flavin-mononucleotide and Metabolism--Inborn-Errors

The aim of this short review chapter is to provide a brief summary of the relevance of riboflavin (Rf or vitamin B2) and its derived cofactors flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) for human neuromuscular bioenergetics.Therefore, as a completion of this book we would like to summarize what kind of human pathologies could derive from genetic disturbances of Rf transport, flavin cofactor synthesis and delivery to nascent apoflavoproteins, as well as by alteration of vitamin recycling during protein turnover.

Topics: Energy Metabolism; Flavin Mononucleotide; Flavin-Adenine Dinucleotide; Genetic Predisposition to Disease; Humans; Metabolism, Inborn Errors; Muscle, Skeletal; Neurons; Riboflavin

As an essential vitamin, the role of riboflavin in human diet and health is increasingly being highlighted. Insufficient dietary intake of riboflavin is often reported in nutritional surveys and population studies, even in non-developing countries with abundant sources of riboflavin-rich dietary products. A latent subclinical riboflavin deficiency can result in a significant clinical phenotype when combined with inborn genetic disturbances or environmental and physiological factors like infections, exercise, diet, aging and pregnancy. Riboflavin, and more importantly its derivatives, flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), play a crucial role in essential cellular processes including mitochondrial energy metabolism, stress responses, vitamin and cofactor biogenesis, where they function as cofactors to ensure the catalytic activity and folding/stability of flavoenzymes. Numerous inborn errors of flavin metabolism and flavoenzyme function have been described, and supplementation with riboflavin has in many cases been shown to be lifesaving or to mitigate symptoms. This review discusses the environmental, physiological and genetic factors that affect cellular riboflavin status. We describe the crucial role of riboflavin for general human health, and the clear benefits of riboflavin treatment in patients with inborn errors of metabolism.

Topics: Acyl-CoA Dehydrogenases; Aging; Animals; Diet; Electron Transport; Energy Metabolism; Fatty Acids; Female; Flavin Mononucleotide; Flavin-Adenine Dinucleotide; Folic Acid; Genetic Variation; Homocysteine; Humans; Immune System; Metabolism, Inborn Errors; Mitochondria; Mutation; Phenotype; Pregnancy; Protein Folding; Riboflavin; Riboflavin Deficiency

Multiple acyl-CoA dehydrogenation disorders result from generalized defects in intramitochondrial acyl-CoA dehydrogenation. Fibroblasts from a riboflavin-responsive multiple acyl-CoA dehydrogenation disorder patient catabolized 14C-butyrate, -octanoate, and -leucine normally after culture in riboflavin-supplemented medium (2 mg/L). After culture in riboflavin-depleted medium (< or = 1.4 micrograms/L), his cells oxidized the same substrates poorly at 20 to 33% of control (p < 0.05). Patient cells incubated in a wide range of D-[2-14C]riboflavin concentrations (3, 31.4, and 100 micrograms/L) synthesized 14C-flavin mononucleotide and 14C-flavin adenine dinucleotide (FAD) normally and had normal cytosolic 14C-flavin mononucleotide and 14C-FAD contents, which argues against defects in cellular riboflavin uptake and conversion to flavin mononucleotide and FAD. After culture in 31.4 micrograms 14C-riboflavin/L for 2 wk, 14C-FAD specific radioactivities plateaued and were similar in patient and control cells. However, culturing these uniformly labeled cells in riboflavin-depleted medium for 2 wk lowered the patient's cellular 14C-FAD content to only 23% of control levels. Similarly, after incubation in low 14C-riboflavin concentrations (4.4 micrograms/L), the patient's mitochondrial 14C-FAD content was only 51% of control after 1 h and 29% of control at 4 h. After a 4-h incubation in a high physiologic concentration of 14C-riboflavin (31.4 micrograms/L), which raised the patient's cellular 14C-FAD levels 3- to 4-fold, his mitochondrial 14C-FAD content rose to normal; control values did not change. We also investigated possible defective FAD binding to flavoenzymes essential for acyl-CoA dehydrogenation.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acyl Coenzyme A; Acyl-CoA Dehydrogenase; Cells, Cultured; Child, Preschool; Electron-Transferring Flavoproteins; Fatty Acid Desaturases; Fibroblasts; Flavin Mononucleotide; Flavin-Adenine Dinucleotide; Flavoproteins; Humans; Male; Metabolism, Inborn Errors; Mitochondria; Oxidation-Reduction; Riboflavin

Topics: Acyl Coenzyme A; Butyrates; Butyric Acid; Cells, Cultured; Fibroblasts; Flavin Mononucleotide; Flavin-Adenine Dinucleotide; Humans; Male; Metabolism, Inborn Errors; Mitochondria; Oxidation-Reduction; Phenotype; Riboflavin

Topics: Animals; Antigens; Carrier Proteins; Chick Embryo; Chromatography, Gel; Eggs; Flavin Mononucleotide; Flavins; Genes, Recessive; Heterozygote; Immunodiffusion; Immunoelectrophoresis; Metabolism, Inborn Errors; Methods; Mutation; Ovalbumin; Poultry Diseases; Rabbits; Riboflavin