Sulfatase

Sulfatases are a group of enzymes that catalyze the hydrolysis of sulfate esters and sulfamates, a crucial step in the metabolism of sulfate esters. These enzymes play a significant role in the degradation of sulfated glycosaminoglycans (GAGs), which are components of the extracellular matrix and the cell surface, as well as in the metabolism of steroid sulfates and bile salt sulfates. The importance of sulfatases in cellular and molecular biology is underscored by the variety of physiological and pathological processes they are involved in, including development, inflammation, and diseases such as lysosomal storage disorders.

Classification

Sulfatases are classified based on their substrate specificity and sequence similarities. The two main classes are:

• Arylsulfatases (EC 3.1.6.1), which act on phenolic or aryl sulfate esters. Arylsulfatase A, for example, is crucial in the degradation of cerebroside sulfate.
• Steroid sulfatases (EC 3.1.6.2), which hydrolyze sulfate esters from steroid sulfates, such as dehydroepiandrosterone sulfate (DHEAS) and estrone sulfate.

Mechanism of Action

Sulfatases catalyze the hydrolysis of sulfate esters through a mechanism that involves the formation of a covalent sulfate-enzyme intermediate. This process typically requires a formylglycine (FGly) residue, which is generated by the post-translational modification of a cysteine or serine residue in the active site of the enzyme. The FGly residue acts as a nucleophile, attacking the sulfur atom of the sulfate ester, leading to the release of the alcohol and the sulfate ion.

Clinical Significance

Sulfatases are implicated in several human diseases. Deficiencies in specific sulfatases can lead to a group of lysosomal storage disorders known as the mucopolysaccharidoses (MPS), which include conditions such as Mucopolysaccharidosis type II (Hunter syndrome) and Mucopolysaccharidosis type III (Sanfilippo syndrome). These disorders are characterized by the accumulation of GAGs in tissues and organs, leading to symptoms such as developmental delay, organ dysfunction, and reduced life expectancy.

In addition, mutations in the gene encoding steroid sulfatase have been linked to X-linked ichthyosis, a condition characterized by the scaling of the skin. Steroid sulfatase deficiency leads to the accumulation of cholesterol sulfate, contributing to the barrier abnormalities observed in this condition.

Treatment and Research

Research into sulfatase activity and its regulation offers potential therapeutic avenues for treating diseases associated with sulfatase deficiencies. Enzyme replacement therapy (ERT) and gene therapy are among the strategies being explored to restore normal levels of sulfatase activity in affected individuals. Moreover, small molecule inhibitors of sulfatases are being investigated for their potential in treating hormone-dependent cancers, such as breast and prostate cancer, by inhibiting the formation of active hormones from their sulfate precursors.

See Also

• Lysosomal storage disorder
• Glycosaminoglycan
• Extracellular matrix
• Enzyme replacement therapy