Riboflavin kinase and FAD synthetase (RFK / FLAD1)

Human flavokinase (Riboflavin kinase, RFK) and FAD synthetase (FLAD1) are the two essential enzymes that mediate the conversion of dietary riboflavin (Vitamin B2) into the vital cofactors flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD). RFK performs the initial phosphorylation of riboflavin to FMN, which is then adenylylated by FLAD1 to produce FAD. These cofactors are required for the activity of over 100 flavoproteins, including those in the mitochondrial respiratory chain, fatty acid beta-oxidation, and epigenetic regulators like lysine-specific demethylase 1 (LSD1). While these two activities are often combined in a single bifunctional enzyme in bacteria, they are distinct proteins in humans. These enzymes have emerged as potential therapeutic targets in various cancers, such as pancreatic ductal adenocarcinoma and triple-negative breast cancer, where their upregulation supports the high metabolic demands of tumor cells. Inhibition of the pathway can deplete cellular FAD levels, leading to mitochondrial failure and the induction of apoptosis or ferroptosis. Conversely, genetic deficiencies in FLAD1 lead to Multiple Acyl-CoA Dehydrogenase Deficiency (MADD), a severe metabolic disorder characterized by impaired fatty acid and amino acid metabolism.

Other names

RFKFLAD1FAD synthaseFMN adenylyltransferaseFlavokinaseRiboflavin kinase

Inhibition of riboflavin phosphorylation and FMN adenylylation to deplete cellular FAD and FMN cofactors.