Sulfatases: Structure, Mechanism, Biological Activity, Inhibition, and Synthetic Utility

Sulfatases, which cleave sulfate esters in biological systems, play a key role in regulating the sulfation states that determine the function of many physiological molecules. Sulfatase substrates range from small cytosolic steroids, such as estrogen sulfate, to complex cell‐surface carbohydrates, such as the glycosaminoglycans. The transformation of these molecules has been linked with important cellular functions, including hormone regulation, cellular degradation, and modulation of signaling pathways. Sulfatases have also been implicated in the onset of various pathophysiological conditions, including hormone‐dependent cancers, lysosomal storage disorders, developmental abnormalities, and bacterial pathogenesis. These findings have increased interest in sulfatases and in targeting them for therapeutic endeavors. Although numerous sulfatases have been identified, the wide scope of their biological activity is only beginning to emerge. Herein, accounts of the diversity and growing biological relevance of sulfatases are provided along with an overview of the current understanding of sulfatase structure, mechanism, and inhibition. Through the cleavage of sulfate esters sulfatases modulate the activity of a broad range of small molecules and proteoglycans (see picture). These enzymes play critical roles in a number of biological events, including lysosomal degradation, hormone regulation, and signaling processes. The structures of sulfatases, their mechanisms of action, their potential as targets for small‐molecule intervention, and applications in synthesis are discussed.