Riboflavin (vitamin B2) is the water-soluble vitamin that is the precursor of the flavin mononucleotide (FMN) and of the flavin adenine dinucleotide (FAD) — the two coenzyme forms of riboflavin that are the essential cofactors for the wide range of the flavin-dependent enzymes that are involved in the carbohydrate metabolism, the fatty acid oxidation, the amino acid metabolism, and the oxidative stress defence. Riboflavin is converted to FMN by the riboflavin kinase enzyme (which uses ATP as the phosphate donor) and to FAD by the FAD synthetase enzyme (which uses ATP as the AMP donor), and both FMN and FAD are used as cofactors by the flavin-dependent enzymes — the FMN is used primarily by the NADH dehydrogenase complex of the mitochondrial electron transport chain, and the FAD is used by a wide range of dehydrogenases and oxidoreductases, including the pyruvate dehydrogenase complex, the alpha-ketoglutarate dehydrogenase complex, the succinate dehydrogenase complex, the fatty acyl-CoA dehydrogenase, and the glutathione reductase. Without adequate riboflavin, FMN, and FAD, the flavin-dependent enzymes cannot function, and the carbohydrate metabolism, the fatty acid oxidation, and the antioxidant defence are all compromised — producing the ariboflavinosis (the clinical syndrome of riboflavin deficiency), which is characterised by the cheilosis (the inflammation and the fissuring of the lips), the glossitis (the magenta tongue), the seborrhoeic dermatitis (the scaly, red rash on the face, nasolabial folds, and scrotum), and the normocytic anaemia.
FAD and the Mitochondrial Dehydrogenases
The FAD is the essential cofactor for the mitochondrial dehydrogenases — the enzymes that transfer the electrons from their substrates to the electron transport chain. The FAD is covalently attached to the active site of these enzymes (forming the flavin covalent bond), and it accepts the electrons from the substrate in the form of a hydride ion (H-), forming the reduced flavin (FADH2). The FADH2 then transfers the electrons to the iron-sulfur clusters of the electron transport chain, and this electron transfer is coupled to the proton pumping across the inner mitochondrial membrane and to the synthesis of the ATP. The FAD-dependent mitochondrial dehydrogenases include the pyruvate dehydrogenase complex (the E3 component, dihydrolipoamide dehydrogenase), the alpha-ketoglutarate dehydrogenase complex (the E3 component), the succinate dehydrogenase complex (complex II of the electron transport chain), and the fatty acyl-CoA dehydrogenases (the enzymes that catalyse the first step of the beta-oxidation of the fatty acids). Without adequate FAD, these mitochondrial dehydrogenases cannot function, and the electron transport chain cannot be fed with the electrons from the NADH and the FADH2 that are produced by the carbohydrate and the fat metabolism — this is the primary mechanism of the energy failure that characterises the riboflavin deficiency.
The clinical importance of the FAD for the mitochondrial energy metabolism is underscored by the observation that the riboflavin deficiency produces a characteristic reduction in the activity of the mitochondrial electron transport chain complexes (particularly complex I and complex II), which is the diagnostic marker of the riboflavin deficiency in the muscle and in the blood cells. The riboflavin supplementation restores the electron transport chain activity and reverses the metabolic dysfunction — confirming the essential role of the riboflavin in the mitochondrial energy metabolism.
Riboflavin and the Glutathione Reductase
The glutathione reductase (GR) is an FAD-dependent enzyme that maintains the reduced glutathione (GSH) pool in the cells — it reduces the oxidised glutathione (GSSG) back to the reduced GSH using the NADPH as the electron donor, and this reaction is essential for the maintenance of the antioxidant defence system. The reduced glutathione is the primary intracellular antioxidant — it neutralises the hydrogen peroxide and the lipid hydroperoxides through the action of the glutathione peroxidase (GPx), and it also directly reduces the radicals and the other reactive oxygen species. Without the adequate FAD and the functional GR, the GSSG cannot be reduced back to the GSH, the GSH pool is depleted, and the antioxidant defence is compromised — this is one of the most important mechanisms of the oxidative stress that is associated with the riboflavin deficiency.
Practical Application
For general riboflavin supplementation, the evidence-based approach is to supplement with 10-50mg of riboflavin daily (as the riboflavin or as the riboflavin-5-phosphate form, which is the active coenzyme form). The RDA of riboflavin is 1.3mg daily for men and 1.1mg daily for women, and it is easily obtained from a varied diet (dairy products, eggs, meat, fish, poultry, leafy green vegetables, whole grains). The riboflavin is generally well-tolerated with no significant adverse effects at doses up to 100mg daily, and the excess riboflavin is excreted in the urine (which gives the urine the characteristic bright yellow colour at high doses). For comprehensive energy metabolism and antioxidant support, riboflavin pairs well with the other B-complex vitamins (which are required for the function of the other cofactor-dependent enzymes in the energy metabolism pathway), with the magnesium (which is required for the conversion of the riboflavin to the FMN and the FAD), and with the iron (which is required for the synthesis of the haemoglobin and whose deficiency is the most common cause of the microcytic anaemia).
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