Riboflavin (vitamin B2) uptake and FMN/FAD cofactor synthesis (SLC52A1/2/3 -> RFK -> FLAD1)

Riboflavin (vitamin B2) is the precursor of the flavin coenzymes FMN and FAD, which are the redox cofactors of dozens of flavoenzymes in mitochondrial fatty-acid and amino-acid oxidation, the respiratory chain, one-carbon and folate metabolism, and many oxidoreductases. Humans cannot synthesise riboflavin and must take it up from the diet, then convert it intracellularly to the active cofactors. Dietary and cellular riboflavin uptake is mediated by the three plasma-membrane SLC52 riboflavin transporters: SLC52A3 (RFVT3), the principal intestinal apical absorptive transporter; SLC52A2 (RFVT2), broadly expressed including brain; and SLC52A1 (RFVT1), important in placenta for maternal-fetal transfer. In the cytosol riboflavin kinase (RFK) phosphorylates riboflavin (ATP) to flavin mononucleotide (FMN), and FAD synthase (FLAD1) then adenylylates FMN (ATP) to flavin adenine dinucleotide (FAD). Defects in the transporters cause riboflavin transporter deficiency: SLC52A2/SLC52A3 loss-of-function causes Brown-Vialetto-Van Laere syndrome / Fazio- Londe disease (childhood sensorimotor neuronopathy with deafness and bulbar palsy, treatable with high-dose riboflavin), and maternal SLC52A1 deficiency causes transient neonatal multiple acyl-CoA dehydrogenase deficiency; FLAD1 deficiency causes a riboflavin-responsive lipid-storage myopathy / MADD-like disorder.