Chapter 149

### Abstract

1. Multiple sulfatase deficiency (MSD) is a rare autosomal recessive disorder with a prevalence of about 1 in 1.4 million births, characterized by deficiencies in all 12 known sulfatases and leading to a clinical presentation that generally resembles late infantile metachromatic leukodystrophy. However, like those of all lysosomal storage disorders, the clinical presentation and progression of MSD are clinically heterogeneous.

2. In MSD all sulfatase polypeptides have reduced catalytic activities toward their natural substrates. This reduced activity is caused by a deficiency in a modification system that generates an α-formylglycine residue by the oxidation of the thiol group of an active site cysteine conserved in all members of the mammalian sulfatase family.

3. This novel protein modification occurs before the sulfatase polypeptide is folded to a native structure and at a late stage of or after cotranslational protein translocation into the endoplasmic reticulum.

4. The aldehyde group of the α-formylglycine residue may accept sulfate during sulfate ester cleavage, leading to formation of a covalently sulfated enzyme complex.

5. The active sites of all sulfatases probably have four conserved amino acid residues involved in metal ion coordination and at least five residues involved in the catalytic mechanism.

6. The active sites of sulfatases and of alkaline phosphatase share remarkable structural homology.

7. Diagnosis of MSD can be made biochemically from the characteristic pattern of sulfatase deficiencies observed in various cell types. Affected individuals have abnormal urinary oligosaccharide, mucopolysaccharide, and glycopeptide profiles. Prenatal diagnosis is reliable, and carrier detection may be possible.

8. There is no definitive treatment for patients with MSD.

### Introduction

The existence of sulfatases has been known for almost 90 years. The sulfatases catalyze the hydrolysis of sulfate esters such as O-sulfates and N-sulfates.

Their importance in modern medicine and biochemistry has been appreciated over the past 40 years, when the association of deficiencies in many of the sulfatases with a number of clinical syndromes was discovered.

It is now recognized that the hydrolysis of sulfate esters requires the action of a family of sulfatase enzymes. These sulfatases share structure and function characteristics to achieve cleavage of O- and N-linked sulfate esters.1 In fact, sulfatases also share structural and functional characteristics with phosphatases.2 Sulfate ester substrates include complex molecules such as sulfated glycosaminoglycans, glycolipids, glycopeptides, and hydroxysteroids. At least 12 different sulfatases are needed for the hydrolysis of these complex substrates. Sulfatases appear to act on small molecules or at the nonreducing, or polar, end of the sulfated macromolecular compounds. A number of different cellular locations are involved in the hydrolysis of these substrates. Eight different sulfatases act in the lysosome to desulfate glycosaminoglycans, glycolipids, and glycopeptides, whereas four different sulfatases act on sulfated hydroxysteroids and other, as yet unknown, substrates in neutral cellular compartments, including microsomes, endoplasmic reticulum, and the Golgi network.

Recent reports have identified the likely locations and natures of the active sites of all ...

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