Human sulfatase active-site cysteine (FGly)

The human sulfatase family consists of 17 enzymes that share a highly conserved active-site architecture characterized by a unique post-translational modification. A specific cysteine residue within the conserved motif (Cys-X-Pro-X-Arg) is converted into C-alpha-formylglycine (FGly) by the formylglycine-generating enzyme (FGE) in the endoplasmic reticulum [Dierks et al., 2003]. This FGly residue is essential for the catalytic hydrolysis of sulfate esters from various substrates, including glycosaminoglycans, sulfolipids, and steroid sulfates [Hanson et al., 2004]. Because this residue is critical for activity, it serves as a primary target for covalent inhibitors, particularly in the context of steroid sulfatase (STS) for hormone-dependent cancers and extracellular sulfatases (SULF1/2) in the tumor microenvironment [Thomas and Potter, 2015]. Dysregulation or genetic deficiency in the modification of these residues leads to Multiple Sulfatase Deficiency (MSD), a severe lysosomal storage disorder characterized by the loss of all sulfatase activity. Consequently, therapeutic strategies targeting these residues must balance potent inhibition of specific disease-related sulfatases with the risk of systemic toxicity resembling MSD.

Other names

Formylglycine-generating siteSulfatase catalytic cysteineC-alpha-formylglycine residueConserved sulfatase active siteFGly residue

Covalent modification and irreversible inhibition of the catalytic formylglycine residue