FAD / FADH₂

FAD and FADH₂ are the oxidized and fully reduced forms of flavin adenine dinucleotide, a redox cofactor used by many enzymes. FAD contains a flavin group derived from riboflavin, or vitamin B2, linked to an adenine nucleotide. Its flavin portion can accept electrons and protons during oxidation-reduction reactions, allowing enzyme-bound FAD to be reduced to FADH₂ and later oxidized back to FAD .^1,2

FAD is frequently bound tightly to enzymes known as flavoproteins rather than diffusing freely between enzymes as NAD⁺ and NADH often do. Within these enzymes, the flavin group can participate directly in oxidation of metabolic substrates. For example, FAD in succinate dehydrogenase accepts electrons when succinate is oxidized to fumarate in the citric acid cycle. These electrons are then transferred through the enzyme to ubiquinone in the mitochondrial respiratory chain .^1,2

FAD-dependent enzymes also participate in fatty acid beta-oxidation. Acyl-CoA dehydrogenases use enzyme-bound FAD to accept electrons during the first oxidation step of each beta-oxidation cycle. These electrons are subsequently passed through electron-transfer flavoprotein and related proteins to ubiquinone. Thus, the common shorthand that free FADH₂ simply “enters the electron transport chain at complex II” is not generally accurate .²

FAD/FADH₂ differs from NAD⁺/NADH partly in how the cofactors interact with enzymes. NAD⁺ and NADH commonly act as diffusible cosubstrates, whereas FAD is often a tightly bound, and in some enzymes covalently attached, prosthetic group whose redox properties are influenced by its specific protein environment .^1,2