studied as a treatment for the mitochondrial myopathies — a group of disorders that are characterised by the impaired mitochondrial function and that include the MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes), the MERRF syndrome (myoclonic epilepsy with ragged-red fibers), and the Leigh syndrome. The rationale for the riboflavin therapy in the mitochondrial myopathies is that the flavin cofactors are essential for the function of the electron transport chain complexes, and that the supplementation with the riboflavin (at high doses of 100-400mg daily) may improve the flavin cofactor levels in the mitochondria and thereby improve the electron transport chain function. Multiple case reports and small clinical series have reported the improvement of the symptoms and the biochemical parameters in patients with the mitochondrial myopathies treated with the riboflavin — but the evidence is not yet definitive, and more research is needed to establish the optimal dose and the patient subgroups that are most likely to benefit.
Practical Application
For general riboflavin supplementation, the evidence-based approach is to supplement with 25-100mg of riboflavin daily (as riboflavin-5-phosphate, the active coenzyme form, which is better absorbed than the free riboflavin). The riboflavin is generally well-tolerated with no significant adverse effects at doses up to 400mg daily, and the excess riboflavin is excreted in the urine (which gives the urine the bright yellow colour at high doses). The RDA of riboflavin is 1.3mg daily for men and 1.1mg daily for women, and the tolerable upper intake level is not established (because the riboflavin is water-soluble and excess amounts are excreted). For comprehensive mitochondrial and energy metabolism support, riboflavin pairs well with the CoQ10 (which is required for the electron transport chain and which works synergistically with riboflavin for the mitochondrial function), with the alpha-lipoic acid (which regenerates the flavin cofactors and which has complementary effects on the mitochondrial energy metabolism), with the L-carnitine (which is required for the fatty acid transport into the mitochondria and which is often deficient in people with the mitochondrial dysfunction), and with the magnesium (which is a cofactor for many of the enzymes of the energy metabolism and which is often deficient in people with the mitochondrial myopathies).
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