FAD

**Structure and synthesis** - FAD is made from riboflavin (B2): riboflavin → FMN (flavokinase, uses ATP) → FAD (FAD synthetase, uses ATP). - It is a prosthetic group, usually tightly or covalently bound to its enzyme (flavoprotein). - Redox states: FAD (oxidized) ⇄ FADH• (semiquinone) ⇄ FADH₂ (reduced). It can carry 1 or 2 electrons, which is useful in reactions that bridge 2-electron and 1-electron carriers.

**Key FAD-dependent enzymes (high-yield)** - **Succinate dehydrogenase (Complex II)**: succinate → fumarate in the TCA cycle. It is the only TCA enzyme embedded in the inner mitochondrial membrane. It is also part of the ETC and yields about 1.5 ATP per FADH₂. - **Acyl-CoA dehydrogenases (SCAD, MCAD, LCAD, VLCAD)**: the first step of β-oxidation. MCAD deficiency causes hypoketotic hypoglycemia, with dicarboxylic aciduria and a history of fasting or illness in infants or children. - **α-Ketoglutarate dehydrogenase complex and pyruvate dehydrogenase complex**: the E3 subunit (dihydrolipoyl dehydrogenase) uses FAD to reoxidize lipoamide, then passes electrons to NAD⁺. These complexes need 5 cofactors: **T**hiamine PP (B1), **L**ipoic acid, **C**oA (B5), **F**AD (B2), **N**AD⁺ (B3) ("Tender Loving Care For Nancy"). - **Glycerol-3-phosphate dehydrogenase (mitochondrial)**: part of the glycerol phosphate shuttle, which yields FADH₂ and less ATP than the malate-aspartate shuttle. - **Glutathione reductase**: needs FAD to regenerate reduced glutathione from NADPH. Riboflavin status can be assessed with the erythrocyte glutathione reductase activity coefficient. - **Monoamine oxidase (MAO)**: FAD-dependent. - **Xanthine oxidase** and **D-amino acid oxidase**: both use FAD. - **Fatty acid desaturases and others**: also use flavin cofactors.

**Energetics** - FADH₂ enters the ETC at Complex II (or via ETF-ubiquinone oxidoreductase for β-oxidation). It bypasses Complex I, so it pumps fewer protons. - Yield is about 1.5 ATP per FADH₂, compared with about 2.5 ATP per NADH.

**Clinical significance: riboflavin (B2) deficiency** - Features: cheilosis, angular stomatitis, glossitis (magenta tongue), corneal vascularization, seborrheic dermatitis. Mnemonic: the "2 C's": cheilosis and corneal vascularization. - Causes: malnutrition, alcoholism, phototherapy in neonates (riboflavin is light-sensitive). - Treatment: riboflavin supplementation. - Related: multiple acyl-CoA dehydrogenase deficiency (MADD, glutaric aciduria type II) is caused by ETF or ETF-QO defects and is sometimes riboflavin-responsive.

**Other meanings of "FAD" (context-dependent)** - **Familial Alzheimer disease**: early-onset AD from mutations in APP (chromosome 21), PSEN1 (chromosome 14, the most common), or PSEN2 (chromosome 1). Down syndrome patients develop early AD from the extra APP copy. APOE ε4 is the main risk factor for late-onset AD, not early-onset FAD. - **Fibroadenoma** is usually abbreviated FA, not FAD. - **FAD (Fetal akinesia deformation sequence)** is rarely abbreviated this way.

**Boards pearls** - FAD and NAD⁺ are the two main electron carriers of oxidative metabolism. NAD⁺ is derived from niacin (B3), and FAD from riboflavin (B2). - Succinate dehydrogenase is the link between the TCA cycle and the ETC. Mutations are associated with paragangliomas and pheochromocytomas (SDHx). - Complex II inhibitors include malonate (competitive inhibitor of SDH).