Title : Molecular basis for multiple sulfatase deficiency and mechanism for formylglycine generation of the human
formylglycine-generating enzyme
Abstract :
- Sulfatases are enzymes essential for degradation and remodeling of sulfate esters
- Formylglycine (FGly), the key catalytic residue in the active site , is unique to sulfatases
- In higher eukaryotes, FGly is generated from a cysteine precursor by the FGly-generating enzyme ( FGE )
- Inactivity of FGE results in multiple sulfatase deficiency (MSD), a fatal autosomal recessive syndrome
- Based on the crystal structure, we report that FGE is a single-domain monomer with a surprising paucity of secondary structure and adopts a unique fold
- The effect of all 18 missense mutations found in MSD patients is explained by the FGE structure, providing a molecular basis of MSD
- The catalytic mechanism of FGly generation was elucidated by six high-resolution structures of FGE in different redox environments
- The structures allow formulation of a novel oxygenase mechanism whereby FGE utilizes molecular oxygen to generate FGly via a cysteine sulfenic acid intermediate